Timing, Sequence Critical for Efficacy of Combination Immunotherapy Treatment

Surabhi Dangi-Garimella, PhD

A research study conducted in a mouse mammary cancer model has found that optimal timing, based on sequencing of immunotherapy agents, is important for treatment efficacy.
For their study, the authors used an anti–programmed death-1 (PD-1)–refractory orthotopic mammary cancer model to investigate the antitumor effect of an anti-OX40 antibody in combination with an anti–PD-1 agent. OX40 is a T-cell costimulatory receptor that can be targeted to prevent primary and secondary resistance to immune checkpoint blockade. In this study, published in Clinical Cancer Research, the authors observed the impact of concurrent versus sequential treatment with anti-OX40 followed by anti–PD-1.
According to James Gulley, MD, PhD, physicians are currently struggling with identifying ways to achieve durable and rapid responses with immunotherapy agents and to broaden the number of patients who have outstanding responses. Tumors of nonresponders have the ability to counteract the immune response induced by the drug: “With a single immunotherapy, the tumor can find a way to shut down the antitumor immune response,” Gulley said in a statement.
Combining the anti–PD-1 agent with anti-OX40 significantly attenuated the effect of the OX40 inhibitor, the authors found. Further, simultaneous administration of the 2 agents resulted in a considerable increase in serum cytokines, which resembled cytokine release syndrome (CRS). CRS can lead to side effects such as low blood pressure, fever, nausea, and rash. Additionally, the concurrent administration also increased the expression of inhibitory receptors or exhaustion markers, CTLA-4 and TIM-3, on T cells. T-cell proliferation was reduced in mice that were simultaneously administered the combination, compared with untreated mice.
However, when administered sequentially, treating mice with an OX40 inhibitor followed by a PD-1 inhibitor was more successful and resulted in complete tumor regression in 30% of treated animals. Additionally, survival doubled in mice who were administered the drugs in a sequential manner, compared with mice who were administered the OX40 inhibitor alone. Interestingly, administering the PD-1 inhibitor first, followed by the OX40 inhibitor was not successful in slowing down tumor growth.
“These results highlight the importance of timing for optimized therapeutic effect with combination immunotherapies and suggest the testing of sequencing in combination immunotherapy clinical trials,” the authors concluded.
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