Biomarkers, Novel Combinations Key to Improving Response to Immunotherapy

James P. Allison, MD

James P. Allison, MD

For some cancers, response rates with immunotherapy will reach 100% within 5 years, said James P. Allison, MD. Achieving that level of response will require tailoring treatment to each patient’s specific cancer through the identification of new biomarkers, and the goal is within reach, he said.

“Now that we've got 4 pillars of cancer therapy, immunology is the only one that can work with the others. The others are pretty much siloed. They always have been and always will be,” said Allison, chair of Immunology and executive director of the Immunotherapy Platform at The University of Texas MD Anderson Cancer Center. “Now that we understand about immunotherapy and what's needed, the people in the other cancer therapies can quit worrying about killing every last tumor cell; just kill enough to let the immune system take it out.”

Allison was taking part in a roundtable discussion at the 2018 International Cancer Immunotherapy Conference. He was joined on the dais by conference co-chair Nina Bhardwaj, MD, PhD, director of cancer immunotherapy, professor of medicine, and Ward-Coleman Chair in Cancer Research at Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai and Crystal Mackall, MD, director of the Stanford Center for Cancer Cell Therapy and associate director of the Stanford Cancer Institute. The discussion was moderated by Jill O’Donnell-Tormey, PhD, CEO and director of scientific affairs at the Cancer Research Institute (CRI).

Allison, along with Tasuku Honjo, MD, PhD, of Kyoto University, had been named a Nobel Laureate earlier in the day for his work researching immunotherapy, and the speakers took a few minutes to acknowledge the importance of his achievement. O’Donnell-Tormey said that, after 31 years at CRI, she never thought she'd see the day when the Nobel Prize would go to cancer immunotherapy, and that cancer immunotherapy would be curing patients.

“Prior to Dr Allison’s work, so much of the effort was about how you activate your immune system to recognize and destroy cancer,” she said. “There was a sea change and a paradigm shifting when he discovered it wasn't all about activation. You needed to deal with how you get over this immune suppression; these brakes that are naturally there in the immune system. That's a fundamental change that has really affected everybody that's doing immunology.”

To achieve Allison’s goal, Mackall said investigators will need to develop “rational combinations” that attack tumors from multiple directions. The industry, biotechnology firms, and pharmaceutical companies are supporting immunotherapy, but physicians have to be careful about which combinations make it to the clinic.

“There isn't anything new, we just have to do good science and clinical trials based on the most sound preclinical models,” she said. “If we do that and if we've studied the patient, then we will make progress. If we just throw darts at the wall and see what sticks, it's not going to get us anywhere.”

“We're going to start seeing combinations in the clinic and a lot of iterative testing and design will be necessary to understand how these [combinations] work,” Bhardwaj added. “What's very encouraging also is just the breadth of new technologies we now have to monitor responses at the single cell level and in patients from patient tissue. That will help us really understand how these different combinations work.”

Developing this level of response will require personalized immunotherapy. That, in turn, will require further identification and development of biomarkers to distinguish therapeutic targets. Bhardwaj said some biomarkers, such as PD-L1, already exist, but the field needs more biomarkers if the goal is to administer truly individualized treatments.

“In terms of personalized therapies, understanding an individual's tumor microenvironment will be key. Meaning, what is the landscape of someone's tumors? What inhibitory molecules do they express? What activating molecules? What is the constitution of the tumor from the frequency, the nature of immune cells, and the tumor cell itself,” she said. “Getting a better understanding of the tumor landscape, developing tumor atlases, combined with investigation of a patient's blood will lead us to the development of biomarkers in conjunction with clinical trials.”

Allison said that investigators and clinicians will need to analyze a cancer both at baseline to identify potential biomarkers, but also to see how the cancer changes after treatment. Those changes will help guide the next step of treatment, which may be different for different kinds of cancer and different individuals. “It will have to be personalized even with these things that are pretty broadly useful,” he said.

While immunotherapy is often associated with very durable response—Allison has said that 1 patient who received ipilimumab (Yervoy) for advanced melanoma in a phase I trial is still alive after nearly 19 years—there is a subset who will experience recurrence. Understanding the underlying mechanisms of resistance, and developing therapies to combat resistance, is a vital question that remains unanswered, O’Donnell-Tormey said.

Mackall said T-cell exhaustion is at the cutting edge of research into overcoming resistance. Checkpoint blockade is a form of reinvigoration for exhausted T cells, she said, which illustrates what a T cell can do if the problem of exhaustion can be overcome.

“But we also know that checkpoint blockade is not complete in terms of its ability to do this,” she added. “There's a lot of very exciting work happening, some in the engineered T cell space, to understand the biology of T cell exhaustion and to be able to come at it from completely different angles. Rather than the checkpoint receptors, there are also other intrinsic features that mediate exhaustion in T cells. We're still diving deep into understanding those T cells, but there's still a lot more we have to learn about how they become less functional and how we can reinvigorate them.”

Research into immunotherapy has led to a renewed interest in anticancer vaccines. O’Donnell-Tormey said improved understanding of immunosuppression may mean that vaccines have a new role just a few years after the modality was all but dead.

“The most exciting development in cancer vaccines is the discovery of neoantigens, which rise from a patient's specific mutations,” said Bhardwaj, who has done extensive research into vaccines. “We're learning that some of these are shared, so we can potentially have shared neoantigens that are targeted in vaccine. Some, of course, will be very specific and specific to the patient, but the exciting thing is the technology that's emerged to identify these antigens. For the first time, we have rational approaches and rational targets that can be applied today.”