The Future of Immunotherapy: Building on Checkpoint Blockade

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THE EMERGENCE of anticancer agents that block immune checkpoints has transformed the field of oncology, leading to durable responses and improvements in overall survival in melanoma, renal cell carcinoma, head/neck squamous cell carcinoma, urothelial bladder cancer, and non–small cell lung cancer. Promising clinical activity has also been demonstrated, particularly for programmed cell death protein 1 (PD-1) pathway blockade, in lymphomas, hepatocellular carcinoma, triple-negative breast cancer, and ovarian cancer among others.

Jedd D. Wolchok, MD, PhD, FASCO

Jedd D. Wolchok, MD, PhD, FASCO

However, according to Jedd D. Wolchok, MD, PhD, FASCO, combination therapy—whether with other immune modulators, oncolytic viruses, vaccines, radiation treatment, chemotherapy, targeted therapy, or antiangiogenic therapy—will be necessary for immunotherapy to achieve its full potential. Dr. Wolchok is the Lloyd J. Old/Virginia and Daniel K. Ludwig Chair in Clinical Investigation; Chief of the Melanoma and Immunotherapeutics Service; and Director of the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center in New York.

At the 2019 ASCO–Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Symposium, Dr. Wolchok discussed efforts underway to study precise mechanisms of primary and acquired resistance to rationally inform future combinations.1 Despite the long list of new agents in early clinical development, Dr. Wolchok also called for patience among stakeholders expecting the next 5 years to progress as rapidly as the past 5 years.

Foundational Pathways

“WE NEED TO THINK carefully about how to interpret the results of next-generation immunotherapies by first taking a step back and recognizing that the foundational pathways of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and PD-1 are very important,” said Dr. Wolchok. “These pathways have shown us that the patients who derive clinical benefit are those in whom there is a preexisting immune response. If we move this next generation of agents into patients who aren’t benefiting from those agents, we are unlikely to see single-agent activity unless there is another foundational pathway uncovered.”

According to Dr. Wolchok, researchers must first decide whether these new agents are hitting their molecular target and behavingin the pharmacodynamically expected manner. Targets for intervention are sometimes abandoned too early, he explained, after failing to elicit a response in patients already refractory to CTLA-4 or PD-1 inhibitors, or even the combination. Researchers should first see whether new agents are safe and demonstrate the mechanism of action expected based on the preclinical science.

“Because there has been so much progress in the past 5 years, it may take us a little bit longer to dig into the mechanisms and understand who needs which of these interventions to help them to achieve tumor control,” he added.

“Because there has been so much progress in the past 5 years, it may take us a little bit longer to dig into the mechanisms and understand who needs which of these interventions to help them to achieve tumor control.”
— Jedd D. Wolchok, MD, PhD, FASCO

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New Antibody

WITH THAT IN MIND, Dr. Wolchok expounded the clinical development of an agent that targets glucocorticoid-induced tumor necrosis factor receptors. First identified as a selective marker of regulatory T cells, glucocorticoid-induced tumor necrosis factor receptors can also be upregulated and expressed on activated effector cells. Dr. Shimon Sakaguchi, who discovered the molecule, developed a mouse anti–glucocorticoid-induced tumor necrosis factor receptor antibody called DTA-1, which caused exposed cells to start producing interferon gamma. “After exposure to DTA-1, these cells started to behave like effector T cells,” said Dr. Wolchok. “They stopped making interleukin 10 and stopped behaving like regulatory T cells. This represented another approach to immunotherapy by changing the lineage commitment of this inhibitory cell population.”

Based on this preclinical research, Dr. Wolchok and colleagues embarked upon a first-in-human phase I trial starting in 2010, enrolling patients with advanced refractory solid tumors. The trial explored an antibody called TRX518, which is a humanized monoclonal antibody that is aglycosylated against glucocorticoid-induced tumor necrosis factor receptors.

As Dr. Wolchok explained, the TRX518 trial opened on the heels of treatment-related fatalities from a CD137 agonist program and severe adverse events from CD28. Because of the significant safety concerns around agonist agents, patients received only a single dose of the drug. Aside from safety, the pharmacokinetic endpoints included an assessment of changes in T-cell subsets and the peripheral blood as well as in the tumor site in patients who agreed to have a biopsy.

“In the peripheral blood, it was quite clear that, over time and in a somewhat dose-dependent manner, the only population of circulating cells that showed a consistent change were regulatory T cells, and specifically, the regulatory T cells that were glucocorticoid-induced tumor necrosis factor receptor–positive,” said Dr. Wolchok. “That synced with what we would have predicted based on the animal models…. It was also extremely important because, as expected, there was not very much clinical activity from a single dose, especially at very low doses of this experimental agent, although some patients did have stable disease for a longer time.”

Further analysis of human samples showed that exposure to the glucocorticoid-induced tumor necrosis factor receptor agonist led to a decrease in the number of regulatory T cells and mixed lymphocyte reactions. Moreover, activated regulatory T cells underwent activation-induced cell death. “This was a real change of their lineage commitment,” said Dr. Wolchok. Analysis of tumor samples showed that the number of regulatory T cells in the tumor was also decreased in the same patients who showed a decrease in the peripheral blood. “We could see concordant downregulation of regulatory T cells in the peripheral blood and the tumor after patients received the agent, yet there was little to no clinical activity.”

Further Investigation

INVESTIGATORS THEN went back to the mouse models to understand what should be given along with the new therapy to increase the therapeutic index. A gene-expression analysis demonstrated a striking difference in levels of markers of T-cell exhaustion between day 4 and day 7 in anti–glucocorticoid-induced tumor necrosis factor receptor–treated tumors. Day-4 treated tumors had very low levels of markers—specifically PD-1 and lymphocyte-activation gene 3—whereas day 7 tumors had these markers expressed at a much higher level.

This difference gave rise to the hypothesis  that PD-1 also should be blocked as a way to “reinvigorate” this population of cells. By combining anti–PD-1 with the anti–glucocorticoid- induced tumor necrosis factor receptor antibody, Dr. Wolchok and colleagues were then able to show that they could actually control 7-day-old tumors better than 4-day-old tumors with anti–glucocorticoid-induced tumor necrosis factor receptor by itself.

“A tumor at baseline has regulatory T cells in it and some exhausted T cells,” Dr. Wolchok explained. “After we expose the tumor to anti–glucocorticoid-induced tumor necrosis factor receptor, the number of regulatory T cells is decreased, but there are still these exhausted T cells. By adding anti–PD-1, however, we now have more cytotoxic T cells and, eventually, fewer tumor cells.” 

According to Dr. Wolchok, this model presents a reasonable, mechanistically based rationale for moving this combination into a clinical trial. A multicenter study combining TRX518 with either chemotherapy, pembrolizumab, or nivolumab is ongoing.

DISCLOSURE: Dr. Wolchok is a consultant for Adaptive Biotech, Advaxis, Amgen, Apricity, Array BioPharma, Ascentage Pharma, Astellas, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, F Star, Genentech, Imvaq, Janssen, Kleo Pharma, Linneaus, MedImmune, Merck, Neon Therapeutics, Ono, Polaris Pharma, Polynoma, Psioxus, Puretech, Recepta, Trieza, Sellas Life Sciences, Serametrix, Surface Oncology, and Syndax; has received research support from Bristol-Myers Squibb, MedImmune, Merck Pharmaceuticals, and Genentech; has equity in Potenza Therapeutics, Tizona Pharmaceuticals, Adaptive Biotechnologies, Elucida, Imvaq, BeiGene, Trieza, and Linneaus; and has received honorarium from Esanex.


1. Wolchok J: Cancer immunotherapy: Building on checkpoint blockade. 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. Keynote Lecture. Presented March 1, 2019.