Timing and Sequencing of Immunotherapies May Be Critical to Therapeutic Efficacy

October 2, 2017
John Schieszer

Concurrent administration of the T-cell stimulating anti-OX40 antibody and an anti-PD1 antibody attenuated the effect of anti-OX40 in mice, prompting researchers to take a closer look at how sequencing of therapies can affect outcome.

It may be time to take a closer look at combination immunotherapies and the importance of timing and sequencing of individual immunotherapies for optimized therapeutic effect. A study recently published in Clinical Cancer Research has found that concurrent administration of the T-cell stimulating anti-OX40 antibody and the immune checkpoint inhibitor anti-PD1 antibody attenuated the effect of anti-OX40 and resulted in poor treatment outcomes in mice.

The researchers found that concurrent treatment with anti-OX40 and anti-PD1 immunotherapies suppressed the therapeutic effect of anti-OX40 antibody. In addition, it produced a cytokine storm-like event that made the mice lethargic and resulted in enlargement of their spleens. It also led to an increase in the levels of the immune checkpoint proteins CTLA-4 and TIM-3 on T cells.

In another study published in Cancer Immunology Research, researchers 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.

Bernard Fox, PhD, chair for cancer research at Providence Cancer Center and chief of the Laboratory of Molecular and Tumor Immunology at the Earle A. Chiles Research Institute in Portland, Oregon, said it is important to look at checkpoint inhibitors and what happens when they are combined with other immunotherapies. He said trials that are only looking at toxicity and clinical response may not be adequate.

“Given that there are almost 900 combination immunotherapy trials enrolling patients, there is a need to prioritize patient accrual to trials that are not ‘black box’ trials,” Dr. Fox told OncoTherapy Network. “In our opinion, priority should be given to phase I and II trials that are closely monitoring biomarkers that are relevant to the proposed mechanism of action of the drugs under investigation.”

The study by Dr. Fox and colleagues showed that sequential treatment with anti-OX40 followed by anti-PD1 (but not in reverse order) significantly improved the therapeutic efficacy of the combination. It resulted in delayed tumor progression, including complete regression of tumors in about 30% of the mice. This is unprecedented in this model of human breast cancer, according to Dr. Fox.

He said treating patients with anti-OX40 followed by anti-PD1 should be evaluated because 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.

Currently, Dr. Fox and his team are planning a clinical trial in which women with triple-negative breast cancer will receive a vaccine prior to receiving anti-OX40 therapy. The patients will be randomly assigned to anti-PD1 or nothing after anti-OX40 administration. The investigators plan to study whether anti-OX40 alone or anti-OX40 plus anti-PD1 increases the tumor-reactive T-cell clones and the extent of antibody responses against a wide spectrum of tumor antigens.