Cancer immunotherapy, or immuno-oncology, boosts the immune system’s ability to eradicate malignancies. Starting with the approval of ipilimumab (Yervoy) a decade ago, immunotherapies have prolonged life and even offered remission for people with advanced cancer. More recently, these therapies have emerged as first-line treatment for some cancers. Still, challenges remain. Immunotherapies don’t help most patients, and it’s difficult to predict in advance who will benefit. In addition, tumors may find ways to develop resistance to immunotherapies, just as they do with chemotherapy and targeted therapies.

Justin F. Gainor, MD, director of targeted immunotherapy at Massachusetts General Hospital and an assistant professor of Medicine at Harvard Medical School, answers three questions about the state of the art in immunotherapy, the possibilities of combination therapy, and the problems with predictive tests.

Interview condensed and edited for clarity

We hear a lot about the excitement around immunotherapies. Can you summarize the state-of-the-art in terms of the successes of immunotherapies in specific cancers?

When immunotherapies work, they produce more durable responses than traditional therapies such as chemotherapy. Two types of immunotherapies are currently generating the most excitement: checkpoint inhibitors and CAR-T cells.

T cells are the workhorses of the immune system. One way that tumors survive is by engaging molecular “brakes” on T cells to stop them from working. Checkpoint inhibitors are drugs that release the brakes, enabling T cells to mount an immune system attack.

Immune checkpoint inhibitors have been complete game changers in the treatment of solid tumors. In 2011, the FDA approved the first checkpoint inhibitor for melanoma. Since then, checkpoint inhibitors have been approved for at least 12 other solid tumors, including non-small cell lung cancer, kidney cancer, bladder cancer, and most recently triple-negative breast cancer. The approved drugs include the PD-1 inhibitors pembrolizumab (Keytruda), nivolumab (Opdivo) and cemiplimab (Libtayo); the PD-L1 inhibitors atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi); and a CTLA-4 inhibitor, ipilimumab (Yervoy).

In hematologic cancers, CAR-T therapy has achieved the most promising results. This approach addresses another challenge: T cells have a hard time recognizing cancer cells, which arise out of mutations from normal cells and, therefore, do not look foreign.

In CAR-T therapy, scientists genetically engineer a patient’s own T cells to contain the chimeric antigen receptor (CAR). This receptor binds to a specific protein, or antigen, on tumor cells. Once the CAR-T cells are infused into the patient’s bloodstream and begin circulating, they recognize and attack cancer cells. So far, CAR-T cells are FDA-approved for pediatric acute lymphoblastic leukemia and adult lymphoma.

What does the near-term landscape look like for combination therapies involving immunotherapies?

Immunotherapy only works in a small subset of patients. For example, about 20 percent of patients with non-small cell lung cancer and 25 percent of those with kidney cancer respond to these drugs.

Researchers are exploring many different combination therapies in order to boost that response rate and overcome resistance mechanisms developed by cancer cells. What we’ve seen, particularly in lung cancer, is that chemotherapy plus immunotherapy improves both response rate and survival. In addition, combining certain immunotherapies has also been effective. Based on the research, the FDA has already approved combining a PD-1 and CTLA-4 inhibitor for melanoma, kidney cancer, and colon cancer.

How good are current diagnostic tests at predicting who will respond to immunotherapies? Are there better predictive approaches in the pipeline?

The tests are imperfect. The earliest efforts to look at predictive biomarkers centered around expression of PD-L1, a protein that cancer cells use to cloak themselves and become less visible to immune cells. But it’s not great at predicting response. In lung cancer, for example, if you are PD-L1 positive, the chances of responding to a PD-1 inhibitor is about 40 percent. If you’re negative, you have about a 10 percent chance of responding.

A second biomarker under investigation is TMB (tumor mutation burden), where we determine the number of mutations a tumor has. Tumors with higher TMB have increased likelihood of response to immunotherapy.

The real challenge is that these biomarkers are not binary—either you have one, or you don’t. They are assessed on a continuum. And that speaks to the point that there are many variables that go into generating an immune response against a tumor. There are tumor-intrinsic factors, such as genetic alterations within the tumor. The tumor-immune system interface and characteristics unique to individual patients also factor into immune response. And a huge focus of research right now is how a patient’s microbiome affects immune system response to these drugs.

This remains an area of immense study. Right now, we are just scratching the surface.

Continue the conversation on Twitter by connecting with us @HMS_ExecEd or with Dr. Gainor @MGHCancerCenter.

-Ann MacDonald