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Immunotherapy Using Checkpoint Inhibitors

Currently, the most exciting area of cancer research revolves around harnessing our own immune system to combat cancer. There are now several “checkpoint inhibitors” on the market, with the most common being nivolumab (Opdivo), pembrolizumab (Keytruda), and ipilimumab (Yervoy). Despite the commonly exaggerated efficacy reported with checkpoint inhibitors, unfortunately, only approximately 20% of patients respond positively when this therapy is used as the sole treatment, with most of the responses limited to patients with melanoma.

Checkpoint inhibitors, although sometimes beneficial, when used according to the recommended dosing guidelines, may be associated with significant toxicity. The question that many cancer scientists are asking, as well as a few oncologists who have reviewed the published literature, is why are we using such high doses of these drugs? An article published on Oct 1, 2019 expounds upon this issue: Immune Checkpoint Inhibitor Dosing: Can We Go Lower Without Compromising Clinical Efficacy?

There is a large amount of data showing that checkpoint inhibitors have significant activity at doses much lower than those currently approved. Using high or maximum tolerated dose (MTD) immunotherapy is analogous to using MTD chemotherapy for solid tumors. It is certainly not clear that MTD chemotherapy is optimal for solid tumors, nor is it clear that MTD immunotherapy is optimal for solid tumors. Apparently, one does not need high doses of checkpoint inhibitors in order to get a therapeutic effect. The efficacy of low doses could be explained because the programmed death-1 [PD-1] receptor [the molecular target of both Opdivo and Keytruda] reaches maximum occupancy at low doses for these agents, translating into a flat exposure-response curve, where increasing the dosage does not lead to an increase in tumor response.

Another article was published in 2018 demonstrating similar findings, and was entitled, “Impact of immune checkpoint inhibitor dose on toxicity, response rate, and survival: A pooled analysis of dose escalation phase 1 trials.” The investigators analyzed clinical data from patients treated in phase 1 immune checkpoint inhibitor dose escalation trials at MD Anderson Center for Targeted Therapy. Patients were stratified into a low-dose [LDG] ( < 33% of maximum tolerated dose), medium dose [MDG] (34-66% of maximum tolerated dose), high dose [HDG] (67-100% of maximum tolerated dose), or very high dose [VHDG] ( > 100% of maximum tolerated dose) group. Groups were compared for immune related adverse events (irAE), progression-free survival (PFS), overall survival (OS), overall response rate (ORR – those who had a complete response or partial response), and disease control rate (DCR -those who had a complete response, partial response, or stable disease for > 6 months).

Conclusions: Despite a dose-dependent increase in irAE, we identify no improvement in PFS, OS, or DCR with escalating doses of checkpoint inhibitors administered in phase I trials. Lower doses may reduce toxicity and cost without compromising disease control or survival.

Based on the available data, the current guidelines for checkpoint inhibitor dosing are causing significant financial and immunological toxicity, without improving PFS or OS.

Cancer scientists have been evaluating methods to improve the efficacy of checkpoint inhibitors; Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other Than Abscopal Effect: A Systematic Review.

The data reveals that combining checkpoint inhibitors with modalities, such as radiation, chemotherapy, angiogenesis inhibitors, and targeted drugs, improves the response.

At Advanced Medical Therapeutics, we recommend combining low dose combination checkpoint inhibitors with other modalities which release tumor antigens and improve the tumor microenvironment, thereby increasing the chances of an optimal immune response to cancer.

2-Methoxyestradiol

2-methoxyestradiol has attracted much interest in the last 10 years due to its potent anticarcinogenic properties, and to its possible beneficial actions in the cardiovascular system. 2-Methoxyestradiol (2ME) is an estrogen metabolite which has no estrogenic activity. 2ME is naturally produced in copious amounts during pregnancy. In vitro, the growth of cells of such different tumors as carcinoma of the lung, colon carcinoma, tumors of the nervous system, melanoma, ovarian carcinoma, carcinoma of the kidney, prostate carcinoma, tumors of the musculature, tumor of the eye, cervical carcinoma, endometrial cancer, vascular tumors, esophageal cancer, stomach cancer, pancreatic cancer, and breast cancer was able to be inhibited by 2-methoxyestradiol. In-vitro, there are, however, varying sensitivities, with breast cancer being by far the most sensitively to 2-methoxyestradiol.

Mechanism of Action

Many mechanisms for the effect of 2ME on the various cancer cells have been elucidated. The most important seem to be inhibition of neoangiogenesis (development of new blood vessels for cancer growth), microtubule disruption (preventing cancer cell division), and upregulation of the extrinsic and intrinsic apoptotic pathway (stimulates the mitochondria to kill the cancer cells).

Clinical Studies

Several experimental investigations demonstrated that the combination of 2ME with other tumor-suppressing agents (such as chemotherapy) can lead to an additive or synergistic inhibition of cancer cell proliferation, while not affecting non-malignant cells. Some clinical studies have already been conducted investigating the possible antitumor potency of 2ME in prostate cancer, recurrent and metastatic breast cancer, and other solid malignancies that were unresponsive to standard of care therapy.

In a phase II trial, 31 men with hormone-refractory prostate cancer were enrolled. 2ME was well tolerated and, despite suboptimal plasma levels and limited oral bioavailability with the available capsule formulation, still showed some anticancer activity at 1200 mg/day. All of the other trials were only phase 1 trials (assessing safety and side effects), but the data showed the drug was well tolerated.

Bioavailability

Although 2ME appears extremely exciting as an anti-cancer agent, the main obstacle to the development of 2ME (and further clinical trials) is the lack of oral bio-availability. 2ME is dosed orally and is well absorbed, but it is rapidly deactivated in the liver. This has led to multiple companies attempting to develop alternative oral preparations, such as placing 2ME in a nanoparticle. A simple way to increase bioavailability, however, is to bypass the liver by delivering 2ME as a rectal suppository.

Taurolidine

Taurolidine, derived from the naturally occurring amino acid taurine, was originally designed as a broad-spectrum antibiotic and originally used in the local treatment of peritonitis. It is currently licensed for intraperitoneal use in several European countries for the treatment of peritonitis. The compound appears to be nontoxic and has an excellent safety record since its initial introduction over 30 years ago. Taurolidine also possesses a strong anti-inflammatory action. This action appears, at least in part, to arise through its ability to inactivate endotoxin. Inflammation-induced tumor development is well described in the literature. Taurolidine's anti-inflammatory and anti-adherence properties prompted an investigation to examine whether it has a role in antitumor therapy.

Mechanism of Action

Taurolidine reduces inflammation by suppressing the activity of IL-1, IL-6, IL-8, endotoxin, and tumor necrosis factor alpha. In addition, it inhibits development of new blood vessels for cancer growth by inhibiting a growth factor, called vascular endothelial growth factor (VEGF). Taurolidine has also been shown to increase free radical production selectively in cancer cells. Finally, taurolidine promotes apoptosis (stimulates the mitochondria to kill cancer cells).

Safety

Over 33 studies have utilized taurolidine intravenously, and no adverse effects apart from vein irritation at high doses have been experienced (which is why taurolidine must be infused through a central line, such as a PICC line or Port). To date, taurolidine's safety profile has been excellent; no allergic reactions have been observed.

Human Studies

A phase III trial examined the influence of intravenous taurolidine (2% TRD, 300 mg/kg body weight/day) on gastric and pancreatic cancer recurrence (n=50). The monthly repeated 7-day treatment sessions were performed using a central vein port catheter and a pump perfusor system. No clinically relevant side-effects were seen in the first 15 patients. Additionally, quality of life, response rate and mortality rate were evaluated under a standardized protocol. Reduced tumor markers at the end of a 7-day therapy have been observed in most patients. Stable disease was observed in three cases (gastric cancer recurrence group).

Two patients with malignant glioblastoma were treated with IV taurolidine (2% TRD 1000 ml=20 g/day). Although both patients died 4 months later due to complications unrelated to taurolidine (acute thromboembolism and pneumonia), a transient improvement in quality of life and a partial tumor remission were observed. A clear response on the TRD treatment was seen in the computed tomography scan.

Memorial Sloan Kettering Cancer Center completed a Phase 1 trial in patients with recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, as well as another Phase 1 trial in patients with glioblastoma. These studies, however, were only evaluating toxicity and side effects.

Why Are There Limited Studies on Taurolidine?

The composition patent on Taurolidine has long expired, meaning there is no financial value in this drug, as it exists now. Clinical trials cost many millions of dollars. A pharmaceutical company is unlikely to fund a trial without the possibility of bringing a drug to market. To bring a drug such as taurolidine to market, the molecule would have to be altered, so a new composition patent can be obtained. Once this new drug is developed, a clinical trial would have to show that this new altered version, is more effective than the previous version. This is a common problem; we have many efficacious drugs that are no longer being used because the patent life has expired.

References

2-Methoxyestradiol

Taurolidine

Paul Calabresi; Taurolidine; Cytotoxic and Mechanistic Evaluation of a Novel Antineoplastic Agent; Cancer Research; Sept 2001
Peter M. Neary; The Evolving Role of Taurolidine in Cancer Therapy; Ann Surg Oncol (2010) 17:1135-1143
https://www.cancertreatmentsresearch.com/taurolidine/