Monday, November 11, 2024

Dostarlimab - the first Cancer Treatment I've Seen with a 100% Success Rate in Shrinking Tumors in a Trial

 Please note, I'm not a doctor, this is not medical advice, I'm just sharing what I found on the internet. Please do your own research as well!


'Tumors just vanished': Cancer patients now in remission after drug trial




Medical Trial Of Cancer Drug Dostarlimab Cures All Patients, Providing Hope Across The World







Why does dostarlimab work?



#Dostarlimab | Uses, Dosage, Side Effects and Mechanism | Jemperli


https://www.mdpi.com/2079-6374/12/8/617

Review

Dostarlimab as a Miracle Drug: Rising Hope against Cancer Treatment

by  1, 1, 2,3 and 1,*

1
Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
2
Department of Pharmaceutics, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
3
Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Minia University, Minia 61519, Egypt
*
Author to whom correspondence should be addressed.
Biosensors 2022, 12(8), 617; https://doi.org/10.3390/bios12080617
Submission received: 27 June 2022 / Revised: 29 July 2022 / Accepted: 4 August 2022 / Published: 8 August 2022
(This article belongs to the Section Nano- and Micro-Technologies in Biosensors)
 
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Abstract

Immunotherapy is one of the four pillars of cancer treatment that has recently emerged as a beacon of hope for cancer patients. Certain immunotherapies, for example, immune checkpoint inhibitor therapy, monoclonal antibody therapy and chimeric antigen T-cell therapy have garnered extensive interest in response to their exceptional properties that activate the immune system to respond to cancer cells, inhibiting their progression. In the era of rapid development, dostarlimab, an anti-programmed cell death protein (PD-1) monoclonal antibody has mesmerized the medical profession by showing complete (100%) cure of patients with colorectal cancer. Not only this, the results obtained from clinical trials revealed no major side effects in any of the participants in the study. Dostarlimab has also shown promising results in endometrial cancer, ovarian cancer, melanoma, head and neck cancer, and breast cancer therapy. This review focuses upon the action of immunotherapy, extensively emphasizing the miraculous therapy to activate T-cells for cancer treatment. Based on this, we discuss major ongoing clinical trials and combination immunotherapies to enlighten future clinicians and researchers about the response of dostarlimab against various cancers.

1. Introduction

Cancer remains one of the deadliest diseases that humankind has ever encountered, and despite of years of research in this field it is still a leading health problem responsible for over 10 million deaths per year [1]. Several forms of treatment have been brought to use, including treatment with drugs in chemotherapy, radiation in radiotherapy, surgery, and immunotherapy. Immuno-oncology is the newest field of research in this area and its scope and full potential are yet to be explored. As part of immunotherapy, specific parts of the patient’s immune system are used to treat a range of diseases, including cancer and mostly solid tumors [2,3,4,5,6,7,8]. Cancer immunotherapy aims to re-activate the immune system, which has been suppressed by tumor cells in numerous ways. Several novel strategies involving immunotherapy are being developed to treat cancer or to minimize the associated cytotoxic effects caused as a result of different cancer therapies. Immunotherapies are very specific and when stimulated; they target cancerous stem cell and even metastatic cancer, which in turn highlights their potential of reaching the smallest of tumors where surgeons might not. Immunotherapy has also brought into focus the development of cancer vaccines, which have shown potential results in minimizing tumor growth, but still fall short in eradicating it completely. Additionally, there are several antibody-based drugs employed for cancer treatment which indirectly or directly relate to immunotherapy [9,10,11,12].
Another brilliant insight in cancer immunotherapy was brought forth by the Nobel-prize-winning discovery of T-cell checkpoints such as CTLA-4 and PD1 by Drs. Allison and Honjo [13]. This research highlighted the complexity of immune surveillance and how it can be utilized for building auto immunity. The signals in our body are hardwired to maintain immunity by either fighting against foreign pathogens or different abnormal cells. Restricting T-cell surface receptors by blocking them not only enhances immunity by increasing the immune response against tumors, but also induces certain autoimmune responses. As a form of immunotherapy, adoptive cell therapy (ACT) involves supplying immunologically active cells to a patient for treatment and the prevention of disease formation [14,15]. There are, in total, five classes of immunotherapy, including: checkpoint inhibitors, antibody-based targeted therapies, cancer vaccines, antigenic receptor T-cells, and lastly oncolytic viruses [16,17,18,19]. Today, mAB-based immunotherapy is considered an important part of cancer treatment, alongside other methods. These antibodies can not only target tumor cells, but can also trigger long-lasting antitumor immune responses. The versatility of antibodies as a therapeutic platform has led to the development of new cancer treatment strategies that will change the way cancer is treated in the future.

2. Monoclonal Antibody-Based Cancer Immunotherapy

Antibodies are large glycoproteins belonging to the immunoglobulin (Ig) superfamily which are found naturally in blood and are responsible for recognizing foreign antigens, neutralizing them, and evoking further immune responses. They structurally comprise two heavy and two light chains in the shape of a Y. There are five different types of immunoglobins based on the type of heavy chains. These include IgA, IgD, IgE, IgG, and IgM. The Y-shaped immunoglobins consists of different parts, while the Fab (fragment antigen-binding) portion of the antibody is located at each tip of the Y; the fragment crystallizable (Fc) region is present at the base of the Y structure. Antibodies recognize specific antigens by their Fab portion, whereas Fc receptors mediate interactions between antibodies and other components of the immune system. The most common form of immunoglobulin used for antibody-based immunotherapy is IgG, attributed to its interaction with FcR and FcγR, which are largely found in natural killer cells, macrophages, monocytes and granulocytes such as eosinophils or basophils. They are involved in specific functions related to complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Moreover, IgGs are further subdivided based on the ability of FcR to elicit CDC or ADCC response; while IgG1 and IgG3 can successfully induce these responses, IgG2 and IgG4 cannot [20,21].
mABs means “all for just one” specific type of antibody; that is, each mAB has multiple copies of just one type of antibody isotype meant for targeting a unique antigen. There are various mABs available for the treatment of cancer, and while they all act through different pathways, some of them might act by more than a single process. mAB therapy for cancer has advanced considerably after unmodified murine mAbs were first considered as anticancer agents. Several mAB-based strategies have proven to have good potential in treating cancer patients. Their action involves the use of unlabeled IgG that specifically binds to the tumor cells, or alters the active host response towards the tumor [22]. These mABs are also capable of acting as immunoconjugates to deliver cytotoxic moieties at cancerous sites, altering the specificity of mABs to retarget cellular immunity. The mechanisms involved in the process include: (a) ADCC, which is composed of targeted mABs formed from chimeric or human antibody components that are meant for binding tumor-associated antigens; (b) CDC, as the name suggests, depicts complement activation; (c) and factor and receptor inhibition, which involves restricting the receptors that are involved in the activation of signal pathways for cancer cell proliferation or in the process of angiogenesis. Certain examples of mABs that act by ADCC include transtuzumab, pertuzumab, rituximab and cetuximab, while those acting by CDC are alemtuzumab, ofatumumab, rituximab and cetuximab. mABs used in immunotherapy that bind to a specific antigen are divided into two classes, depending on if they carry any chemotherapeutic drug or radioactive substance. Nonconjugated, self-acting mABs include alemtuzumab and transtuzumab, while the second class of mABs are conjugated with drugs or radioactive substances to deliver these mABs at the cancerous site. Examples of mAB conjugated with drugs include gemtuzumab ozogamicin, whereas ibritumomab thiuxetan is a radioactive, conjugated mAB. It can be seen that understanding the mechanisms by which mABs lyse tumors is vital to achieving more effective treatment. Despite the fact that mABs have different mechanisms of action, all of these have directly or indirectly become a part of the standard treatment protocol in combination with chemotherapy and/or radiation. Indeed, cancer mAb-based therapy investment and the speed of progress are at an all-time high in both the public and private sectors [23].
It is a time of unprecedented progress in mAb-based therapy, with new therapeutic agents and constructs being developed rapidly, with an enhanced understanding of their biological effects and growing clinical experience based on both clinical trials and the community use of FDA-approved products. Dedicated research in the translational and clinical field of mABs have brought forth miraculous results for the very first time in anticancer therapy. A trial performed for dostarlimab on 12 patients with colorectal cancer produced complete cancer recovery. Although, this trial is at the phase II stage and was conducted only on limited individuals, a proven complete cure for cancer makes the world wonder upon this drug with high hope [24,25]. On top of these positive results, another main characteristic feature of the trial was that the drug was not accompanied with any surgery, chemotherapy or radiotherapy. This review provides an overview of dostarlimab, its mechanism of action and information about other checkpoint inhibitor mABs. It also consolidates different ongoing trials of dostarlimab as a monotherapy and as a combination therapy for different cancers including endometrial, ovarian, colorectal, lung, head and neck squamous cell cancer, and many more.

3. Dostarilimab and Mechanism of Action

Dostarlimab (Jemperli™) or dostarlimab-gxly is a humanized mAB which acts as an antagonist for programmed death-1 (PD-1) receptors. It is being developed by GlaxoSmithKline (GSK) under a license from AnaptysBio Inc for the treatment of several forms of cancer including endometrial cancer, colorectal cancer, ovarian cancer, cancer of the head and neck, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell cancer (SCC), fallopian tube cancer, pancreatic cancer, and many more. According to preliminary findings from the GARNET trial, dostarlimab has recently been approved (22 April 2021) for adults with advanced or recurrent advanced mismatch repair-deficient endometrial cancer (dMMR) in the EU and USA. The dose of dostarlimab that is generally recommended is 500 mg every 3 weeks (for the first four doses), after the fourth dose, 1000 mg every 6 weeks is administered until disease progression or any unacceptable toxicity is noticed [26,27,28] (Figure 1).
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Figure 1. Illustration of the activity of dostarlimab against cancer cells. The PD-1 inhibitor (dostarlimab) inhibits the interaction of T-cells over-expressing PD-1 protein with the ligands (PD-L1) present in cancer cells.
PD1 is an immune checkpoint receptor found in T-cells that suppresses cancer-specific immune responses. The humanized IgG4 mAB, dostarlimab, is derived from a Chinese hamster ovary cell and has a molecular weight of approx 144 kDa. A binding between the PD-1 ligands (PD-L1 and PD-L2) and the PD-1 receptor on T-cells inhibits cytokine and T-cell proliferation. In some tumors, PD-1 ligands are upregulated, and signaling through this pathway may contribute to the suppression of active T-cell immunity. This is where the drug dostarlimab comes into the picture. It inhibits programmed cell death receptor-1 (PD-1) and blocks the interaction of receptors with PD-L1 and PD-L2, which in turn activates T-cells and enhances overall immunity. Studies have depicted that dostarlimab binds with PD-1 receptors of both humans and cynomolgus monkeys with high affinity, as seen from the results obtained in flow cytometry and plasmon resonance. Moreover, a human CD4+ mixed lymphocyte reaction assay showed that dostarlimab worked as a functional antagonist, resulting in increased IL-2 production. This assay also showed the enhanced activity of dostarlimab when TIM3 antibodies or LAG3 antibodies were present. In the presence of antibodies, dostarlimab exhibited increased activity, but no significant cytokine release was observed from human PBMCs (peripheral blood mononuclear cells) [29].
A pharmacokinetic study for dostarlimab-gxly was performed on patients with solid tumors which included 150 endometrial cancer patients. It was noted that there was a proportionate increase in mean Cmax, AUC0−inf and AUC0−τ over the dose range of 1.0–10 mg/kg. Moreover, the mean cycles of Cmax and AUC0−τ after the administration of 500 mg dostarlimab once every 3 weeks was reported to be in the range of 171 µg/mL and 35,730 µg∙h/mL, respectively, and 309 µg/mL and 95,820 µg∙h/mL, respectively, at a dose of 1000 mg administered once every 6 weeks. Similarly, the study also evidenced the mean steady-state volume of the distribution of dostarlimab to be around 5.3 L, and the mean steady-state clearance to be in the range of 0.007 L/h. There were no clinically significant differences observed in the pharmacokinetics characteristics of dostarlimab based on gender, age, ethnicity, tumor type, or renal or hepatic impairment. Although, there are no studies conducted to determine whether dostarlimab-gxly is carcinogenic or genotoxic. Fertility studies have been performed for this drug on monkeys which, after repeating doses for one and three months, found no significant effects on male or female reproductive organs, although most animals in these studies were not sexually mature by the time of study [30].
The first-in-human study, 4010-01-001, otherwise known as the GARNET trial (NCT02715284), evaluated dostarlimab pharmacokinetics (PK), pharmacodynamics (PD), tolerability, clinical activity and safety across multiple solid cancer types, which included endometrial, NSCL and cancer of the ovaries and fallopian tubes. A modified 3 + 3 design was used to evaluate three weight-based doses (1, 3 and 10 mg/kg) administered every 2 weeks intravenously in Part 1. Part 2A used two fixed-dose regimens, 500 mg every 3 weeks intravenously, and 1000 mg every 6 weeks intravenously was administered in in Part 2B. Data from Part 1 demonstrated a maximum receptor occupancy at 2.4 g/mL dostarlimab serum concentrations. Furthermore, a PK model was constructed using the PK data from Part 1 to predict dostarlimab concentrations that would exceed those leading to maximal receptor occupancy at fixed doses. Similarly, Part 2A demonstrated dose-proportional PK and the median serum trough concentrations to be approximately 40 and 50 ng/mL after a single dose of 500 mg and 1000 mg, respectively [31].

4. Ongoing Clinical Trials for Dostarlimab

June 2022 saw a revolutionary discovery in the field of cancer treatment. For the very first time in science, a drug under clinical trial showed the complete eradication of a tumor with no reoccurrence. The mAB-based drug dostarlimab was evaluated for safety under efficacy against locally advanced rectal cancer [32].
Primary locally advanced rectal cancer is also known as stage III rectal cancer and is also indicative of resectable tumors with the involvement of lymph nodes. These tumors are characterized for invading and extending close to the mesorectal fascia. These types of colorectal cancer are generally treated with aggressive chemoradiation, short course radiotherapy, and total mesorectal surgery (TME) surgery. The results from this collective therapy are positive, showing excellent survival rates and low reoccurrence. Moreover, in some cases with locally advanced tumors, a complete removal of the tumor is the most preferred and beneficial option for control and survival [33].
As stated above, the standard method of treatment of locally advanced rectal cancer is radiation and neo-adjuvant chemotherapy followed by the surgical removal of the rectum. Additionally, it has also been noted that the cause of some rectal cancers is a lack of mismatch repair. In the context of metastatic disease, mismatch repair-deficient colorectal cancer responds to the programmed death 1 (PD-1) blockade, thus suggesting that a checkpoint blockade may be effective in mismatch repair-deficient patients. Scientists in partnership with GSK initiated a prospective phase 2 study in patients with stage II or III rectal adenocarcinomas who were mismatch repair-deficient. They were administered with single-agent anti-PD-1 mAB dostarlimab every 3 weeks for 6 months. Although this treatment is supposed to be followed with standard surgery and chemoradiotherapy, the patients who depict a clinically complete response following dostarlimab therapy would not undergo chemotherapy, radiotherapy, or surgery. This is also the primary endpoint for the study. Interim results were obtained from the study completed on a total of 12 patients that had successfully completed treatment with dostarlimab and had also undergone a minimum of 6 months’ follow-up. It was evidenced that all 12 patients (100%; 95% confidence interval, 74 to 100) had a complete clinical response and no form of existing tumor, progression and recurrence was noticed in 18F-fluorodeoxyglucose–positron-emission tomography, magnetic resonance imaging, biopsy, digital rectal examination, or endoscopic evaluation. Moreover, no adverse events of grade 3 or higher were reported. The study clearly depicted that a single agent PD1 was highly sensitive to mismatch repair-deficient, locally advanced rectal cancer and could bring about positive results; however, a longer follow-up study still needs to be performed to validate this point [34,35].
Dostarlimab was evaluated in a phase 1 nonrandomized clinical trial for patients with deficient mismatch repair endometrial cancer to assess antitumor activity and safety. Part 1 of this ongoing open-label, multicenter single group study began on 7 March 2016, and enrollment for patients with deficient mismatch mutation repair endometrial cancer began on 8 May 2017. Around 104 women with deficient mismatch mutation repair endometrial cancer were enrolled and each patient received intravenous dostarlimab 500 mg every three weeks for four doses, then 1000 mg every six weeks until disease progression, treatment discontinuation or withdrawal occurred. Specifically, the objective of this study was to evaluate the antitumor activity of dostarlimab on recurrent or advanced dMMR (mismatch repair deficiency) endometrial cancer (EC) patients, using the objective response rate (ORR) which was defined by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. A similar concept is the duration of response (DOR), defined as the time from the first documented evidence of complete or partial response to the first documented evidence of disease progression or death, whichever occurs first. Following the first dose of dostarlimab administration, radiographic evaluations were performed 12 weeks after the first dose, every 6 weeks (±10 days) until month 12, and then every 12 weeks thereafter.
The results obtained from this analysis on patients with recurrent or advanced dMMR EC who had progressed after platinum-based chemotherapy and dostarlimab monotherapy were associated with an ORR of 42.3% (95% CI, 30.6–54.6%) in almost 30 patients, 29.6% in around 21 patients, and around 12.7% in 9 patients. The responses were durable, and the median DOR was not reached at 11.2 months in the follow-up period. The safety profile depicted by dostarlimab was manageable and comparable to that of other anti-PD-1 antibodies. Additionally, treatment-related adverse events (TRAEs) accounted for less than 2% of patients discontinuing treatment, and there were no treatment-related deaths. To the best of our knowledge, these results are the largest set of data to date on dMMR EC treated with a PD-1 inhibitor [31,36].
Although cross-trial comparisons cannot be performed, it is generally noted that the response rates with anti-PD-1 therapies appear to be more favorable, as evidenced from the ORR range offered by single-agent therapies that ranged from 13.5% (90% CI, 6.5–27.5%) for bevacizumab to 21–27.3% (95% CI, 15–42.8%) for paclitaxel before the introduction of anti-PD-1 therapies. Although the GARNET trial was a single-group study, the antitumor activity observed in patients with dMMR EC was promising, suggesting that dostarlimab might have a role to play in the treatment of patients with dMMR EC. Dostarlimab demonstrated high ORR and a longer duration of response, reflecting its high potential against cancer. Furthermore, one year after inclusion in the GARNET trial, 74% of patients in the dMMR EC population are still alive. In addition to these wide actions of dostarlimab, a unique characteristic of this drug is its dosing regimen. Patients and caregivers both benefit from this unique dosing schedule after 12 weeks of initial treatment with dostarlimab, which may result in less frequent clinic visits and possibly lower healthcare costs. Altogether, the data from the GARNET study has demonstrated durable anticancer action not in only patients with (MMR-proficient) MMRp and dMMR endometrial cancers, but also for non-EC dMMR solid tumors. According to the GARNET trial data, dostarlimab monotherapy was accelerated for approval in the US as a treatment for recurrent/advanced dMMR solid tumors, following the progressive results obtained from prior treatment. Additionally, it has been approved in both Europe (conditional) and the USA (accelerated) for dMMR/MSI-H and dMMR endometrial cancer, respectively, during and after platinum-based chemotherapy [37,38,39]. Another trial similar to it was conducted for evaluating anti-PD-1/PD-L1 axis therapy for patients suffering from inoperable endometrial cancer. This ongoing study is being performed to establish the safety and efficacy of the drug and its generated antitumor immune response [40].
In the past few years, scientists have also tried exploring the potential of dostarlimab against locally advanced cervical cancer (LACC). They hypothesize that the use of dostarlimab as a consolidation therapy following chemotherapy might enhance progression-free survival rate in patients. Based on this rationale, a randomized, phase II, open-label study was set as maintenance therapy for patients with a high risk of LACC. This ongoing study is a randomized study that began in 28 June 2019, and included around 132 participants. Interim data and hence the results for this study are yet to be reported [41,42].
Lung cancer is another cancer that is accountable for the most cancer-related deaths worldwide. Amongst the type of lung cancer, almost 85% belong to the category of non-small cell lung cancer (NSCLC), for which the primary option for treatment is chemotherapy. In recent years, the introduction of immune checkpoint inhibitors has revolutionized the process of cancer treatment.
In a recent trial, the safety and antitumor activity of dostarlimab were studied in a first-in-human, phase 1, multi-center, open-label, two-part study GARNET cohort of 67 patients with recurrent or advanced NSCLC who had previously been treated with platinum-based chemotherapy. While Part 1 of the study was a dose escalation study and involved the evaluation of pharmacodynamics and pharmacokinetic characteristics of the drug at different doses of 1,3 and 10 mg/kg, Part 2, on the other hand, was conducted in two different subparts: Part 2A evaluated the dose safety and Part 2B dealt with evaluating the clinical efficacy of the drug. Immuno-related objective response rate (irORR) and safety were used as the primary endpoint to determine dostarlimab’s antitumor activity in patients with recurrent or advanced NSCLC. An irORR was defined as the proportion of patients achieving immune-related complete response (irCR) or immune-related partial response (irPR) based on the investigators’ assessment per immune-related RECIST (irRECIST). Monotherapy with dostarlimab produced strong antitumor activity and durable responses across all PD-L1 Tumor Proportion Score (TPS) status subgroups. It was noted that, in NSCLC, the safety profile of dostarlimab was acceptable, with low to a manageable toxicity, and was consistent with that of the other agents that block PD-L1. In the entire study, four patients, i.e., almost 6%, discontinued the study due to treatment-related TEAEs (treatment-emergent adverse effects) (TRAEs), and two deaths were caused because of treatment-emergent adverse effects (TEAEs) which were not considered related to treatment with dostarlimab. Furthermore, dostarlimab is currently being studied as a combination regimen for the treatment of NSCLC, as well as other solid tumors, including in the first-line setting [43].
Besides the above-stated studies performed particularly on some specific kinds of cancer, other trials meant for advanced solid tumors are also being performed for dostarlimab. It is being evaluated for safety and efficacy in the phase 1 GARNET study (NCT02715284) in patients with advanced solid tumors. Participants in Cohort F of the GARNET trial had dMMRs or DNA polymerase epsilon (POLE) mutation non-endometrial solid tumors; the majority had GI origins. The patients were administered with 500 mg of dostarlimab for Q3W for four cycles followed by 1000 mg Q6W until discontinuation. Objective response rate (ORR) and duration of response (DOR) were noted by a blinded independent central review per RECIST. The patients receiving ≥1 dose of the drug were included in the safety analysis (around 144 patients), while the ones that had measurable disease at baseline were included as part of the efficacy analysis at the 6-month follow-up (106 dMMR patients). Results from the study showed that amongst 106 patients, around 99, i.e., 93.4% of them, had gastrointestinal tumors. Moreover, the confirmed ORR in dMMR patients was around 38.7% and the complete response rate was approx. 7.5%. The median duration of follow-up was 12.4 months while median DOR was not achieved. In addition, treatment-related adverse events (TRAEs) were also noted in 68.8% of patients, amongst which almost 8.3% of patients were evidenced to experience at least one grade ≥3 TRAE, the most common of which was an increase in lipase in around 1.4% (two patients). Additionally, no deaths were caused as a result of drug administration and only two patients discontinued drug administration because of TRAE. These results obtained from the study show evidence of the potential antitumor activity of dostarlimab against solid tumors. Lastly, the safety profile was also observed for other cohorts in GARNET and the results obtained were very consistent with low to no immune-related TRAEs [44,45,46].
A sarcoma is a malignant solid tumor with high heterogeneity accounting for over 100 subtypes classified so far. Over the years, chemotherapy combined with surgery has proven to be an effective treatment procedure that has resulted in a comparative increase in overall survival rate. Dostarlimab is also being employed to study its activity against sarcomas. A phase II, single-arm, not-randomized, European multicentric study was designed to evaluate the action of TSR-042 (dostarlimab), in patients diagnosed with advanced/metastatic clear cell sarcoma. The study was initiated on February 19, 2021, and around 16 patients were enrolled for the study [47]. The major timestamps of dostarlimab are represented in Figure 2.
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Figure 2. Major milestones of dostarlimab against cancer.

5. Dostarlimab and Other Combination Therapies under Trial

There are several other immune check point inhibitors such as nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab that are utilized for cancer treatment (Table 1). Since dostarlimab is a mAB and not a drug transporter substrate or a cytokine modulator, it is unlikely to show any interactions between other drugs. However, a comparison of dostarlimab based on its pharmacodynamic and pharmacokinetic properties must be conducted with other such immune checkpoint inhibitor-based therapies to obtain a clear and optimal understanding. Dostarlimab, similar to nivolumab and pembrolizumab, specifically targets anti-PD-1 receptors, while atezolizumab, durvalumab and avelumab not only act through anti-PD-1 receptors but also block interaction with the PD-1 and B7.1 receptors. Similarly, the mean peak occupancy for dostarlimab is approx. ~90% and around 85% (70–97%) for nivolumab. The cumulative dose has also been recorded for these drugs: approximately 2-fold for dostarlimab, 3.7-fold for nivolumab, 2.2-fold for pembrolizumab, around 1.91-fold for atezolizumab, and 4.3-fold and 1.25-fold for durvalumab and avelumab, respectively. The three-week dosing schedule is similar for pembrolizumab and nivolumab dose schedules, and ensures the closer monitoring of patients as they begin a new treatment. A dose of 500 mg IV every 3 weeks, then 1000 mg IV every 6 weeks is generally administered as a safety regimen for dostarlimab, while this is 240 mg IV every 2 weeks and 200 mg IV every 3 weeks for nivolumab and pembrolizumab, respectively. Similarly, atezolizumab’s administered dose is 1200 mg or 15 mg/kg IV every 3 weeks; for durvalumab, this is 1500 mg IV every 4 weeks and for ICI avelumab this is 10 mg/kg IV every 2 weeks.
Table 1. The major clinical trial of dostarlimab.
Table
Dostarlimab is also being studied for its activity with one or more chemotherapeutic drugs, including niraparib, pembrolizumab, bevacizumab, cobolimab, and many more. Most of these studies conducted for different cancer types are still under trial. The data below covers some of such ongoing studies.
A combination study investigated the PARPi drug niraparib and anti-PD-1 mAB dostarlimab administered in patients with advanced head and neck squamous cell carcinoma (HNSCC). Niraparib is a type of targeted therapy that inhibits poly adenosine diphosphate-ribose polymerase (PARP), which is an enzyme that repairs DNA in times when it gets damaged. Blocking these PARP might prevent DNA repair in cancerous cells, causing them to die. This phase II trial involving 49 patients was initiated on February 8, 2021 [48]. Researchers hypothesize that combinatory immunotherapy might lead to a reduction in loco-regional recurrence (LRR) and distant metastasis (DM) rates in patients under high risk of HNSCC [49]. Similarly, a phase III trial was designed to study the effect of dostarlimab and niraparib for studying their effects in treating small cell lung cancer and other high-risk neuroendocrine carcinomas. This single-group open-label trial began on February 1, 2021, with an estimated enrollment of 48 patients [50]. Different phase II trials for this combination therapy (dostarlimab and niraparib) are currently being performed for patients with germline or somatic BRCA1/2- and PALB2-mutated pancreatic cancer [51], for breast cancer in patients with BRCA mutations [52], pediatric solid tumors [53], mesothelium NSCLC [54,55], and pancreatic [56], endometrium [57,58] and ovarian cancer [59,60].
In addition to these, other combinations such as cobolimab, docetaxel, and dostarlimab [61]; dostarlimab and pembrolizumab [61]; feladilimab, dostarlimab, and cobolimab [62]; bevacizumab, carboplatin, cobolimab, dostarlimab, niraparib, paclitaxel, and pemetrexed [63]; and dostarlimab, niraparib and pembrolizumab [64] are being studied currently for NSCLC. Moreover, dostarlimab, cobolimab, nivolumab, encelimab, and docetaxel [65]; B intrafusp alfa, cobolimab, dostarlimab, feladilimab, GSK 3174998, and pembrolizumab [66]; and dostarlimab and encelimab [67] are being studied for other colorectal and solid tumors. As interim results from these trials are obtained, more positive points can be reported on behalf of the safety and efficacy of both monotherapy and combination activity.

6. Conclusions and Future Prospects

Driving the patient’s own immune system to act against the deadly disease of cancer could potentiate the fast remission of neoplastic cells. Generally, any invasion of pathogens or the non-responsiveness of certain stimuli in the human body turns the T-cell “on”, causing the immune-defense system of the body to respond against them. These T-cells have proteins on their surface called immune checkpoint proteins. Most cancer cells over-express certain proteins that inactivate T-cells, which should be in the field to attack cancer cells in response to their growth and proliferation. Thus, cancer cells switch “off” the immune-response button of T-cells so that they can no longer detect and suppress the cancer cells. Immunotherapy, therefore, acts on tumors, disabling their function to act on T-cells. This, in turn, pushes T-cells to immediately act against them. Dostarlimab is one the immune checkpoint inhibitors that blocks the binding of PD-1 protein on T-cells to the ligand PD-L1/2. It is under trial for different cancer therapies, but, recently, it has shown positive results and complete remission for the very first time in history, and has therefore attracted the interest of clinicians, oncologists, researchers, and even industrialists. The clinical trial was performed on a subset of 12 patients with colorectal cancer with mismatch repair deficiency (MMRd). Such tumors are, however, non-responsive towards radiation or chemotherapy. Nonetheless, in the above trial, all of the 12 patients were completely cured, suggesting that immunotherapy could turn out to be a major milestone in the history of cancer therapy. It is essential to note that all the patients were at same stage of cancer and were given no previous chemotherapy or surgical treatment. The treatment appeared to be effective within this group; however, it is still difficult to suggest that the same response will be reported in large groups of individuals. A phase 3 clinical trial should be carried out covering heterogeneous samples to accurately determine the strength of dostarlimab. Furthermore, studies could be carried out at various locations for different types of cancers as well. As of now, immunotherapy has not reached the wider clinical market and, in this context, the concept of nanotechnology could mark a new beginning in oncotherapy. Overall, it cannot be overlooked that the immunotherapeutic agent dostarlimab is a star compound against colorectal cancer.

Author Contributions

Writing—review and editing, V.S. and A.S.; resources, M.A.S.A.; project administration, P.K. All authors have read and agreed to the published version of the manuscript.

Funding

The author (Mohammed A. S. Abourehab) would like to thank the Deanship of scientific research at Umm Al-Qura University for supporting this work by grant code (22UQU4290565DSR50). The author (P. Kesharwani) acknowledges the financial support from the Indian Council of Medical Research (ICMR), New Delhi, India, through Extramural Research Grants [35/10/2019-Nano/BMS and 5/13/8/2020/NCD-III].

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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MDPI and ACS Style

Singh, V.; Sheikh, A.; Abourehab, M.A.S.; Kesharwani, P. Dostarlimab as a Miracle Drug: Rising Hope against Cancer Treatment. Biosensors 2022, 12, 617. https://doi.org/10.3390/bios12080617

AMA Style

Singh V, Sheikh A, Abourehab MAS, Kesharwani P. Dostarlimab as a Miracle Drug: Rising Hope against Cancer Treatment. Biosensors. 2022; 12(8):617. https://doi.org/10.3390/bios12080617

Chicago/Turabian Style

Singh, Vanshikha, Afsana Sheikh, Mohammed A. S. Abourehab, and Prashant Kesharwani. 2022. "Dostarlimab as a Miracle Drug: Rising Hope against Cancer Treatment" Biosensors 12, no. 8: 617. https://doi.org/10.3390/bios12080617

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.



https://pmc.ncbi.nlm.nih.gov/articles/PMC9777321/

Natural Blockers of PD-1/PD-L1 Interaction for the Immunotherapy of Triple-Negative Breast Cancer-Brain Metastasis

 1,*,  2
Editor: Claudia De Lorenzo
PMCID: PMC9777321  PMID: 36551742

Abstract

Simple Summary

Aggressive types of breast cancer spread to the brain and can form a new tumor there. The treatment of such a tumor is more difficult because there is a membrane around the brain that limits the entrance of drugs. Currently, chemotherapy is the most well-known treatment for these patients, but it cannot pass through that membrane and such patients often die within two years. Here, we looked at some of the drug candidates that are extracted from plants and traditional herbal medicines and these candidates can activate the immune system to kill cancer. We reviewed whether these molecules could pass the brain membrane to activate the immune system inside the brain to kill cancer there.

Abstract

The limited treatment options for triple-negative breast cancer with brain metastasis (TNBC-BM) have left the door of further drug development for these patients wide open. Although immunotherapy via monoclonal antibodies has shown some promising results in several cancers including TNBC, it cannot be considered the most effective treatment for brain metastasis. This is due to the protective role of the blood–brain barrier (BBB) which limits the entrance of most drugs, especially the bulky ones such as antibodies, to the brain. For a drug to traverse the BBB via passive diffusion, various physicochemical properties should be considered. Since natural medicine has been a key inspiration for the development of the majority of current medicines, in this paper, we review several naturally-derived molecules which have the potential for immunotherapy via blocking the interaction of programmed cell death protein-1 (PD-1) and its ligand, PD-L1. The mechanism of action, physicochemical properties and pharmacokinetics of these molecules and their theoretical potential to be used for the treatment of TNBC-BM are discussed.

Keywords: triple-negative breast cancer, brain metastasis, immunotherapy, natural medicine, blood–brain barrier

1. Introduction

Triple-negative breast cancer (TNBC) mainly occurs in younger, premenopausal women with a more aggressive nature, i.e., it is more likely to metastasize to other organs such as the brain. Metastatic TNBC (mTNBC) has a poor overall survival of about 17.5 months, which shows its poor prognosis []. This is partly due to the fact that TNBC does not overexpress the common targets of breast cancer treatment including estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2 (HER-2); therefore, the common breast cancer-targeted therapies cannot be utilized in these patients. The mainstay of TNBC treatment has remained chemotherapy for decades, which, due to its non-selective nature, causes adverse reactions and toxicities in patients, leading to decreased patient compliance and increasing tumor resistance to treatment []. Consequently, the effort to find novel, targeted therapies for TNBC has been of special interest and attention. As an example, patients with BReast CAncer gene 1/2 (BRCA1/2) mutations undergo treatment with inhibitors of poly(ADP-ribose) polymerase (PARP) []. With the hope of boosting the patient’s immune system to kill cancer, one strategy has been to use immunotherapy targeting PD-1/PD-L1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3) and the hedgehog (Hh) and neuropilin-2 (NRP-2) signaling pathway (reviewed in []). So far, the most studied immunotherapy target in TNBC belongs to a group of antibodies targeting PD-1 and PD-L1 []. A subgroup of TNBC patients overexpressing PD-L1 were studied in the IMpassion130 Trial. The mTNBC patients received a combination of anti-PD-L1 atezolizumab and nab-paclitaxel, which improved their progression-free survival []. This led to the US food and drug administration (FDA) approval of atezolizumab for unresectable advanced PD-L1-positive TNBC patients []. The mechanism of this drug relies on the interaction of T cells and cancer cells. Following the interaction of the T cell receptor (TCR) and the cancer antigen, PD-1 expressed on cytotoxic T cells (CTLs) interacts with PD-L1 expressed on cancer cells, leading to the inhibition of the activation of CTLs and an “immune escape”. PD-L1 also plays some roles in the proliferation of cancer cells by affecting the mitogen-activated protein kinase (MAPK) pathway []. Therefore, blocking PD-L1 has at least two different outputs: Activating the immune system to kill cancer and inhibiting the proliferation of cancer cells [,].

TNBC with brain metastasis (TNBC-BM) is the most severe form of mTNBC to treat. This is because the BBB, a complex structure surrounding the brain, is a highly specialized and selective structure that tightly controls and regulates the delivery of necessary materials to the brain to maintain brain homeostasis [,]. Several cellular layers that comprise the BBB include the endothelial cells (ECs), pericytes, astrocytes and the basement membrane. The space between the BBB endothelial cells is sealed with more tight junctions compared to endothelial cells in other parts of the body, which makes them impermeable to hydrophilic molecules [,]. Moreover, the electrical resistance of ~1000–2000 ohm cm2 in the BBB restricts the movement of ionic molecules []. Chemotherapeutics have bulky structures with limited access to the brain and the same applies to monoclonal antibodies targeting PD-1 or PD-L1. In addition, these molecules have animal-derived domains and, therefore, naturally inherit a structure that might cause immunogenic reactions. This has made the medicinal intervention of brain tumors challenging, leading to the failure of these options and keeping the overall survival of these patients to less than two years [].

Natural molecules have always been used as a template for the development of the majority of medicinal treatments. Moreover, research in this area has been ongoing to develop novel treatments for TNBC and mTNBC from natural origins such as ginsenosides, bacopasides and silibinin via inhibiting cell proliferation, angiogenesis, and cell migration mechanisms [,,,]. Some of these molecules, such as ginsenoside Rk1 and silibinin, have shown an immunotherapeutic potential [,]. Furthermore, silibinin crosses the BBB [] and impairs the activation of signal transducer and activator of transcription 3 (STAT3), which plays roles in the formation of breast cancer brain metastasis [,]. Likewise, several herbal molecules have shown potency in inhibiting the interaction of PD-1/PD-L1; however, their potential to traverse the BBB has not been studied. This paper aims at reviewing these molecules and evaluating their potential as immunotherapeutic agents for the treatment of TNBC-BM.

2. Molecules

The majority of the molecules discussed in this paper are flavonoids, which are polyphenolic structures usually found as secondary metabolites in plants. In addition, other natural molecules with heterocyclic and macrocyclic structures are also discussed (Figure 1). Here, we briefly introduce each molecule and then focus on the studies that evaluated the potential of these molecules as blockers of PD-1/PD-L1 interaction.

Figure 1.

Figure 1

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Chemical structure of: (a) apigenin (API) and cosmosiin (COS); (b) kaempferol (KMF) and kaempferol 7-O-rhamnoside (KFR); (c) quercetin (QUE); (d) eriodictyol (ERI) and fisetin (FIS); (e) 1-caffeoylquinic acid (1-CQA), 3-caffeoylquinic acid (3-CQA), 4-caffeoylquinic acid (4-CQA), and 5-caffeoylquinic acid (5-CQA); (f) glyasperin C (GC); (g) ellagic acid (EA); (h) gramicidin S (GS); and (i) rifabutin (RIF).

2.1. Apigenin (API) and Cosmosiin (COS)

Apigenin (API) and Cosmosiin (COS) are extracted from the traditional medicinal plant Salvia plebeia R. Br (SP) and API and COS share similar structures (Figure 1a). API is a trihydroxyflavone, and COS is API 7-O-beta-D-glycoside, which also exists in an L-glycoside enantiomer form. API, together with some other flavonoids such as quercetin (QUE) and kaempferol (KMF), is the most ubiquitous plant flavonoid among more than 5000 []. It has a low toxicity in normal cells compared to cancer cells with antioxidant, and anti-inflammatory properties and influences the induction of apoptosis and cell cycle arrest in cancer cells. These functions are via its effect on several cellular signaling pathways such as PI3K/AKT, MAPK/ERK, and NF-κB Signaling, the Wnt/β-Catenin pathway, STAT 3 and epidermal growth factor receptor (EGFR) (reviewed in []). Moreover, studies have shown the efficacy of this molecule in several cancers such as breast, lung and melanoma models [].

In a study by Choi et al. (2020), the extract of Salvia plebeia R. Br. (SPE) blocked the binding of PD-1/PD-L1 in an enzyme-linked immunoassay (ELISA). This was dose-dependent and with specific blocking with no effect on the CTLA-4/CD80 interaction; however, the potency of the SPE was less than a PD-L1-blocking antibody. The blocking effect was attributed to the ethyl acetate fraction of the extract. This fraction of the extract had about eighteen-fold higher amounts of API and eight-fold COS. At 50 mg/mL, the SPE and the ethyl acetate fraction showed an ~42% and ~63% inhibitory action on the PD-1/PD-L1 interaction. At concentrations <50 mg/mL (24 h), the SPE showed no cytotoxicity in a co-culture system containing Jurkat and aAPC/CHO-K1 cells (CHO cells engineered to express a hPD-L1 and TCR agonist). The SPE and the ethyl acetate fraction were used in a co-culture system of aAPC/CHO-K1 cells and Jurkat cells. In this system, a half-effective concentration (EC50) of the PD-L1 blocking antibody was ~0.3 µg/mL in activating TCR signaling. The relevant EC50 value for the SPE and the ethyl acetate fraction was ~27 and 1 µg/mL, respectively []. This demonstrated the importance of the ethyl acetate fraction.

When humanized PD-L1-expressing MC38 cells (hPDL1-MCs) co-cultured with humanized PD-1 mouse splenocytes were exposed with the non-cytotoxic concentrations of SPE, the cell viability was significantly decreased. A co-culture of hPDL1-MCs with CTLs isolated from the tumor showed that cell death was induced by the activation of T cells; however, these effects were not compared with a blocking antibody control. In an hPD-L1 knock-in MC38 tumor-bearing humanized PD-1 mouse model, mice received 5 mg/kg of anti-hPD-1 antibody (intraperitoneal (IP)—twice a week) as the control or 100 and 300 mg/kg of oral SPE. The 100 and 300 mg/kg of SPE inhibited tumor growth by ~45% and 78%, respectively, while the efficacy of the control antibody was 88%. This treatment increased the number of CTLs and CD3+ tumor-infiltrating lymphocytes [].

Among the seven components of SPE tested at 2 µM as single agents, API and COS showed the best improvement of T cell function, by about two-fold, and also showed a dose-dependent increased T cell function. Both molecules showed a dose-dependent blockage of the PD-1/PD-L1 interaction in an ELISA assay. In both experiments, the COS showed a more effective action. The structure–activity relationship studies confirmed that the monosaccharide group at C7 played a major role in the observed effects. This effect of COS was specific to the PD-1/PD-L1 and did not affect the CTLA4/CD80 interaction. The COS showed a dissociation constant (KD) of 386 and 85 µM for PD-1 and PD-L1, respectively (R2 0.9804 and 0.9866, respectively). Due to its higher binding rate, the COS had an ~4.5-fold higher affinity for PD-L1 [].

Molecular docking using AutoDock Vina between COS and the crystal structure of hPD-1/hPD-L1 (4ZQK) predicted the binding affinities of −6.2 and −5.8 kCal/mol with PD-L1 and PD-1, respectively. The interaction site was found to have hydrogen bonds between the residues N63, D61, N58 and the glycoside of COS, in addition to a hydrophobic interaction between R131, M115, Q66, and I54 and the backbone of COS (API) [].

2.2. Kaempferol and Kaempferol 7-O-Rhamnoside

A variety of edible, non-medicinal and medicinal plants such as Geranii Herba produce the flavonol, KMF []. KMF is produced to protect plants against oxidative reactions; therefore, an inherent nature of this molecule is its antioxidant property which is important in chemoprevention and anti-inflammatory reactions. Like API, several studies have shown the anticancer properties of KMF in breast, colon and liver cancers []. Figure 1b shows the structure of KMF and its glycoside derivative, kaempferol 7-O-rhamnoside (KOR), both of which are found in the extract of Geranii Herba.

In 2020, Kim et al. studied the active ingredients of the Geranii Herba extract and showed that it inhibited the interaction of PD-1/PD-L1 (a half inhibitory concentration of (IC50) ~88 µg/mL). KMF, among its glycosylated derivatives, was the most potent one (IC50~8 µM) with a dose-dependent effect (Table 1); however, its IC50 was higher than the controls, neutralizing antibodies and the PD-1/PD-L1 inhibitor C1 [].

Table 1.

Key data on the activity of the natural blockers of PD-1/PD-L1 interaction.

CandidateInhibiting PD-1/PD-L1Interaction with PD-L1EC50—T Cell
Activity		In Vivo Studies
PotencyIC50KDBinding ScoreDoseReduced TG 1
SPE 242%
(50 mg/mL)		27 µg/mL100 mg/mL
300 mg/mL		45%
78%
SPE-EA 363%
(50 mg/mL)		1 µg/mL
API 4
COS 585 µM−6.2 kcal/mol
KMF 68 µM−5.4 kcal/mol16 µM
KOR 7156 µM−5.6 kcal/mol
QUE 880%
(5 µM)		0.2 µM4.53 µM60 mg/mL
TVE 926 µM
ERI 100.04 µM
FIS 110.04 µM
CQA 120.17 µM
GC 1365%
(100 µM)
RCE 1484 µg/mL56 µg/mL50 mg/mL
100 mg/mL		67%
74%
EA 1523 µg/mL
GS-d 1695%
(20 µM)		1.42 µM
Rifabutin25 µM
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1 Tumor growth, 2 Salvia plebeia extract., 3 Salvia plebeia-Ethyl acetate fraction, 4 Apigenin, 5 Cosmosiin, 6 Kaempferol, 7 Kaempferol 7-O-rhamnoside, 8 Quercetin, 9 Toxicodendron vernicifluum extract, 10 Eriodictyol, 11 Fisetin, 12 Caffeoylquinic acid, 13 Glyasperin C, 14 Rubus coreanus Miquel extract, 15 Ellagic Acid, and 16 Gramicidin S derivative.

KMF or its glycosides showed no cytotoxicity (< 100 µM) on Jurkat and CHO-K1 cells but showed a dose-dependent decreased interaction of PD-1/PD-L1. Both the KMF and KOR showed a similar half-effective concentration (EC50) of ~16 µM. The KOR was shown to have a KD of 1.56 × 10−4 M. In silico molecular docking studies between KMF and the crystallographic structure of human PD-L1/PD-1 (PDB code: 4ZQK) showed that KMF and KOR attached to PD-L1 at the interaction site of PD-1 with different modes of action (i.e., binding energies of −5.4 and −5.6 kcal/mol, respectively) []. It was decided that the glycoside group was associated with the functional activity of KOR in blocking the PD-1/PD-L1 interaction. The binding scores were not compared with a control molecule and, therefore, it cannot be concluded whether this interaction is a strong one or not.

2.3. Quercetin

The other abundantly found flavonoid in fruits and vegetables such as broccoli, onion, pepper and apple is QUE. As shown in Figure 1c, QUE has a similar backbone to KMF, API and their derivatives and, therefore, similar anti-inflammatory and antioxidant actions can be expected. Its pro-apoptotic properties, induction of cell cycle arrest and DNA damage have made QUE a good anticancer candidate [,]. Some of the suggested anticancer mechanisms of action of QUE include a decreased production of cyclooxygenase and lipoxygenase and its effect on some signaling pathways such as NF-κB, ERK, and JNK [,,]. In addition, QUE, via inducing the expression of interferon-γ(IFN-γ) and interleukin-4 (IL-4) and promoting the natural killer (NK) cell function, improves the immune system [,,]. Moreover, due to its anti-inflammatory effects, QUE has shown efficacy in several disease models including infection and cardiovascular disease.

Jing et al., in 2021, used an ELISA system on a library of 1018 compounds and showed that 5 µM of QUE-dihydrate showed the best (80%) and dose-dependent inhibition of a PD-1/PD-L1 interaction with an IC50 of ~0.2 µM []. At 5 µM, the QUE showed a 50% inhibition of the PD-1/PD-L1 interaction. Table 1 summarizes the results obtained on each molecule.

These results are not comparable to those of KMF, as different techniques were applied to evaluate the inhibitory actions. This study also showed that QUE had a stronger interaction with PD-L1 (KD PD-L1 4.53 µM vs. PD-1 10.19 µM). It was previously shown that the interaction of PD-1/PD-L1 is in the glycosylated form of the PD-L1 [] and that the QUE inhibited the binding of these glycosylated proteins (IC50 0.5 µM) (Table 1). In a co-culture system of Jurkat and cancer cells (MDA-MB-231 and H460), QUE potentiated the activity of Jurkat T cells causing about a 40% cancer cell death. Furthermore, in a xenograft mouse model, 60 mg/kg of QUE inhibited tumor growth, the population of cytotoxic T cells increased and the expression of cytokines such as interferon-gamma (IFN-γ) and granzyme B in the tumor microenvironment increased to kill the tumor [].

2.4. Eriodictyol and Fisetin

Toxicodendron vernicifluum (TV) or Rhus verniciflua Stokes is another traditional herbal medicine native to China, India, Japan, and Korea and is a source of flavonoids and polyphenols such as eriodictyol (ERI), fisetin (FIS) and QUE []. ERI and FIS share a similar backbone structure to those of API, KMF, and QUE (Figure 1d) and have also shown some anticancer potential in several cancer models such as breast, colon, and pancreas cancers [,,,,]. In 2020, Li et al. showed that the extract of TV (TVE) inhibited the interaction of PD-1/PD-L1 in a dose-dependent manner (IC50~26 µM in a competitive ELISA—Table 1). The efficacy of TVE was attributed to the ethyl acetate fraction. TVE, at 5 µg/mL showed an ~30% inhibitory action on the interaction of CTLA4/CD80, with the ethyl acetate fraction being the most effective []. Among several active ingredients in TVE (e.g., ERI, FIS, protocatechuic acid, and caffeic acid), ERI and FIS showed a potent and specific blocking of the PD-L1/PD-1 interaction (IC50 0.04 µM) with no effect on the CTLA4/CD80 interaction []. Based on the presented results, this low IC50 seemed to be higher than the IC50 of the control, i.e., the PD-L1 inhibitor C1 (value not reported in the paper). Additionally, the binding affinity of these molecules needs to be studied.

2.5. Caffeoylquinic Acid

Caffeoylquinic acids (CQAs) are a group of phenolic molecules with a quinic acid core that is acetylated with caffeoyl groups (Figure 1e). CQAs have shown a wide range of therapeutic activity such as antioxidant, antibacterial, anticancer, antiviral, and anti-Alzheimer’s activities (reviewed in []). In 2018, Han et al. compared the affinity of several mono-CQAs (e.g., 1-CQA, 3-CQA, 4-CQA and 5-CQA) and di-CQAs (e.g., 1,3-diCQA, 1,5-diCQA, 3,4-diCQA, 3,5-diCQA, and 4,5-diCQA) to the affinity of PD-1 and PD-L1. The KD for the PD-1/PD-L1 interaction was 0.17 µM, while the CQAs showed a weaker but comparable affinity of 0.50–0.81 µM. A surface plasmon resonance competition assay showed that the mono-CQAs had a better inhibitory action on the PD-1/PD-L1 compared to di-CQAs. The IC50 values of 1-, 3-, 4- and 5-CQA were ~87, 37, 38 and 45 µM, respectively [].

2.6. Glyasperin C

Glyasperin C (GC) is a methoxyisoflavan derivative (Figure 1f) that has been extracted from the ethyl acetate fraction of the traditional herbal medicine, Glycyrrhiza uralensis. The bioactive compounds existing in this fraction were determined to be 10 flavonoids, 4 coumarins and 2 benzophenones. At 100 µM, a 30–65% inhibitory action on the PD-1/PD-L1 interaction was observed with these molecules with the GC showing the highest inhibitory action []. This makes GC another potential candidate. The backbone structure of GC shares some similarities with the previously mentioned flavonoids (Figure 1) and, therefore, this mechanism of action could be expected.

2.7. Ellagic Acid

Ellagic acid (EA) is a chromene-dione derivative that has a hydrophobic moiety of two hydrocarbon rings and a hydrophilic moiety of four hydroxyl groups and two lactones (Figure 1g). It is found in a variety of fruits, vegetables and seeds and has several medicinal activities including anticancer, neuroprotective, anti-inflammatory, antioxidant, hepatoprotective, and skin protection actions (reviewed in []). The fruit of Rubus coreanus Miquel, commonly known as black raspberry, has been used in traditional herbal medicine for centuries. The extract of the plant (RCE), which contains polyphenolic and flavonoid molecules such as QUE and EA, has antioxidant and anti-inflammatory effects [,,].

Kim et al. in 2020, used RCE in a competitive ELISA and showed a dose-dependent inhibition of the PD-1/PD-L1 interaction (IC50~84 µg/mL), vs. that of anti-PD-L1 antibody, ~1.7 µg/mL. The RCE was non-cytotoxic on aAPC/CHO-K1 and Jurkat cells at <100 µg/mL. In a co-culture system containing these two cell lines, the RCE activated TCR (EC50~56 µg/mL), and at 100 µg/mL it increased the activation of T cells as indicated by an increased production of interleukin 2 (IL-2) by 1.8-fold compared to an untreated control.

In a humanized PD-1 mouse model, 50 and 100 mg/kg of orally administered RCE decreased the tumor growth rate by 67% and 74%, respectively. The anti-hPD-L1 antibody at 5 mg/kg showed a 95% decreased tumor growth. None of the treatments affected the mice’s body weights [].

EA is the major constituent of RCE. IC50 of EA in blocking the PD-1/PD-L1 interaction in a competitive ELISA assay was ~23 µg/mL. A Western blot analysis showed that EA interacted with both PD-1 and PD-L1. Up to 120.9 µg/mL, EA was non-cytotoxic to Jurkat cells and showed a minor decreased viability in aAPC/CHO-K1 cells at 7.56 µg/mL. At a concentration < 7.56 µg/mL, the EA blocked the PD-1/PD-L1 interaction and showed a dose-dependent increase in IL-2 production [].

2.8. Heterocyclic Compounds

Lung et al. (2020) used the ZBC natural product dataset (180,000 molecules) and 5J89, the dimer structure of the PD-L1 IgV domain protein data bank, to perform a virtual molecular docking screening and contact fingerprint analysis. The top 22 selected molecules were subject to in vitro testing using an AlphaLISA PD-1/PD-L1 binding assay and two molecules, i.e., ZINC67902090 ((3S,3aR,6S,6aR)-N6-[4-(3-fluorophenyl)-pyrimidin-2-yl]- N3-(2-pyridylmethyl)-2,3,3a,5,6,6a-hexahydrofu) and ZINC12529904 (1-isopropyl-3-[(3S,5S)-1-methyl-5-[3- (2-naphthyl)-1,2,4-oxadiazol-5-yl]pyrrolidin-3-yl]urea), inhibited the interaction by 30 and 40%, respectively. The ZINC12529904 was more potent than the ZINC67902090 in increasing the PD-L1 dimerization [].

2.9. Gramicidin S

Gramicidin S (GS) is an antibiotic produced by the bacterium, Bacillus brevis, which is active against some bacteria and fungi. GS is an amphiphilic molecule with a stable β-sheet with hydrophilic and hydrophobic residues (Figure 1h). Consequently, due to the amphiphilic properties of the interaction surface of PD-L1 with PD-1, Sun et al. used GS as an anti-PD-L1 candidate []. The GS showed a weak inhibitory action on the PD-1/PD-L1 interaction (~7%), while a synthesized derivative of GS, namely, Cyclo(-Leu-DTrp-Pro-Thr-Asp-Leu- DPheLys(Dde)-Val-Arg, showed a high potency of 95% at 20 µM and a low IC50 of 1.42 µM [].

In a B16F10 tumor-bearing mouse model, 40 mg/kg of GS (IP) plus anti-CD8 antibody reduced the tumor volume and tumor weight by~55% and 65%, respectively, while this molecule increased the level of CD3+ T cells and CD8+ CTLs [].

2.10. Rifabutin (RIF)

RIF is a macrocyclic antibiotic mostly known as a treatment for tuberculosis (Figure 1i). Using an AlphaLISA human PD1–PDL1 binding assay, Patil et al. (2018) screened RIF together with 19 other FDA-approved macrocyclic molecules for their inhibitory action on the PD-1/PD-L1 interaction. The positive control was an anti-human PD1 antibody with an IC50 of 400 ng/mL. In this assay, at 50 µM, rifampin showed an inhibitory action of 48%.

Then, the efficacy of rifampin was compared with four other orally available molecules of this class: RIF, 3-formyl rifamycin, rifamycin SV, and rifapentine. The RIF and rifapentine showed the highest inhibition by ~68% and 52%, respectively. The RIF, rifampin and rifapentine all showed a dose-dependent inhibition of the PD-1/PD-L1 interaction, while the best IC50 belonged to the RIF (25 μM). Based on molecular docking studies, RIF formed a stable complex via several hydrogen bonding and π–π interactions [].

3. Druggability of the Candidate Molecules to Brain Tumors

The passive diffusion of molecules across a BBB requires a kinetic process with a plasma concentration high enough to produce a sufficient drug concentration at the receptor in the brain [,]; however, the concentration is not the sole parameter here. The parameters that affect the passive transport of molecules across the BBB and the PK of the above-mentioned molecules are discussed below.

3.1. Physicochemical Properties

The solubility of a drug, which is a function of the physicochemical properties of the molecule, plays a pivotal role in determining the fate and therapeutic efficacy of the drug. For the molecule to be water soluble, H2O molecules should break the intermolecular and intramolecular forces; therefore, the water solubility is dependent on the bulk properties of the molecule, and the placement of the polar and non-polar residues and areas [,]. Moreover, drug molecules reversibly bind to blood proteins at different levels. It is not yet conclusive whether high protein binding is beneficial towards drug delivery to the brain. For example, albumin or its complexes with drugs cannot traverse the BBB; however, exceptions such as benzodiazepines, steroids or some hormones have high central nervous system (CNS) concentrations rather than their unbound plasma concentrations []. The potential explanations include changes in the conformation of the protein in interaction with the capillary walls [,,], protein-mediated transport, especially with AAG [] and a more permeable structure of the endothelium in some parts of the BBB [,].

The brain-to-blood drug concentration ratio (BB) expressed as Log(BB) at a certain time point (Equation 1) has been questioned [] and the BBB permeability-surface area (PS) or the BBB permeability coefficient, as a quantitative measure of the rate of drug transport (Equation (2)) using in situ vascular perfusion techniques is added as another indicative measurement [,,]:

Log (BB)=𝐷⁢𝑟⁢𝑢⁢𝑔 𝑐⁢𝑜⁢𝑛⁢𝑐⁢𝑒⁢𝑛⁢𝑡⁢𝑟⁢𝑎⁢𝑡⁢𝑖⁢𝑜⁢𝑛 𝑖⁢𝑛 𝑏⁢𝑟⁢𝑎⁢𝑖⁢𝑛𝐷⁢𝑟⁢𝑢⁢𝑔 𝑐⁢𝑜⁢𝑛⁢𝑐⁢𝑒⁢𝑛⁢𝑡⁢𝑟⁢𝑎⁢𝑡⁢𝑖⁢𝑜⁢𝑛 𝑖⁢𝑛 𝑝⁢𝑙⁢𝑎⁢𝑠⁢𝑚⁢𝑎(1)
Log (PS)=𝑂⁢𝑏⁢𝑠⁢𝑒⁢𝑟⁢𝑣⁢𝑒⁢𝑑 𝑝⁢𝑒⁢𝑟⁢𝑚⁢𝑒⁢𝑎⁢𝑏⁢𝑖⁢𝑙⁢𝑖⁢𝑡⁢𝑦 𝑎⁢𝑐⁢𝑟⁢𝑜⁢𝑠⁢𝑠 𝐵⁢𝐵⁢𝐵 (cm/s)𝑆⁢𝑢⁢𝑟⁢𝑓⁡𝑎⁢𝑐⁢𝑒 𝑎⁢𝑟⁢𝑒⁢𝑎 𝑜⁢𝑓 𝑏⁢𝑟⁢𝑎⁢𝑖⁢𝑛 𝑐⁢𝑎⁢𝑝⁢𝑖⁢𝑙⁢𝑙⁢𝑎⁢𝑟⁢𝑦 𝑒⁢𝑛⁢𝑑⁢𝑜⁢𝑡⁢ℎ⁡𝑒⁢𝑙⁢𝑖⁢𝑢⁢𝑚 (cm2/g)(2)

Some of the factors affecting the uptake of a drug from the blood into any given tissue include the blood flow to the tissue, the permeability of the endothelial cells, and the amount of drug available for uptake. The brain tissue is highly perforated however, and the microvascular wall is not permeable to most drugs. The amount of a drug is inversely related to the area under the plasma concentration-time curve (AUC) which is an indication of systemic clearance [].

The lipophilicity of a molecule is determined using the partition coefficient (LogP) between oil (octanol) and water and is one of the important determinants in drug discovery. High LogP values show low water solubility and poor absorption and usually lead to rapid and high metabolism. This also increases the chance of non-specific binding to hydrophobic molecules and, therefore, a related toxicity []. Based on initial studies by Hansch et al., an optimal LogP = 2 showed the highest biological activity in barbiturates []. It has also been demonstrated that the optimal LogP for a BBB penetration is 1.5–2.7 with 0 < LogD < 3, and Clog 2.5 [,,,].

Molecular weight (MW) also plays an important role in the delivery of a drug across the BBB. Regardless of the lipophilicity, a 400 Da cut-off was considered for the MW of drug candidates []. Meanwhile, it was also shown that candidates can be divided into three groups based on the relationship between the PS and LogP/MW2. Those molecules that have a good correlation or have a greater PS value than their LogP can use passive diffusion and facilitated transport mechanisms. For those with a smaller PS value than their LogP, the MW of a molecule is greater than 400 Da []. Marketed CNS drugs, for example, have a mean MW value of 310 [].

Many other QSAR factors are also important to consider. Hydrogen bonding is a fundamental QSAR factor and is related to the count of heteroatoms, hydrogen bond donor and acceptor counts, polarity, and the polar surface area (PSA). The sum of oxygen and nitrogen counts (O + N), which measures the hydrogen bond acceptors, when less than 5, meets the requirement for CNS penetration []. A higher hydrogen bond potential decreases the penetration into the BBB. The average O + N for marketed CNS drugs is 4.32, with hydrogen bond acceptors and donors of 2.12 and 1.5, respectively, and an average %PSA (polar surface area/total surface area ×100) of 16.3% []. CNS drugs have a generally lower PSA than other drugs, being about 60 to 90 Å2 [,]. The rotatable bond counts and the number of rings that account for a molecule’s conformations affect a molecule’s volume. For orally administered drugs, a rotatable bond count > 10 is now correlated with a decreased bioavailability [], while this count is usually <5 for CNS drugs []. Strong acids and bases cannot penetrate the BBB. Meanwhile, the penetration of molecules to lipids is a function of the lipophilicity of the molecules and the concentration of their neutral species. CNS drugs are mostly basic and, therefore, in physiologic conditions, they are charged. At pH 7–8, having a positive charge or tertiary nitrogen is in favor of permeation to the BBB [,]. Moreover, a pKa limit of 4–10 has been considered for the penetration of drugs into the BBB []. Table 2 summarizes the physicochemical properties of the candidate herbal-derived molecules. The table shows that these molecules do not meet the required conditions described here to penetrate the BBB.

Table 2.

Physicochemical properties of candidate molecules. Data from: https://foodb.ca/ (accessed on 1 November 2022) based on ChemAxon.

CandidateFormulaMW 1O+N 2LogPPSA 3pKa a. 4pKa b. 5Charge 6H acc. 7H don. 8R bond 9
APIC15H10O5270.236952.7186.996.57−5.4−1531
COSC21H20O10432.3775100.44166.147.3−301064
KMFC15H10O6286.236362.56107.226.38−3.9−1641
KORC21H20O10432.3775101.24166.147.08−3.601063
QUEC15H10O7302.235771.48127.456.38−4−1751
ERIC15H12O6288.25562.53107.227.85−50641
FISC15H10O6286.236361.81107.226.32−3.9−1641
1-CQAC16H18O9354.30879−0.42113.22−3.2−1865
3-CQAC16H18O9354.30879−0.27164.753.33−3.2−1865
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1 Molecular weight, 2 Oxygen plus Nitrogen count, 3 Polar surface area (Å2), 4 Strongest acidic, 5 Strongest basic, 6 Physiological charge, 7 Hydrogen acceptor count, 8 Hydrogen donor count, and 9 Rotational bond count.

3.2. Pharmacokinetic (PK) Properties

In addition to the physicochemical properties, the PK properties of a molecule are also a determinant of its druggability. For orally administered drugs, the first-pass metabolism effect (FPE), occurring especially in the liver and intestines, has a major effect on the bioavailability of drugs. A rapid FPE decreases the required systemic level of a drug and increases its elimination. In an ideal case, 60 min after the administration of a drug, 80% of it should be available in the body []. Metabolism occurs via cytochrome p450 oxidation (CYPs) or conjugation. CYPs are responsible for the majority of metabolism. Successful orally administered CNS drugs, for example, should not have a significant metabolism via CYP2D6 or CYP3A4 to avoid any considerable interaction with co-administered drugs []. Serum albumin and α1-acid glycoprotein (AGP) are two major plasma proteins responsible for drug-protein binding and binding to weak basic CNS drugs (discussed above). For CNS drugs, a low binding affinity (KD < 10 µM) to albumin is suggested []. Here we have a look at the PK parameters of the candidate molecules. The PK factors that help with the comparison of these candidate molecules include the highest plasma drug concentration (Cmax), the time to peak drug concentration (Tmax), the AUC from time 0 to the last measurable concentration (AUC(0-t)) and the half-life (T1/2)

The PK of API was evaluated in a few studies. An oral administration of 13.5 mg/kg of API to rats had an approximate Cmax of 42 ng/mL, Tmax 0.5 h, AUC(0-t) 659 ng×h/mL and T1/2 2 h []. Increasing the dose to 60 mg/kg increased these values to an approximate Cmax 1330 ng/mL, Tmax 2.5 h, AUC(0-t) 11,763 ng×h/mL and T1/2 4.2 h []. The intravenous (IV) administration of 20 mg/kg of API to rats showed a Cmax~11,000 ng/mL, AUC(0-t) ~3300 ng×h/mL and T1/2 1.75 h []. The relative bioavailability of API is about 30%, which is considered to be low for human consumption, where a minimum of 50% is needed []. The poor bioavailability of API is partly due to FPE, and enterohepatic/enteric recycling which delays its elimination []. In comparison, IV administration of 18 mg/kg of COS to rats showed a much lower Cmax of 0.68 ng/mL, AUC(0-t) 1.34 ng×h/mL and T1/2 2.03 h. This shows that API has a better PK profile compared to COS.

API has a large volume of distribution (Vd) greater than the total body water of rats (0.67 L/kg). For example, a Vd of ~16 L/kg after a 20 mg/kg IV dose [] or 2 L/kg after a 5.4 mg/kg dose []. This shows the distribution and tissue accumulation of API. In silico studies suggest that API binds to human serum transferrin glycoprotein []. The LogP 2.7 makes API a lipophilic agent that should be able to penetrate the cell membrane and BBB [] and due to a small MW, it can interact with several cell components [].

Data on KMF is not as conclusive as API. An IV administration of 1, 2 and 4 mg/kg of KMF to rats showed a rapid clearance (4.40–6.44 L/h/kg), while its bioavailability after a 5, 10, and 20 mg/kg oral administration was poor due to an extensive metabolism []. Higher doses of 10, 25 mg/kg IV and 100, 250 mg/kg oral were also tested in rats, which also confirmed a high clearance rate of the molecule (3 L/h/kg), a large Vd of 8–12 L/kg and a terminal T1/2 of 3–4 h. The oral administration showed a rapid absorption (Tmax~1–2 h), though the bioavailability was still poor (2%). This low bioavailability was attributed to an extensive gastrointestinal and liver metabolism []. An administration of 10 mg/kg of KMF to rats showed that the metabolism of KMF is mostly via Phase II metabolism, which concerts KMF to metabolites such as KOR, KMF-7-sulphate and KMF-3-glucuronide, with the latter being the major one. More importantly, the expression of efflux transporters such as BCRP, MRP-1 and -2 also affect the level of KMF conjugates []. KMF is suggested to be a substrate of efflux proteins, which can improve the bioavailability of other chemotherapeutics such as etoposide and QUE [,].

In rats, 10 mg/kg of QUE as an IV or in oral doses were administered. The bioavailability of this dose was only 5.3% with about 93% metabolism occurring in the gut and 3% in the liver. The oral dose led to a Tmax of ~0.08 h, Cmax of ~0.2 µg/mL, and AUC (0–8) 0.06 h×µg/mL. This study did not suggest any enterohepatic recirculation [], while the human study, probably due to a higher dose, did suggest an enterohepatic recirculation []. An oral administration of 100 mg/kg of QUE in rats showed a T1/2 of 0.8 h, Tmax 0.3 h, Cmax 842 mg/mL and clearance of 0.8 L/h/kg []. This study clearly shows the effect of higher doses on the observed PK parameters. Healthy human cases received 500 mg of QUE, three times a day. This study resulted in an oral clearance of 3.5 × 104 L/h, Cmax~15 ng/mL, Tmax 3 h, AUC~62 ng/mL h, and a terminal T1/2 of 3.5 h []. In cancer patients, an IV injection of 60–2000 mg/m2 of QUE showed a safe dose of 945 mg/m2 with a T1/2 3.8–86 min, clearance of 0.23–0.84 L/min/m2 and Vd 3.7 L/m2 [].

ERI administered to rats at 20 mg/kg IV showed that R(+)-ERI reached a higher serum concentration compared to L(-)-ERI. The ERI showed a rapid distribution within 1 h and an elimination up to 72 h. The T1/2 of R(+)-ERI and L(-)-ERI were about 4 and 3.6 h, respectively. The glucuronidated ERI metabolites did not indicate an enterohepatic recirculation. Enantiomers of the ERI showed a similar Vd of about 4.8 L/kg, which correlates with the lipophilic nature of ERI [].

An IP administration of 223 mg/kg of FIS to mice showed a Cmax of 2.5 µg/mL at 15 min and a T1/2 ~3 h []. A 3 mg/kg IV dose of FIS in rats showed an AUC of ~276 mg/kg, Cmax~74 µg/mL, Vd 935 mL and clearance of 111 mL/min [].

To evaluate the PK of CQAs, 0.16 g/kg of Ainsliaea fragrans extract was orally administered to rats. This was equivalent to 0.828 mg/kg of COA, 3.61 mg/kg of 1,5-diCQA, 8.74 mg/kg of 4,5-diCQA, 17.52 mg/kg of 3,4-diCQA, and 15.81 mg/kg of 3,5-diCQA. The CQA and diCQAs were rapidly absorbed with a Tmax of 0.22–0.5 h and another peak at 4 h which suggests their enteric/enterohepatic recirculation. The T1/2 of these molecules were all below 2 h; however, 1,5-diCQA showed a 5–25 times higher peak concentration compared to the other diCQAs [].

To assess the PK of EA, 0.8 g/kg of the Punica granatum extract equivalent to 85.3 mg/kg of EA was orally administered to rats. This led to a Cmax of ~0.2 µg/mL, Vd 334 L/kg, AUC 840 µg g/mL, and plasma T1/2α and T1/2β of 0.7 and 0.5 h, respectively []. Several studies have indicated a poor absorption and rapid distribution of EA, which can limit its availability to the tissues [,,]. This is while the administration of EA as a total extract has a better PK profile rather than EA alone [].

4. Conclusions

Brain metastasis originating from breast cancer constitutes the largest portion of brain metastases after lung. Almost 15% of these cases are originated from TNBC, with 12% from Her-2+ and 3% from luminal breast cancers []. There are many potent small molecules that are of clinical interest. For example, tyrosine kinase inhibitors (TKIs) are examples that are mostly administered to Her-2+ patients and TKIs have shown an improved progression-free survival in Her-2+ breast cancer brain metastases []. The efficacy of TKIs versus pertuzumab (anti-Her-2 monoclonal antibody) in Her-2+ patients is being studied (NCT04760431). Other examples of such TKIs in clinical trials are pyrotinib (NCT03933982 and NCT04582968), sorafenib (NCT01724606), and lapatinib (NCT00263588). Immunotherapy for breast cancer brain metastasis is also under investigation in many clinical trials using haploidentical hematopoietic stem cells, cytotoxic lymphocytes, a dendritic vaccine, and dendritic cells (NCT01782274 and NCT03638765), durvalumab (anti-PD-1 antibody—NCT04711824), and bintrafusp alfa (targeting PD-1—NCT04789668). Due to an overexpression of PD-L1 in a subpopulation of TNBC patients, immunotherapy has found a unique attention; however, due to the challenging delivery of anti-PD-L1 antibodies to the brain, newer candidates are being investigated. The molecules reviewed in this paper have shown some efficacy as blockers of the PD-1/PD-L1 interaction; however, not all these studies have shown a relatively good preclinical evaluation of the molecules and many of them lack animal trials. Another drawback is that due to using different assays and evaluation techniques, it is not easy to compare the efficacy and potency of these molecules together. Therefore, further studies are encouraged to determine the best potential candidates. Moreover, flavonoids are substrates of ABC transporters [] and many of them have enterohepatic recirculation. The PK studies demonstrate that these molecules lack an appropriate bioavailability to be considered for oral administration.

In theory and based on the parameters discussed in this paper, these molecules do not have the proper physicochemical properties to cross the BBB; therefore, some other interventions will be required to deliver these drugs to the brain. These interventions could include the application of nanotechnology methods, using nanocarriers targeted to the brain. Some examples are targeted nanoscale immunoconjugates on polymeric scaffolds bound to antibodies for T-lymphocyte-associated antigen 4 (CTLA-4) or PD-1 [], or aptamers targeting the transferrin receptor-mediated transcytosis and PDGRβ-mediated transcytosis, which are good examples [,,,]. These aptamers are used as drug carriers, can traverse the BBB using transcytosis and deliver the payload to intracranial tumors.

Further comprehensive QSAR studies could facilitate finding the best backbone structure and using it for synthesizing more potent molecules. This would facilitate the application of these drugs as immunotherapeutic agents in other severe cancers with low survival rates such as high-grade sarcomas of the limbs []. It is, however, important to remember that immunotherapeutic agents, including the natural molecules, are still required to be used as combination and neo/adjuvant therapies together with chemotherapies, and not as single agents.

Author Contributions

Conceptualization, M.N.; methodology, M.N.; investigation, M.N. and S.S.; resources, M.N. and S.S.; data curation, M.N. and S.S.; writing—original draft preparation, M.N.; writing—review and editing, S.S.; visualization, M.N.; supervision, S.S.; project administration, M.N. and S.S.; funding acquisition, M.N. and S.S. All authors have read and agreed to the published version of the manuscript.






Melatonin is a hormone that can downregulate PD-L1 expression and enhance anti-tumor immunity: 
 
  • Ovarian cancer
    Melatonin can reduce PD-L1 expression and increase sensitivity to paclitaxel therapy. 
     
  • Head and neck squamous cell carcinoma (HNSCC)
    Melatonin can suppress PD-L1 expression and inhibit epithelial–mesenchymal transition (EMT). Melatonin levels are lower in HNSCC patients and are associated with lymph node metastasis. 
     
  • Non-small cell lung cancer
    Melatonin can downregulate PD-L1 expression and modulate tumor immunity. 
     
  • Synergistic effects
    Melatonin can have synergistic effects with chemotherapies and anti-PD-1 antibodies. 
     
Melatonin's anti-tumor properties are being explored as a repurposed drug in cellular and preclinical models. Melatonin's ability to downregulate PD-L1 expression may reduce the immunosuppressive tumor microenvironment and enhance anti-tumor immunity. 


Carvacrol is a bioactive compound that may inhibit the PD-1/PD-L1 axis. PD-1/PD-L1 is an immune checkpoint pathway that has been the subject of extensive research. Cancer immunotherapy that targets the PD-1/PD-L1 pathway has shown promising clinical results. 
 
Carvacrol is a monoterpenoid phenol with many biological activities, including:
anti-inflammatory, antioxidant, antimicrobial, anticarcinogenic, antiseptic, and immunomodulatory. 
 
Carvacrol has also been used in traditional medicine for a variety of purposes, including: Treating periodontal diseases, Treating hyperglycemia, and Treating pulmonary inflammatory diseases. 
 
In vitro studies have shown that carvacrol has a higher binding affinity to PD-1 than thymol. A molecular dynamics simulation also predicted that the carvacrol-docked PD-1 complex would be stable. 
 





Check out this paragraph from THIS ARTICLE

Tyson took part in a clinical trial involving amplified concentrations of the protein interleukin-15 (IL-15). Recently, the two oncologists who conducted the trial, human surgical oncologist Robert J. Canter and veterinary oncologist Robert B. Rebhun, published their findings that showed that IL-15 can stimulate immune system defenses against some cancers in dogs. The dogs inhale a mist containing IL-15, a type of immunotherapy, twice daily. Within a few weeks, some of the dogs exhibited significant responses that lasted well beyond the two-week course of treatment. 




From the A.I. Overview:

Artemisinin can inhibit the expression of IL-15, an inflammatory cytokine. Artemisinin is a natural compound that has been used as an antimalarial drug. It has also been shown to have anti-inflammatory properties, and may be useful in treating other conditions such as sepsis, ARDS, and COVID-19. 
Here's some more information about artemisinin and IL-15:

  • Artemisinin
    Artemisinin can inhibit the release of inflammatory factors, such as IL-15, IL-1β, and IL-6. It can also improve the inflammatory response in the brains of mice. Artemisinin is often recommended at a daily dose of 400–800 milligrams, and has been shown to be safe for six to 12 months. 
  • IL-15
    IL-15 is a cytokine that is produced by epithelial cells, fibroblasts, activated monocytes, and dendritic cells. It is thought to be involved in the physiopathological mechanisms of RA. IL-15 is a candidate for cancer therapy, and is being studied in clinical trials for renal cancer and melanoma. 

Artemisinin for Malaria, Viral Infections and Cancer ...

Dr. Axe
https://draxe.com › health › artemisinin
Apr 24, 2022 — This dose range has shown to be safe for six to 12 months, with no apparent artemisinin side effects.

Artemisinin: A Promising Adjunct for Cancer Therapy - PMC

National Institutes of Health (NIH) (.gov)
https://pmc.ncbi.nlm.nih.gov › articles › PMC6347441
by Y Waseem2018Cited by 13 — ... 400 to 800 mg per day can be used for at least six to 12 months, with no apparent adverse effects [2]. Artemisinin is invariably a valuable ...

Here's some information about Cleavers / Bedstraw for cancer (this actually seemed to help to make my dog's tumors a little softer and smaller)

https://thecanceralternative.blogspot.com/2024/04/cleavers-bedstraw-goose-grass-for.html


The Groundbreaking Cancer Expert: (New Research) "This Common Food Is Making Cancer Worse!"












I couldn't help wondering if Carvacrol might have a similar effect, and found this online:

Carvacrol—A Natural Phenolic Compound with ...

National Institutes of Health (NIH) (.gov)
https://www.ncbi.nlm.nih.gov › articles › PMC10215463
by W Mączka2023Cited by 49 — Carvacrol has a strong antimicrobial effect against many strains of bacteria and fungi that are dangerous to humans or cause significant losses in the economy ...
Missing: PD- ‎L1 ‎axis:

Carvacrol is a phytochemical that has shown potential to inhibit the PD-1/PD-L1 axis:
Carvacrol and PD-1/PD-L1
In vitro studies have shown that carvacrol has a higher binding affinity to PD-1 than thymol, another compound that also inhibits the PD-1/PD-L1 axis. The docking energy of carvacrol with PD-1 was -4.2 kcal/mol, while thymol's docking energy was -4.1 kcal/mol.
PD-L1 and cancer
PD-L1 is an immunosuppressive protein found on the surface of tumor cells that can prevent T cells from attacking cancer cells.

Carvacrol and other biological effects
Carvacrol is a monoterpenoid phenol that has many biological effects, including antimicrobial, insecticidal, anti-angiogenic, and anti-tumor activity. It's also used in traditional medicine for its antioxidant and anti-inflammatory properties.
Carvacrol is found in the essential oils of oregano and thyme. The FDA has approved its use as a food additive, which indicates its non-toxic nature.


Uses of Wormwood herb

 
Wormwood contains small amounts of thymol and carvacrol, as well as other phenolic compounds with potent antioxidant and free radical scavenging effects. 2.



Antitumor Effects of Carvacrol and Thymol: A Systematic Review

Please note here are some different excerpts from the study,plasted below (not in order). Click the link above to see the full study.

Results: A total of 1,170 records were identified, with 77 meeting the established criteria. The studies were published between 2003 and 2021, with 69 being in vitro and 10 in vivo. Forty-three used carvacrol, 19 thymol, and 15 studies tested both monoterpenes. It was attested that carvacrol and thymol induced apoptosis, cytotoxicity, cell cycle arrest, antimetastatic activity, and also displayed different antiproliferative effects and inhibition of signaling pathways (MAPKs and PI3K/AKT/mTOR).

Conclusions: Carvacrol and thymol exhibited antitumor and antiproliferative activity through several signaling pathways. In vitro, carvacrol appears to be more potent than thymol. However, further in vivo studies with robust methodology are required to define a standard and safe dose, determine their toxic or side effects, and clarify its exact mechanisms of action.

There is, therefore, an ongoing search for substances that can be used to develop more effective treatments, with less side effects, to use against cancer; one promising group of substances are natural products (NPs). There are many medicinal plants whose pharmacological properties have already been described and scientifically proven (Nelson, 1982; Mishra and Tiwari, 2011; Carqueijeiro et al., 2020). However, the enormous diversity of nature still holds many plant compounds without sufficient studies, particularly in the oncology area (Gordaliza, 2007; Asif, 2015). Historically, secondary plant metabolites have made important contributions to cancer therapy, such as, the vinca alkaloids (vinblastine and vincristine) and the paclitaxel terpene that was obtained from the Taxus brevifolia Nutt. species (Martino et al., 2018). More recently, other compounds, such as perillyl alcohol and limonene -monoterpenes found in aromatic plant species, have been widely studied due to their antitumor potential, and have been included in clinical phase studies (Shojaei et al., 2014; Arya and Saldanha, 2019).

In this context, carvacrol (5-isopropyl-2-methylphenol) and its thymol isomer (2-isopropyl-5-methylphenol), classified as natural multi-target compounds, deserve attention. Both are monoterpenoid phenols, the main components present in essential oils obtained from several plant species of the Lamiaceae and Verbenaceae families, such as oregano (Origanum vulgare L.), thyme (Thymus vulgaris L.) and “alecrim-da-chapada” (Lippia gracilis) (Santos et al., 2016; Salehi et al., 2018; Sharifi-Rad et al., 2018; Baj et al., 2020), which have already been reported to exhibit beneficial effects against many diseases (Silva et al., 2018), including cancer (Elbe et al., 2020; Pakdemirli et al., 2020). In addition, these compounds present anti-inflammatory (Li et al., 2018; Chamanara et al., 2019) and antioxidant (Arigesavan and Sudhandiran, 2015; Sheorain et al., 2019) activities that enable the reduction of inflammation and an increase in enzymatic and non-enzymatic antioxidants in the tumor environment (Gouveia et al., 2018). Hence, this systematic review aims to examine and synthesize knowledge about the antitumor and antiproliferative effect of carvacrol and thymol, as well as to report the main mechanisms of action already described for the two compounds against cancer. to provide guidance for future research.




 


 







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