Exploring Immunotherapy’s Present and Future

Exploring Immunotherapy’s Present and Future

Dr. Gregory Beatty
Photo courtesy of David DeBalko
Although the use of immunotherapy has become mainstream in oncology, the field currently offers more potential than practical use. There are now approved immunotherapies in certain malignancies that offer substantial benefit in some patients but still do not help many individuals. Immunotherapeutic approaches with other targets beyond those approved therapies are making progress through the drug development process, but outcomes continue to be mixed, and the future is murky.

This year, the ASCO Annual Meeting will feature a number of sessions focused on immunotherapy.* These will help attendees understand both the current use of immunotherapy, as well as the future of the field, from approved PD-1 and PD-L1 inhibitors to trials involving peptide vaccines and a variety of other therapies.

“Although immunotherapy is producing remarkable success stories for some patients across a wide range of malignancies, most patients still do not benefit significantly from this approach,” said Gregory Beatty, MD, PhD, of the University of Pennsylvania Perelman School of Medicine, who will chair the Education Session “Immunotherapy: Beyond Checkpoint Inhibitors” on June 6. “This is not to say that immunotherapy cannot be helpful for these patients, but it does mean that, as a research community, we need to understand why immunotherapy is not working in many cases. And moreover, why immunotherapy works for some patients. I think this will be a major theme of [this year’s Meeting].”

The session Dr. Beatty will chair will focus on strategies for altering immunity in cancer other than by targeting checkpoints. These will include novel approaches to inducing tumor-specific immunity, engineering a patient’s immune system, and overcoming barriers that could regulate the efficacy of immunotherapy. Dr. Beatty will discuss the role of inflammation in cancer and its ability to act as a barrier to effective immunotherapeutics.

“Understanding strategies for manipulating inflammation in cancer is fundamental to knowing how to combine them with existing immunotherapies,” Dr. Beatty said. There are ongoing clinical trials evaluating three distinct strategies toward this goal, he said: depleting myeloid cells from tumors, inhibiting the tumor-promoting properties of those cells, and redirecting myeloid cells with tumor-inhibitory activity. Dr. Beatty believes attempts to restrain inflammation will be more difficult than the idea of shifting cells’ behavior from pro-tumor to antitumor.

Dr. George Earl Peoples
“Because most solid malignancies are associated with an inflammatory response, I view cancer inflammation as a potential opportunity, and I hope that educating clinicians, researchers, and the pharmaceutical industry on this topic will incite a surge in clinical investigations around how to harness inflammation in cancer for therapeutic benefit,” Dr. Beatty said.

Marcela Valderrama Maus, MD, PhD, of Massachusetts General Hospital, and George Earl Peoples, MD, of the San Antonio Military Medical Center, will also speak during this Education Session.

Dr. Peoples told the ASCO Daily News that cancer vaccine trials have been looking in the wrong place, which the lack of success in this field reflects. Previous work has most often tested cancer vaccines in advanced cancer settings, but he thinks the adjuvant setting makes more sense for these as a monotherapy. This is because it may be easier to prevent a tumor from becoming established than to treat it once it has advanced.

“I think the field of cancer vaccines has moved toward adjuvant trials,” Dr. Peoples said, noting that adjuvant trials can be difficult to conduct. If the recurrence rate in a given malignancy is already relatively low, testing cancer vaccines could mean large trials that take many years to complete. “Adjuvant trials are not easy, but I do believe that’s the right place for cancer vaccines as monotherapy.”

He also noted that there is an obvious synergy between the more mature immunotherapy options—checkpoint inhibitors—and cancer vaccines. “The checkpoint inhibitors work by allowing T cells to do their job in the hostile tumor microenvironment,” Dr. Peoples said. And vaccines’ primary job is to elicit T cells, meaning the two immunotherapies may work well together. “However you want to look at it, either one makes the other better. I think you’ll see a lot of combination trials coming out,” he said.

Other Immunotherapeutic Targets

During the June 7 Education Session, “Immunotherapy: Beyond Anti–PD-1 and Anti–PD-L1 Therapies,” chaired by Scott Joseph Antonia, MD, PhD, of the H. Lee Moffitt Cancer Center, experts will discuss some of the other targets for immunotherapy agents that are in development.

Dr. Johan F. Vansteenkiste
Anti–PD-1/–PD-L1 agents can produce rapid and durable responses and associated survival benefits in certain malignancies, such as lung cancer, but many patients still do not benefit. This is due, in part, to malignancies’ potential to co-opt many different immunosuppressive mechanisms beyond aberrant expression of PD-L1.

In fact, there is a wide array of immunosuppressive mechanisms that could operate within the tumor microenvironment and that could represent therapeutic targets. This includes surface membrane checkpoint proteins, such as CTLA-4, LAG-3, TIM-3, BTLA, and adenosine A2aR; soluble factors and metabolic alterations to proteins, including IL-10, TGF-b, adenosine, IDO, and arginase; and inhibitor cells, cancer-associated fibroblasts, regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages.

The Education Session will feature discussion of several strategies aimed at thwarting some of the immunosuppressive mechanisms. Some of the sessions will focus on generating more tumor-reactive T cells, which, as Dr. Peoples said, is a primary purpose of therapeutic cancer vaccinations. Johan F. Vansteenkiste, MD, PhD, of University Hospital Gasthuisberg, in Leuven, Belgium, will discuss some of the difficulties in developing cancer vaccines and how best to move ahead.

“Despite promising initial findings, all large phase III studies with vaccination for non–small cell lung cancer did not result in patients’ benefit,” Dr. Vansteenkiste said. For example, the extremely large MAGRIT trial—of which Dr. Vansteenkiste was the lead investigator and which screened almost 14,000 patients with completely resected non–small cell lung cancer (NSCLC; more than 2,300 patients were randomly assigned)—could not demonstrate any improvement in survival with the MAGE-A3 cancer immunotherapeutic in comparison with placebo.1 Dr. Vansteenkiste will discuss why the earlier-phase successes have not translated into phase III positive results, and where the field of cancer vaccines must head in the future.

Day-to-Day Immunotherapy Concerns

Dr. Jean-Charles Soria
Photo courtesy of Harris DPI
During the June 5 Clinical Problems in Oncology Session “Now That We Have Immunotherapy, What Do We Do?” experts will focus on the current, practical issues relating to immunotherapy in oncology.

“The approval of PD-1 inhibitors in NSCLC has been a particularly significant change for medical oncologists,” said Edward B. Garon, MD, of the Ronald Reagan University of California, Los Angeles Medical Center, who will chair the session. “Advertisements on television and in major lay publications go a long way to increasing awareness of a therapy, but the nuances of treating patients require a more extensive discussion. The goal of this session is to [provide] practitioners [with] data and experience that can help them deal with issues such as which patients are most likely to benefit from therapy, when should therapy be stopped, and how should toxicity be managed.”

In recent years, agents such as nivolumab and pembrolizumab have been approved for the treatment of NSCLC and melanoma. Jean-Charles Soria, MD, PhD, of Gustave Roussy Cancer Campus, in Villejuif, France, will also speak at this session and will focus on tips for daily practice with these drugs. This will include the ability to identify the most common adverse events associated with immune checkpoint inhibition and to detect radiological pseudo-progression. “I will also provide details on the next kids on the block,” Dr. Soria said, including durvalumab, atezolizumab, and avelumab.

Durvalumab was recently granted Breakthrough Therapy designation by the U.S. Food and Drug Administration; the drug, which targets PD-L1, is under investigation for the treatment of PD-L1–positive inoperable or metastatic urothelial bladder cancer. The most recent promising results from a trial of atezolizumab, another PD-L1–targeted agent, in the same malignancy, were presented during the 2016 Genitourinary Cancers Symposium in January (Abstract 355). Avelumab is under investigation in a number of malignancies, including NSCLC.

Julie R. Brahmer, MD, FASCO, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, will also speak at this session.

These and other sessions this year on immunotherapy highlight how this field, which for many years existed largely as a promising future avenue for cancer therapy, has moved into the spotlight.

“The checkpoint inhibitors have ushered in the new era of immunotherapy,” Dr. Peoples said. “It was more of a religion than a science for a long time, but I think we’re past that now. People realize that immunotherapy is here to stay, and that the immune system has the capacity to recognize and destroy cancer. We’re not there yet, but we’re off to a great start.”  

– David Levitan