Immunotherapy, Checkpoint inhibitors, Cancer, Fasting, Vitamin C, Metformin, ClinicalTrials.gov, FDA

Shorts

By Jule Klotter

Questions About CPIs and Immunotherapy

“Why do the majority of patients not respond at all, or only partially or transiently, to immunotherapy?” asks Angus G. Dalgleish in a recent Expert Review of Anticancer Therapy editorial. Dr. Dalgleish is a professor of oncology at St George’s University in London, United Kingdom. For over two decades, he has investigated the use of biological substances to increase the body’s immune response against cancers. The field of immunotherapy has expanded far beyond the use of killed bacteria, like William Coley’s toxins, and now includes cytokines (e.g., interleukin 2), and checkpoint inhibitors (CPIs), such as pembrolizumab (Keytruda), Ipilimumab (Yervoy), and atezolizumab (Tecentriq). “The response to immunotherapy is often dramatic but relatively uncommon,” Dr. Dalgleish writes, “and until recently difficult to improve upon.”

Checkpoint inhibitors (CPIs), which are monoclonal antibodies, have increased survival of some people with melanoma and some other cancers. Immune checkpoints are molecules on certain immune cells that need to be activated (or inactivated) to start an immune response, according to the American Cancer Society website. Some cancer cells develop ways to use these checkpoints to prevent immune system attack. For example, the checkpoint protein PD-1 found on T-cells works as an off switch; when that protein attaches to a protein (PD-L1) on another cell’s surface, it protects the cell from attack: “Some cancer cells have large amounts of PD-L1, which helps them hide from an immune attack.” Unfortunately, CPIs have “significant toxicity,” according to Dalgleish. Adverse effects include diarrhea, inflammation of the lungs, rashes, itchiness, hormonal effects, and kidney infections.

After years of trying to figure out why some patients respond to immunotherapy and others do not, Dr. Dalgleish and colleagues came to realized that non-responders show more biomedical signs of inflammation before treatment: “…whereas there is no single predictive biomarker to predict possible patient response to a CPI-based treatment, there is an exciting trend that a signature of several chronic inflammatory markers is associated with non-responsiveness.”

Chronic inflammation causes cell mediated immunosuppression and increased angiogenic and wound healing activity, making it more difficult for the body to fight cancer. Dalgleish and colleagues have begun to investigate the use of non-steroidal anti-inflammatory agents and immune modulators before using checkpoint inhibitor treatment.

Gastrointestinal microbiome composition is another, perhaps related, factor that affects a patient’s response to CPI treatment. In some cases, CPI response has improved after the patient receives fecal transplants. Dalgleish notes that a healthy microbiome is associated with a healthy diet and less inflammation.

Dalgleish and colleagues have also observed that patients who had received treatment with the immune modulator IMM-101 had a faster and better response to subsequent CPI treatment. IMM-101 a heat-killed Mycobacterium obuense preparation, provokes innate immune activity (i.e., NK cells and gamma delta T-cells).

“The sequence of treatments may be more important than combination,” Dalgleish writes, “…and this may well apply to any treatment that activates and sheds antigens, such as radiotherapy (RT) ablations and certain chemotherapy regimens.” In addition to using anti-inflammatory agents and immune modulators to prime the body before using CPIs, Dalgleish says that CPI dosage needs to be investigated: “…more is not always better, a situation that has not been fully explored with CPIs, given that overweight patients seem to do better with CPIs in a number of cancer types, compared to their non-overweight counterparts.”

A clinical trial with unresectable stage III and stage IV melanoma patients is underway to investigate the use of IMM-101 before CPI treatment (NCT03711188).

Dalgleish AG. Why do the majority of patients not respond at all, or only partially or transiently, to immunotherapy? Expert Review of Anticancer Therapy. 2019;19(12):1001-1003.

Fasting and Vitamin C for Cancer

In vitro and mouse studies indicate that a fasting-mimicking diet (FMD) increases the anti-cancer effect of high-dose vitamin C therapy in KRAS-mutated colon cancer, according to a 2020 study. The team of Italian and US researchers report that the diet-vitamin combination delayed tumor progression in mice injected with KRAS-mutated colon cancer cells. The KRAS (or K-RAS) gene produces a protein that has a role in cell growth, maturation, and death. These mutant cells are more susceptible to vitamin C’s anti-cancer effects than KRAS wild-type cancer cells. Mutated forms of this gene have been found in colon cancer, non-small cell lung cancer, and pancreatic cancer.

KRAS-mutant cancer cells need iron to grow and proliferate. The fasting-mimicking diet inhibits vitamin C-induced heme-oxygenase-1 (HO-1) upregulation in KRAS-mutant cells. HO-1 is an enzyme that degrades heme to iron, carbon monoxide, and bilirubin. By inhibiting the cancer cells’ access to iron, the diet makes KRAS-mutated cells more susceptible to vitamin C’s anticancer effects. Fasting/FDM can also sensitize cancers cells to chemotherapy, according to laboratory studies. The researchers say: “Of note, the FMD + vitamin C combination was as effective as oxaliplatin + FMD or oxaliplatin + vitamin C….Moreover, triple treatment (FMD + vitamin C + chemotherapy) was the most active therapeutic intervention in delaying tumor progression…and extending survival” in the mice.

The question is whether a fasting-mimicking diet and high-dose vitamin C, both of which have low toxicity, will have the same effect on humans. Randomized clinical trials involving patients with KRAS-mutated colorectal and, possibly, other tumors are needed.

Di Tano M, et al. Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancer. Nature Communications. 2020;11:2332.

Metformin in Non-Diabetic Cancer Patients

Metformin, an oral medication for type 2 diabetes, has shown a number of anti-cancer mechanisms in laboratory studies, including mTOR inhibition, cytotoxic effects, and immunomodulation. In addition, observational studies have shown decreased cancer risk, improved response to cancer therapy, and lower all-cause mortality in cancer patients who take the drug for diabetes. Studies are now being conducted to see if metformin has the same benefits for cancer patients who do not have diabetes. At this point, “the results are controversial,” write Kailin Chen and colleagues in their 2020 review article.

A few studies indicate that metformin may help prevent colorectal and endometrial cancers in nondiabetic people. A randomized, placebo-controlled, phase 3 trial found a statistically significant reduction in polyps and adenoma recurrence in nondiabetic patients who took low dose metformin (250 mg/day) for a year-long study (Lancet Oncol. 2016;17:475-83). In other studies, women who took metformin in the month preceding surgery for breast cancer or endometrial cancer had “decreased cellular proliferation in tumors” than those in the control groups. But overall, Chen et al say, “…the outcomes in the clinical trials, especially for nondiabetic patients with cancer, are not as satisfactory as expected.”

The authors suggest several reasons for the lackluster clinical study results. First, optimal dose, schedule, and duration for metformin use in nondiabetic cancer patients or those at-risk for cancer have not been determined. Dosages in the reviewed studies varied from 250 mg/day, 850 mg/day, 500 mg twice daily, to 1700 mg/day; and treatment length varied as well. In addition, metformin’s effect may differ with the cancer’s histological subtype and/or genotype. For instance, metformin “induced significant apoptosis only in the small cell carcinoma cell line but not in other human lung cancer cell lines.” Also, it may be that metformin is most effective in combination with some other treatment(s).

Metformin is an inexpensive drug and relatively safe with a low risk of lactic acidosis, according to the authors. “The risk of lactic acidosis increases with renal or hepatic impairment, aged 65 years or older, having a radiological study with contrast, surgery, or other procedures, hypoxic states, and excessive alcohol intake,” according to Drugs.com. Gastrointestinal symptoms, including anorexia, nausea, abdominal discomfort, and diarrhea are the most common side effects. Also, metformin can cause vitamin B12 deficiency in some patients, so patients’ B12 status needs to be monitored.

Chae YK, et al. Repurposing metformin for cancer treatment: current clinical studies (abstract). Oncotarget. 2016;7(26):40767.

Chen K ,et al. Metformin: current clinical applications in nondiabetic patients with cancer. Aging. 2020;12(4):3993-4009.

Transparency Lawsuit Against FDA

On February 25, 2020, Federal Judge Naomi Reice Buchwald ruled that the Food and Drug Administration (FDA), National Institutes of Health (NIH), and Department of Health and Human Services (HHS) misinterpreted a 2007 law that required clinical drug trial results to be posted on ClinicalTrials.gov. This government-funded database was approved by Congress in 1997, in an effort to increase transparency. Studies that show product ineffectiveness or poor safety are rarely published. In fact, negative information about a drug or device often remains hidden unless a lawsuit and the process of discovery brings the information to light. ClinicalTrials.gov was viewed as a possible solution to the lack of transparency.

ClinicalTrials.gov did not work as hoped, however. So, Congress passed the 2007 Food and Drug Administration Amendments Act (FDAAA); it requires basic, summary results for all FDA-approved drug and medical device clinical trials be posted on the website—even if the study did not conclude until after FDA approval of the product. HHS did not publish its regulation on how to interpret this law until 2017, and that document exempted studies completed or approved before January 2017, leaving 10 years of data hidden. In those ten years, universities, companies, and research institutions (including NIH) had repeatedly missed reporting deadlines, according to an investigative article in Science. FDA has not enforced the 2007 law with fines (up to $12,103/day), and NIH continues to give research grants to offenders. This lack of transparency and accountability led to the lawsuit.

The lawsuit was filed by two student law clinics, Yale Media Freedom and Information Access (MFIA) and NYU Technology Law and Police (TLP), with the help of the Yale Collaboration for Research Integrity and Transparency. Charles Seife, an investigative science and technology journalist at NYU, and Peter Lurie, MD, president of the Center for Science in the Public Interest and a former associate commissioner of the FDA, were the plaintiffs. Judge Buchwald’s ruling requires the government agencies to collect and post study results for the clinical trials conducted after the 2007 law went into effect.

In addition to increasing transparency needed to make informed medical and research decisions, the ruling may help increase FDA accountability. A 2020 JAMA article by Jonathan J. Darrow, JD, Jerry Avorn, MD, and Aaron S. Kesselheim, MD, JD, reports: “The number of [FDA] expedited development and approval programs has expanded greatly since 1983, reducing the amount of evidence available at the time of approval and increasing uncertainty about the existence or amount of clinical benefit.” The agency is now using less data, fewer pivotal studies, and more surrogate measures to approve medical drugs and devices than it did twenty years ago. Yet, the amount of Prescription Drug User Fee Act fees, paid to the agency by industry, has exploded from $66 million (annual mean) in 1993-1997 to $820 million in 2013-2017; “…in 2018, user fees accounted for approximately 80% of the salaries of review personnel responsible for the approval of new drugs.” Transparency is one battle; conflict-of-interest is another.

Darrow JJ, Avorn J, Kesselheim AS. FDA Approval and Regulation of Pharmaceuticals, 1983-2018. JAMA. 323(2):164-176.

Kumar S, Morten C, Ross JS. Promoting clinical trial transparency through the courts: A strategic lawsuit against the FDA. www.transparimed.org. October 23. 2019.

Piller C. FDA and NIH let clinical trial sponsors keep results secret and break the law. Science. January 13, 2020.

Transparency Advocates Win Victory for Public Access to Clinical Trial Data. February 25, 2020. https://law.yale.edu