Columbia University Medical Center

Immunotherapy Trial Suggests There’s Still A Lot to Learn

Lymphoma cell immunotherapy (Source: Getty Images)

Cancer immunotherapy is often hailed as a miracle drug. But recent news that these therapies may exacerbate disease in some patients is a sobering reminder that there’s still much to learn about these new treatments.

Immunotherapy includes various strategies that harness a patient’s immune system to attack cancer. The therapies are still new—the first cancer immunotherapy drug, a vaccine for prostate cancer, was approved in 2010. Since then, clinical trials have shown that immunotherapy drugs are effective in a few types of cancer, and many physicians are now trying them, with some success, as a last resort for patients with other types of cancer.

But a report in NEJM that an immunotherapy drug actually worsened disease in patients with a rare and aggressive lymphoma is not a complete surprise, says Columbia immunotherapy expert Pawel Muranski, MD.

“Cancer immunotherapy represents a new era in oncology, but we need to continue to do careful clinical evaluations before offering it to new groups of patients,” says Muranski, who was not part of the NEJM study.

The CUIMC Newsroom sat down with Muranski to discuss the state of cancer immunotherapy and how researchers and physicians should proceed.

Q: The NEJM report described how three patients with adult T cell leukemia/lymphoma (ATLL) got worse after just one dose of an immunotherapy. What do you think happened?

First, ATLL is a rare and more aggressive form of T cell lymphoma that affects T lymphocytes. The immunotherapy used in this study blocks a molecule called PD-1, and in other cancers, PD-1 inhibition activates an immune response against the cancer. But PD-1 also stops T cells from proliferating. Because the T cells are malignant in ATLL, it’s possible that inhibiting PD-1 had the opposite effect of encouraging cancer growth.

Another difference is that ATLL is caused by infection with the HTLV-1 virus. There’s some evidence that the virus may interact with the PD-1 signal and promote the proliferation of cancerous T cells. But that needs to be studied further.

Q: Why was this type of immunotherapy being tested in patients with ATLL?

Researchers have discovered that the immune response against cancer is stronger when the tumor is genetically unstable and has multiple mutations. These mutations create targets for the immune system, so together they elicit a stronger immune response. ATLL has a higher mutation rate than other blood cancers, so the researchers theorized that PD-1 immunotherapy might work in this malignancy.

The experience with ATLL shows that immunotherapy is not a panacea for every type of malignancy.

Also, a previous study found that PD-1 inhibition produced some responses in patients with other T cell lymphoid malignancies, though none of those cancers are associated with HTLV-1 infection.

Q: Does the failure of one type of immunotherapy in ATLL mean immunotherapy can’t work in these patients?

No, there are other types of immunotherapy that may work. One type, approved in Japan for ATLL, targets CCR4, a molecule that is abundant on malignant cells in ATLL. Preclinical studies in the U.S. are investigating the effectiveness of CAR T therapy in targeting CCR4, which genetically engineers a patient’s T cells to attack cells bearing the CCR4 molecule.

The response rate for immunotherapy varies from one type of cancer to another and from one immunotherapeutic strategy to another. CD19 CAR T cells have induced complete remission in some leukemias, and PD-1 inhibitors have been effective in many tumors including melanoma and Hodgkin lymphoma. In the future, it may be possible to apply combinations of these modalities in particular cancers with better efficacy and more reliability than we see now.

Q: There is also recent news about how immunotherapy appears to work in some patients with cancers that weren’t believed to be susceptible to immune-based therapies. What’s going on here? Should physicians offer immunotherapy to any cancer patient as a last resort?

We still have a lot to learn. Some immunotherapy strategies activate the immune response in a general way. This could explain why some patients benefited even though there was no solid evidence supporting the therapy’s use in those patients. It’s fortunate that some patients benefited from immunotherapy even though the drugs hadn’t been studied in those cancers, but you could also easily imagine the opposite result without clinical evidence to guide therapy.

Clinical studies are the best way to learn about the safety of each new immunotherapy and to learn how to use existing therapies in new diseases. Immunotherapy could be counterproductive and even harmful for some patients, and we won’t know that without clinical trials.

Q: Should we be cautious about immunotherapy’s promise or optimistic?

Both. The experience with ATLL shows that immunotherapy is not a panacea for every type of malignancy. As we continue to develop immunotherapy for different types of cancer, it’s critical that we consider the biology of a particular tumor. Clinicians should be optimistic about the possibilities of immunotherapy but should approach new applications with caution until more studies are done.

Dr. Muranski is assistant professor of medicine and of pathology & cell biology at Columbia University Vagelos College of Physicians and Surgeons and director of cellular immunotherapy at Columbia University Irving Medical Center and NewYork-Presbyterian. He is also a principal investigator at Columbia Center for Translational Immunology and a member of Columbia’s Herbert Irving Comprehensive Cancer Center.