Simplified concept of CTLA-4 and PD-1 immune checkpoints.  [P. Momtaz, M.A. Postow/Pharmgenomics Pers Med (2014), NIH]
Simplified concept of CTLA-4 and PD-1 immune checkpoints. [P. Momtaz, M.A. Postow/Pharmgenomics Pers Med (2014), NIH]

Recent advances in immunotherapy have given many cancer patients stricken with tumors intractable to current therapies hope for meaningful remission times. While researchers continue to try and understand the intricacies of the immune system’s response to carcinogenesis, many clinicians are looking for combinations of immunotherapy compounds to provide an even greater response to cancer suppression. However, now two independent studies led by investigators at the Georgia Cancer Center and the Earle A. Chiles Research Institute show that the concurrent administration of the T-cell-stimulating anti-OX40 antibody and the immune checkpoint inhibitor anti-programmed cell death protein 1 (anti-PD1) antibody attenuated the effect of anti-OX40 and resulted in poor treatment outcomes in mice.

Findings from the two studies were released today in Clinical Cancer Research in an article entitled “Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40” and Cancer Immunology Research in an article entitled “Concurrent PD-1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T-Cell Apoptosis.”

“While immune checkpoint inhibitors, such as anti-PD1 and anti-CTLA4, are already in clinics and are used mainly as single agents, there are currently almost a thousand clinical trials that are testing a combination of anti-PD1 with other therapies,” noted senior study investigator of the Cancer Immunology Research article Samir Khleif, M.D., professor and distinguished scientist and clinician at the Georgia Cancer Center. The investigators from the two studies wanted to test whether a combination of anti-OX40 and anti-PD1 could produce outcomes that are better than either treatment alone.

For the Clinical Cancer Research study, researchers found that simultaneous treatment of mice bearing tumors that are refractory to anti-PD1 with anti-OX40 and anti-PD1 immunotherapies suppressed the therapeutic effect of anti-OX40 antibody, produced a cytokine storm–like event that made the mice lethargic, resulted in enlargement of their spleens, and led to an increase in the levels of the immune checkpoint proteins cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) on T cells.

“The complexity of combination immunotherapy is enormous, because there are potentially many different ways it could work,” explained senior study investigator of the Clinical Cancer Research study Bernard Fox, Ph.D., who is chair for cancer research at the Providence Cancer Center and chief of the laboratory of molecular and tumor immunology at the Earle A. Chiles Research Institute in Portland, OR. “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.”

Additionally, in the study published in Cancer Immunology Research, investigators found that in tumor-bearing mice, 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. They found that the detrimental effect of the combination was a result of the induction of antigen-specific T-cell death—or apoptosis.

“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,” Dr. Fox noted. Adding that it is critical for more effort be invested in evaluating the contribution of each agent administered to patients in clinical trials.

The study by Dr. Fox and his team also showed that sequential treatment with anti-OX40 followed by anti-PD1 (but not in reverse order) significantly improved the therapeutic efficacy of the combination, resulting in delayed tumor progression, including complete regression of tumors in about 30% of the mice—an unprecedented finding for human breast cancer.

Given that the majority of patients do not respond to anti-PD1 therapies, the researchers used a mouse model that is refractory to anti-PD1 to study if stimulating the T cells with anti-OX40 would make PD-1 blockade effective in an anti-PD1 refractory population.

“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,” Dr. Khleif stated. “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.”

Dr. Khleif and his team found that the therapeutic efficacy of continuous treatment with anti-OX40 with delayed addition of anti-PD1 was not superior to the outcomes with continuous anti-OX40 alone.

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

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