June 1, 2018 (Vol. 38, No. 11)

The “War on Cancer” May Be a Cliché, But It Still Resonates

Immuno-oncology has opened several lines of attack against cancer, but the one that has aroused much excitement among researchers is immune checkpoint inhibition (ICI). A number of experts view the  delivery of maximum clinical benefit through immune checkpoint modulation as the backbone of immuno-oncology.

There is an increasing focus on identifying mechanisms of resistance, tracking biomarkers, and developing predictive preclinical models. Scientists are looking at how clinical trial data can be used to direct the development of immunotherapies, including combination immunotherapies.

Investigators also are trying to improve their ability to predict how specific cancers might respond to ICI. They believe that ICI will build on its clinical successes, such as the use of ipilimumab (Yervoy) and other monoclonal antibodies against difficult-to-treat cancers. Another encouraging clinical development is our ability to individualize ICI, distinguishing potential responders from nonresponders prior to therapy and mitigating side effects.

Manipulating the Microbiota

An individual patient’s microbiome affects how he or she responds to immune checkpoint therapy (ICT). This statement, which is supported by a growing body of evidence, is “no longer controversial,” said Scott Bultman, Ph.D., an associate professor of genetics at the University of North Carolina School of Medicine. Dr. Bultman cited results from recent publications describing the microbiome as a predictive biomarker for ICT responses. These studies, Dr. Bultman explained to GEN, demonstrate that microbiota can alter cancer susceptibility and progression by “diverse mechanisms, including modulating inflammation, inducing DNA damage, and producing metabolites involved in oncogenesis or tumor suppression.”

The microbiome’s influence on checkpoint inhibitor efficacy was discussed at ICI Boston in a workshop presented by Dr. Bultman and Lata Jayaraman, Ph.D., head of tumor immunotherapy at Seres Therapeutics. Drs. Bultman and Jayaraman agreed that new findings suggest that microbiota can be manipulated in several ways to improve cancer treatment. Possibilities include incorporating probiotics as adjuvants for checkpoint immunotherapy, designing small molecules that target microbial enzymes, or delivering specific consortia of bacteria to a patient’s gut.

A particularly promising approach, they indicated, was suggested by a study from the University of Chicago. According to this study, the commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.

Study results showed that several defined bacterial species occurred in greater prevalence in the intestines of 16 treatment responders than of 26 treatment nonresponders. The investigators collected fecal bacteria from three patients that were responders and three that were nonresponders to checkpoint therapy and transferred those bacteria into the intestines of germ-free mice. Two weeks later, the investigator implanted melanoma cells in the mice.

Two out of three mouse groups given bacteria from human responders had slow-growing tumors, and two out of three with fecal material from human nonresponders had fast-growing tumors. Mice treated with PD-1-blocking drugs showed tumor shrinkage only if they had microbiota from responding patients.

The presence of these specific bacteria in the intestine, the investigators concluded, may have enhanced antitumor immunity by increasing T-cell infiltration into the tumor microenvironment and augmenting T-cell-mediated killing of cancer cells, thereby increasing the odds of a vigorous and durable response.

“When you take stool samples from responders to checkpoint therapy and colonize germ-free mice, their guts become populated with bacteria from the responders,” Dr. Jayaraman explained. “When these mice are inoculated with tumors and treated with a checkpoint inhibitor, the mice behave as responders.

“If you do the same thing with microbiota from nonresponder patients, the mice don’t respond, and their tumors continue to grow. These data suggest that the right ecology of bacteria can modulate the immune tone of the gut in such a way as to enable a positive tumor response to checkpoint therapy.”

Dr. Jayaraman noted that Seres Therapeutics has formed a collaboration with MD Anderson Cancer Center (MDACC) and the Parker Institute for Cancer Immunotherapy (PICI) to test its microbiome therapy, SER-401, in combination with an anti-PD-1 checkpoint inhibitor. “PICI will sponsor the trial,” she continued, “which will be conducted by investigators at the MDACC.” In the randomized, placebo-controlled clinical trial, set to begin later this year, investigators at MD Anderson will assess the effect of giving SER-401 to patients with advanced metastatic melanoma undergoing treatment with an anti-PD-1 checkpoint inhibitor.

SER-401 is a preclinical, orally administered cocktail of live bacteria matching the microbiome signature linked to therapeutic responses. “The goal of the planned clinical studies,” she stated, “will be to identify specific sets of organisms that contribute to responses and to generate data that helps us elucidate the mechanism(s) underlying those responses.” Seres, she asserted, has previously shown that “we can package these organisms and successfully administer them orally to patients.”

Defining Treatment Duration

At the ICI Boson event, treatment duration issues were discussed in a keynote talk delivered by Israel Lowy, M.D., Ph.D., vice president of clinical sciences and head of translational science and clinical oncology at Regeneron Pharmaceuticals. Afterward, Dr. Lowy spoke with GEN to emphasize that optimizing treatment duration can maximize benefit and minimize toxicity. He also noted that Regeneron and Sanofi-Genzyme are jointly developing the human anti-PD1 mAb Cemiplimab as a potential treatment for multiple cancers, either as a monotherapy (cancer) or in combination with other agents.

“Over the last 10 years,” Dr. Lowy told GEN, “cancer immunotherapy has experienced a renaissance due to the dramatic success of immune checkpoint inhibitors such as anti-PD-1 (and anti-PD-L1 and anti-CTLA-4) for a range of tumors. But we still don’t adequately understand the differences between someone who responds and someone who doesn’t.

“When immune responses are good, they are often very good. For example, there were some patients treated with a limited course of interleukin-2 in the early days of immunotherapy, over 25 years ago, and their tumors melted with durable remissions consistent with a possible cure.”

Dr. Lowy also described his experiences during the initial development of anti-PD-1 at Medarex: “If the drug did not prove to have the same success as ipilimumab, I never wanted anyone to wonder if we failed to dose with sufficient duration to achieve a response, so we tested treatment regimens that went on for up two years to give it the best shot. Anti-PD-1s (and subsequently anti-PD L1s) have been so relatively well tolerated and have worked so surprisingly well in so many tumors, that everyone jumped on the treatment paradigm, but no one really questioned if shorter durations were sufficient.”

Longer-than-necessary treatment, he cautioned, has several potential downsides: “Chronic treatment with an immune system activator may predispose to later adverse events, such as chronic fatigue, myalgias, and other rheumatic-like symptoms with prolonged treatment into the second year.”

While patients may have impressive responses, they are not always durable. “If a patient progresses in the face of chronic treatment with anti-PD-1, further treatment with a PD-1 inhibitor may not be useful,” Dr. Lowy explained. “However, if they have a recurrence or progress after they have been off anti-PD-1 for a significant time, they may respond to retreatment with anti-PD-1, either alone or in combination with an additional agent.” Appropriate treatment durations may preserve the future utility of retreatment.

Dr. Lowy said that he believes the best way to help resolve the question about appropriate treatment durations is with rigorous randomized discontinuation trials (RDTs). In these trials, he explained, “all patients are openly treated with the drug under evaluation, and after some predetermined timepoint, such as one year, those who have responded are randomly assigned to continue the same treatment or switched to a placebo.”

Treatment duration questions that could addressed by such trials include the following:

  • When might prolonged treatment raise the risk of adverse effects (late-emerging immune problems and severe infections)?
  • How might treatment regimens compromise retreatment?
  • Which response features might predict durability?

“Some companies have started RDTs, suggesting that field recognizes these questions,” Dr. Lowy noted. “But it will be slow going until we have clear results and can identify biomarkers to enable a physician to confidently advise a patient that it is ok to stop their therapy.”

Overcoming Resistance

Osama Rahma, M.D., assistant professor of medicine at Harvard Medical School and medical oncologist at Dana-Farber Cancer Institute focuses his research on investigating the therapeutic potential of combinations of immunotherapeutic drugs, including checkpoint inhibitors. He discussed the differences between primary and secondary resistance mechanisms to checkpoint inhibition and ways to potentially overcome them.

Although immunotherapy with checkpoint inhibitors has shown potential against several aggressive cancers such as melanoma, non-small cell lung cancer, and head and neck cancers, it still has a record of mixed success. “The clear majority of patients do not respond to checkpoint inhibition therapy,” Dr. Rahma pointed out. “And a minority of patients who do respond to treatment develop secondary resistance and experience relapse through poorly understood mechanisms.”

The way forward, Dr. Rahma suggested, is to combine therapies to enhance and maintain the potential efficacy of checkpoint inhibitors. He noted that 50–60% of melanoma patients who exhibit primary resistance to checkpoint inhibitors don’t respond at all, and that two-thirds of responders at some point stop responding. These figures raise the following question: Do the mechanisms of primary and secondary resistance cross the same pathways?

“We think of pancreatic cancer as an immune desert lacking any kind of immune cell infiltration,” Dr. Rahma elaborated. “However, the literature indicates that tumor-infiltrating immune cells may be present without being effective. They may be restrained by suppressive immune cells, or they may remain inactivated due to defects in the antigen-presenting machinery.

“Other factors, such as stromal effects, may prevent the immune cells from penetrating pancreatic and ovarian cancers. We also know that some tumors, particularly renal cell cancers, use angiogenesis as an escape mechanism from immune attack and depend on it to survive.”

Dr. Rahma also emphasized that tumor angiogenesis serves as link between a tumor and the immune response directed against that tumor. This link depends on vascular endothelial growth factor (VEGF), which not participates in the regulation of angiogenesis in cancer, but also modulates antitumor immunity on multiple levels. For example, VEGF contributes to the promotion and expansion of inhibitory immune cell subsets (regulatory T cells and myeloid-derived suppressor cells), the inhibition of dendritic cell maturation, the suppression of T-cell responses, and the suppression of immune cell trafficking across tumor endothelia.

“We are heavily involved in investigating the combination of checkpoint inhibitors and antiangiogenics,” Dr. Rahma remarked. “Angiogenesis can lead to the activation of suppressor cells. At the same time checkpoint inhibitors can lift a barrier to inhibition.”

T-cell exhaustion also factors into cancer resistance to immunotherapy. Dr. Rahma explained that exhausted CD8 T cells have decreased effector function and proliferative capacity, debilities partly caused by overexpression of inhibitory receptors such PD-1, TIM-3, and LAG-3. Blockade of these inhibitory molecules along with PD-1 pathway can open a new therapeutic avenue for reinvigorating T-cell responses.

“We try to overcome resistance in several ways,” Dr. Rahma discussed. “We irradiate the tumors, triggering tumor inflammation and antigen release, which subsequently stimulate T cells and enhance their movement to the tumor microenvironment.

“I think there are lots of success stories with checkpoint inhibitors, and I believe the field is moving more toward a personalized approach. Something that’s in the works is the repeat biopsy. In patients that stop responding to therapy, a repeat biopsy can be used to customize therapy, redirecting it as necessary by having the tissue drive the treatment rather than the cancer itself.”

In Vitro Tumor Modeling

To better predict responses to cancer treatments, drug developers and clinicians are beginning to use functional assays that model tumor ecosystems. Such assays can be applied by CANscript, a platform provided by Mitra Biotech, suggested Mark Paris, Ph.D., the company’s associate director of translational applications. CANscript is designed to recreate a patient’s tumor microenvironment to evaluate that patient’s tumor response, in real-time, to physician-selected treatments. The platform runs multiple phenotypic assays and analyzes results with a clinically trained algorithm to generate a single score that predicts clinical response.

Mitra’s ex vivo patient tumor culture model, Dr. Paris explained to GEN, uses intact tumor fragments cultured with autologous plasma and peripheral blood mononuclear cells. This fully human ex vivo platform focuses on the contextual preservation of native states of proliferation, morphology, and viability.

“The concept is that we can use this platform to support client needs across several primary purposes,” he stated. “We can use the platform to explore mechanisms of action, to predict single-agent efficacy, and to understand combinatorial advantages (particularly in the checkpoint space). When it is used to evaluate novel drug combinations that are entering clinical trials, it has the potential to mitigate risk.

“Most important, we have defined and validated a series of phenotypic response assessments coupled to a machine-learning algorithm to quantitate drug response in a way that allows prediction of clinical efficacy with 90% accuracy.”

The company recently detailed the responses seen in squamous cell carcinoma of the head and neck (SCCHN) challenged with clinically approved anti-PD1 agents. “Our observations were mechanistically consistent with known functions for anti-PD-1 and mirror published clinical response rates for Pembrolizumab in SCCHN,” Mitra’s scientists concluded. “The platform preserves known mechanisms of resistance that represent opportunities for testing new modalities and rational combinations in the immuno-oncology space.”

Dr. Paris further explained that Mitra functions as a contract research organization that is devoted to oncology: “After our commercial launch in 2017, we started working with drug developers of all sizes engaged in translational science. We are now working with more than 50% of the world’s top pharma companies. We test all oncology drugs regardless of modality, but because our system maintains the tumor microenvironment intact, we are particularly well suited to the evaluation of immune modulatory drugs.”   

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