Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40

Abstract

Purpose Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to impact patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T cell costimulatory receptors such as OX40 remains a critical question. Experimental Design We utilized an anti-PD-1 refractory, orthotopically-transplanted MMTV-PyMT mammary cancer model to investigate the anti-tumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. Since PD-1 naturally aids in immune contraction after T cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 followed by anti-PD-1. Results The concurrent addition of anti-PD-1 significantly attenuated the therapeutic effect of anti-OX40 alone. Combination-treated mice had considerable increases in type 1 and type 2 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+ T cell proliferation at day 13, but at day 19 both CD4+ and CD8+ T cell proliferation was significantly reduced compared to untreated mice. In two tumor models, sequential combination of anti-OX40 followed by anti-PD-1 (but not the reverse order) resulted in significant increases in therapeutic efficacy. Against MMTV-PyMT tumors sequential combination was dependent on both CD4+ and CD8+ T cells and completely regressed tumors in ~30% of treated animals. Conclusions 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.

OX40 triggering concomitant to IL12-engineered cell vaccine hampers the immunoprevention of HER2/neu-driven mammary carcinogenesis

“…30 Combining immunomodulating strategies could increase the proportion of responders, provided that the optimal timing of combination is choosen. 31 , 32 Our study shows that when combining OX40 engagement with an adjuvanted cancer vaccine opposite results can be obtained depending on timing of OX40 triggering. OX40 is therefore emerging as a relevant tuning molecule that might make the difference in combination therapies in either a positive or negative way.…”

“…OX40 is therefore emerging as a relevant tuning molecule that might make the difference in combination therapies in either a positive or negative way. 32 , 33 The negative interference observed with OX40 triggering concomitant with cancer vaccine suggests that preclinical models should be thoroughly interrogated before planning clinical trials of combined approaches.…”

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

“…Two different studies reported that the concurrent addition of a-PD-1 mAb markedly reduced the therapeutic response of a-OX40 mAb. 23 Further, another study that tested the combination of a-4-1BB and a-PD-1 antibodies in a murine spontaneous B-cell lymphoma model found that simultaneous use of a-PD-1 mAb diminished the antitumor activity of a-4-1BB mAb alone. 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.…”

“…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.…”

Stimulating T Cells Against Cancer With Agonist Immunostimulatory Monoclonal Antibodies

“…For example, in preclinical studies, OX40 stimulation has been demonstrated to enhance antitumor effects when combined with multiple therapeutic strategies including cytokines (Redmond, Triplett et al., 2012, Ruby, Montler et al, 2008), adjuvants (Gough, Crittenden et al., 2010, Houot and Levy, 2009, Voo, Foglietta et al, 2014), vaccinations (Murata, Ladle et al, 2006), chemotherapy (Hirschhorn-Cymerman, Rizzuto et al, 2009), or radiotherapy (Young, Baird et al., 2016). In addition, anti-OX40 antibodies have been combined with immunomodulatory antibodies against other costimulatory receptors (Lee, Myers et al, 2004, Morales-Kastresana, Sanmamed et al, 2013, Pan, Zang et al, 2002), or blocking coinhibitory pathways (Linch, Kasiewicz et al, 2016, Messenheimer, Jensen et al, 2017, Redmond, Linch et al, 2014) to treat lymphomas, sarcomas, colon metastases, and spontaneous hepatocellular carcinoma.…”