ATLANTA—One of the hottest topics in medicine is the emerging field of cancer immunotherapy. However, immune-related adverse events (irAEs) are associated with the therapy, and when things go wrong, they can go very, very wrong, said Ryan Sullivan, MD, during the 2019 ACR/ARP Annual Meeting in November.
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“The guiding principle of cancer immunotherapy is [that] an individual’s cancer can be eradicated if the immune system can be instructed to do so.” But, Dr. Sullivan says, “While [the drugs are] helping many patients—some with durable responses—there often is a catch.”
Part of the allure of the therapy is cancer cells’ behavior: Every cancer that has been diagnosed has figured out how to defend itself against the immune system. Dr. Sullivan explained that immune checkpoint inhibitors “take the brakes off” immune system cells, including T cells that keep immune system responses in check, allowing them to kill cancer cells. “The problem is we’re taking away the regulators of the immune system, so it’s like we’re playing with fire, resulting in irAEs that can range from minor to major. So a problem that might mirror rheumatoid arthritis or ulcerative colitis becomes a much more significant problem because you’ve taken away the regulators,” he said.
Dr. Sullivan is board certified in medical oncology and an attending physician in the Division of Hematology/Oncology at Massachusetts General Hospital, Boston. He, along with Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center and professor of medicine at the New York University School of Medicine, and Elad Sharon, MD, MPH, from the National Cancer Institute Cancer Therapy Evaluation Program (CTEP), Bethesda, Md., were the joint presenters of this Basic Science Session.
The emerging central challenge of cancer immunotherapy is uncoupling the anti-tumor response from anti-patient immune activation, or the autoimmunity that comes with generating effective immune responses. “Many of these immune-related adverse events are auto-inflammatory, and as rheumatologists, you might think they’re very similar to things you see in your practice,” said Dr. Weber. “They’re not exactly the same, especially the ones related to [the gastrointestinal] and endocrine [systems].”
Dr. Sullivan said a great deal of progress is being made to understand and solve irAE issues. “The good news is medical oncologists are becoming more and more familiar with these problems and solving them.”
At Mass General, Dr. Sullivan said, they’re treating more and more patients with checkpoint inhibitors because there are more and more indications to do so. “The number of irAEs [related to checkpoint inhibitor use], which went up between 2011 and 2017, is now leveling off—even as the number of patients increases.”
Dr. Sullivan said toxicities typically occur within the first four to 12 weeks, and the first symptoms of fatal toxicities typically develop within five or six weeks.
Keys to an Effective T Cell Response
Dr. Sullivan said the first step in using activated T cells to kill cancer cells is antigen recognition by the T cell receptor—recognizing an antigen that is being expressed by an antigen-presenting cell in the context of major histocompatibility complex genes that code for proteins found on the surfaces of cells to aid the immune system in recognizing foreign substances. The second step is co-activation. “There are a number of cell surface markers on the antigen-presenting cell and on the T cell that interact with each other and steer a reaction toward T cell activation.” These activated T cells infiltrate the tumor and then interact with the cancer and, ideally, kill the cancer cells. But the cancer cells also respond to the threat presented by the activated T cells.
Dr. Sullivan pointed out that CTLA-4 is critical for T cell priming and activation, and plays a crucial role in regulatory T cell function. “There’s also PD-1 [programmed cell death protein 1], a marker of T cell activation. It serves as a key regulator of active cells in the immune microenvironment,” said Dr. Sullivan.
The first immune checkpoint inhibitor approved by the U.S. Food & Drug Administration (FDA) was in 2011. Since then, the number has increased, with five approved in 2016, 10 in 2017, 12 in 2018 and seven in 2019. They’re treating a variety of malignancies and include one CTLA-4 blocker, three PD-1 inhibitors, three PD-L1 inhibitors and one combination. “We’re seeing more combinations of therapies being approved, including combinations with chemotherapy,” said Dr. Sullivan.
While other types of cells can be involved in immunotherapy, including B cells, Dr. Sullivan said most of the magic in immunotherapy is about the T cell.
Dr. Weber, on the other hand sees a great deal of promise with B cells. “I’m convinced that antibodies and B cells are implicated in immune-related adverse events. Do I see it as a possible biomarker? Absolutely. I used to be a T cell chauvinist; now I’m a B and T cell chauvinist.”
In Search of Biomarkers
Dr. Weber says a key part of current research is investigating biomarkers to predict whether significant irAEs may occur, but that the irAEs may themselves be a biomarker. “There’s research showing that the onset of irAEs in some histologies appears to be associated with a favorable outcome.”
Dr. Weber said other key points under investigation include investigating whether patients with prior autoimmune disease and prior irAEs with checkpoint inhibition are at risk of developing subsequent irAEs with further therapy, “but it is usually manageable.”
He also said evidence is mounting that autoantibodies are associated at baseline with subsequent development of some irAEs and that cytokine levels of interleukin (IL) 6 and tumor necrosis factor alpha (TNFα) are likely to be associated with irAEs. “Also, T cell mediated mechanisms and microbial species are associated with irAEs.”
He also made a prediction. “An amalgamated biomarker will be generated that will help us predict who will develop irAEs in the near future.”
Elad Sharon, MD, MPH, joined CTEP in December 2011 as a senior investigator in the Investigational Drug Branch, where he works with academia and industry to develop promising cancer therapies. He said a key part of the program’s research is “learning from our mistakes.” CTEP manages about 750 clinical trials around the country, “and an increasing number of those are related to immunotherapy.” Dr. Sharon said that while it’s encouraging to see many patients deriving significant benefit, a big focus of CTEP is “monitoring safety.”
CTEP publishes Common Terminology Criteria for Adverse Events (CTCAE). It has a number of initiatives, including the Immune-Related Adverse Event Biorepository, which is scheduled to open in 2020. Other key areas of investigation include vaccines to induce immune response against presumed cancer antigens.
One ambitious program underway—which Dr. Sharon co-manages—is NCI-10204: The AIM-NIVO a Phase 1b Study of Nivolumab in Patients with Autoimmune Disorders and Advanced Malignancies (AIM-NIVO).
AIM-NIVO “put together a collection of oncologists and subspecialty autoimmune specialists from across the country to try and better understand what these drugs do in patients who have underlying autoimmunity conditions,” said Dr. Sullivan.
Mike Fillon is a healthcare writer living in the Atlanta area.