Two immunotherapies may not be better than one

Concurrent treatment with two cancer immunotherapeutic agents—OX40 and PD-1 targeted therapies—only diminished the effect of anti-OX40, resulting in poor treatment outcomes in mice, according to two studies, published in the journals Clinical Cancer Research and Cancer Immunology Research.

Researchers conducted these two studies to assess whether a combination of anti-OX40 and anti-PD1 therapies made for better outcomes than either treatment used alone.

In the first, published in Clinical Cancer Research, senior author Bernard A. Fox, PhD, chief, Laboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Portland, OR, and fellow researchers observed that in mice with anti-PD1 refractory tumors, combining anti-OX40 and anti-PD1 immunotherapies suppressed the therapeutic effects of the anti-OX40 antibody. Furthermore, the treatment produced a cytokine ‘storm-like’ event that caused lethargy, spleen enlargement, and increased levels of CTLA-4 and TIM-3, immune checkpoint proteins, on T cells.

Dr. Fox and fellow researchers also showed that sequential treatment with anti-OX40 followed by anti-PD1 brought about significant improvements in therapeutic efficacy that resulted in delayed tumor progression, including complete tumor regression in roughly 30% of the mice in this model of human breast cancer. The same was not true, however, for sequential treatment using these agents in reverse order.

“The complexity of combination immunotherapy is enormous, because there are potentially many different ways it could work,” said Dr. Fox, who is also the Harder Family Endowed Chair for Cancer Research, Providence Cancer Center. “Our study suggests that treating patients with anti-OX40 followed by anti-PD1 needs to be tested as it may be the best sequence to increase T-cell proliferation, reduce T-cell death, and maintain the T-cell numbers without upregulating as many inhibitory molecules.”

“Moving forward, it is important to carefully study the patients, evaluate whether they have any pre-existing immunity, and follow their peripheral blood very closely over the early course of treatment to understand the biological effects of immunotherapy combinations,” he added.

In the second study, led by Samir N. Khleif, MD, professor and CRU Distinguished Scientist and Clinician, Georgia Cancer Center, Augusta, GA, researchers found that the simultaneous addition of anti-PD1 and anti-OX40 therapies inhibited the T-cell specific positive effects of anti-OX40 and suppressed its therapeutic efficacy. The detrimental effects of combination therapy were caused by the induction of antigen-specific T-cell apoptosis. They published their results in Cancer Immunology Research.

Unlike Dr. Fox and colleagues, however, Dr. Khleif and his team found that the therapeutic efficacy of continuous treatment with anti-OX40 with delayed addition of anti-PD1 did not produce superior outcomes compared with treatment with continuous anti-OX40 alone.

“With chemotherapy, you hit the tumor with one hammer, then you hit it with another hammer, and we know that the outcome is better in most cases,” said Dr. Khleif. “But treating a patient with one immunotherapy could change the tumor microenvironment and the biology of T-cell signaling in such a way that when you give another immunotherapy it might work very differently than what is expected and could exhibit the exact opposite outcome than it was supposed to.”

He concluded: “Our findings are very important because current clinical trials are testing this combination. Our studies show that preclinical testing of immunotherapy combinations prior to taking it to clinical trials is very important, and we need more of that research.”