HOW TO COMBINE OX-40 AND PD1 BASED IMMUNOTHERAPY

Although the potential for immunotherapy to improve outcomes for patients with cancer, particularly through a combination of agents targeting immune inhibitory pathways, is becoming increasingly evident, how to optimally combine the many new immunotherapy agents being developed remains a major question in cancer research. Now, two laboratory studies investigating the potential therapeutic and immune effects of the concurrent administration of the T-cell–stimulating anti-OX40 antibody and the immune checkpoint inhibitor anti–programmed cell death protein 1 (PD-1) antibody has found that the simultaneous addition of anti–PD-1 to anti-OX40 negated the antitumor effects of OX40 antibody and resulted in poor treatment outcomes in mice.

One study by Shrimali et al was published in Cancer Immunology Research. The second laboratory study by Messenheimer et al, which was published in Clinical Cancer Research, also found that the combination-treated mice had considerable cytokine storm–like events, which led to an increase in the levels of the immune checkpoint proteins cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and TIM-3 on T cells.

Studies’ Methodologies

In the study published in Cancer Immunology Research, the researchers used the tumor cell (TC)-1 syngeneic mouse model to evaluate the antitumor therapeutic response of the anti-OX40 agonist antibody. Because the TC-1 model requires a vaccine to generate an effector immune response, the researchers first combined the anti-OX40 with an HPV16 E7 peptide vaccine.

In the study published in Clinical Cancer Research, the researchers utilized an anti–PD-1–refractory, orthotopically transplanted MMTV-PyMT mammary cancer model to investigate the antitumor effect of an agonist anti-OX40 antibody combined with anti–PD-1. Since PD-1 naturally aids in immune contraction after T-cell activation, the researchers treated the mice with concurrent combination treatment vs the sequential administration of anti-OX40 followed by anti–PD-1.

Results and Conclusions

In the study published in Clinical Cancer Research, the researchers found that the concurrent addition of anti–PD-1 significantly attenuated the therapeutic effect of anti-OX40 alone. Combination-treated mice had considerable increases in type I and type II serum cytokines and significantly augmented expression of inhibitory receptors or exhaustion markers CTLA-4 and TIM-3 on T cells.

Combination treatment increased intratumoral CD4-positive T-cell proliferation at day 13, but at day 19, both CD4-positive and CD8-positive T-cell proliferation was significantly reduced compared with untreated mice. In two tumor models, the sequential combination of anti-OX40 followed by anti–PD-1 (but not in the reverse order) resulted in significant increases in therapeutic efficacy. Against MMTV-PyMT tumors, the sequential combination was dependent on both CD4-positive and CD8-positive T cells and completely regressed tumors in approximately 30% of treated animals.

“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,” concluded the study authors.

In the study published in Cancer Immunology Research, the researchers tested the antitumor effects of different treatment sequencing of the combination antibody to PD-1 with agonist antibody to OX40/vaccine. They found that the simultaneous addition of anti–PD-1 to anti-OX40 negated the antitumor effects of OX40 antibody. Antigen-specific CD8-positive T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival was reduced.

Although the researchers observed an increase in interferon gamma–producing E7-specific CD8-positive T cells in the spleens of mice treated with the combination of PD-1 blockade with anti-OX40/vaccine, these cells underwent apoptosis both in the periphery and in the tumor. The researchers concluded that the results indicated anti–PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist antibody.

“These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic,” concluded the study authors.

Samir N. Khleif, MD, of the Georgia Cancer Center at Augusta University, is the corresponding author of the Cancer Immunology Research study.

Bernard A. Fox, PhD, of the Earle A. Chiles Research Institute in Portland, Oregon, is the corresponding author of the Clinical Cancer Research study.

HOW TO COMBINE