Concurrent PD-1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T-cell Apoptosis

Abstract

Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with immune stimulatory agonist Abs like anti-OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD-1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti-PD-1 to anti-OX40 negated the antitumor effects of OX40 Ab. Antigen-specific CD8 þ T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNgproducing E7-specifc CD8 þ 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 the tumor. These results indicate that anti-PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab. 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.

Cancer Vaccines: Steering T Cells Down the Right Path to Eradicate Tumors

“…Although anti-PD-1 or anti-PD-L1 antibodies are an obvious combination partner for a cancer vaccine, recent preclinical data suggest that optimal sequencing of these therapies may be critical for achieving maximal antitumor activity. In the lymphocytic choriomeningitis virus (LCMV) model, abrogation of the PD-1 pathway led to impaired formation of LCMV-specific memory T cells while the addition of PD-1 inhibition to a regimen of combined OX-40 agonistic and a peptide vaccine in the human papillomavirus-associated tumor model TC-1 compromised efficacy and led to apoptosis of tumor-infiltrating vaccine-specific T cells (43,44). These data indicate that a cancer vaccine may be most effective if administered prior to initiation of PD-1 pathway inhibition.…”

Metabolism and Gut Microbiota in Cancer Immunoediting, CD8/Treg Ratios, Immune Cell Homeostasis, and Cancer (Immuno)Therapy: Concise Review

“…The order of combination of several immunotherapeutic agents also appears to be important, at least in some cases. For instance, in , the authors showed that concurrent administration of immunostimulatory OX40 agonist with a PD‐1 checkpoint inhibitor negated the effects of OX40, causing diminished infiltration of CD8+T cells and an overall lower antitumor immune response. However, sequential combination of the two agents, where OX40 administration was followed by anti‐PD‐1 therapy, but not in the reverse order, resulted in significantly improved therapeutic efficacy .…”

Switching on the green light for chimeric antigen receptor T‐cell therapy

“…22 However, more recently other studies have reported opposing effects. 23,24 Interestingly, however, a study by Messenheimer et al found that when a-OX40 and a-PD-1 antibodies were administered sequentially by treating MMTV-PyMT tumor-bearing mice with a-OX40 mAb before a-PD-1 mAb, the sequential combination therapy resulted in augmented antitumor efficacy. 23,24 Interestingly, however, a study by Messenheimer et al found that when a-OX40 and a-PD-1 antibodies were administered sequentially by treating MMTV-PyMT tumor-bearing mice with a-OX40 mAb before a-PD-1 mAb, the sequential combination therapy resulted in augmented antitumor efficacy.…”

“…Two different studies reported that the concurrent addition of a-PD-1 mAb markedly reduced the therapeutic response of a-OX40 mAb. 23,24 Interestingly, however, a study by Messenheimer et al found that when a-OX40 and a-PD-1 antibodies were administered sequentially by treating MMTV-PyMT tumor-bearing mice with a-OX40 mAb before a-PD-1 mAb, the sequential combination therapy resulted in augmented antitumor efficacy. However, this improved effect was not observed when a-PD-1 mAb was administered before a-OX40 mAb, highlighting the importance of timing and sequence of such treatments.…”