Agonism of the CD137 co-stimulatory pathway synergizes with the Listeria monocytogenes-based immunotherapy, axalimogene filolisbac, to promote durable tumor regression in a murine HPV+ tumor model
Rachelle E. Kosoff1, Nithya Thambi1, Lauren K. Pettit1, Kimberly Ramos1, Robert G. Petit1, Sandra M. Hayes1* 1Advaxis, Inc. *Corresponding author
Axalimogene filolisbac (AXAL), a live attenuated Listeria monocytogenes (Lm)-basedimmunotherapy targeting the human papillomavirus (HPV) E7 protein, is currently being evaluated as a monotherapy or in combination with co-inhibitory blockade in the treatment of HPV-associated cancers. Because signaling through the CD137 co-stimulatory pathway is essential for immunity to Lm, we hypothesized that agonism of the CD137 pathway would enhance AXAL-mediated tumor control. To test this, HPV+ TC-1 tumor-bearing mice were treated with AXAL in combination with an agonistic anti-CD137 monoclonal antibody (mAb) or with either agent alone. Although treatment with AXAL or anti-CD137 mAb inhibited tumor growth, only treatment with AXAL + anti-CD137 mAb resulted in tumor regression, with 8/10 mice exhibiting complete regression. Tumor regression in mice treated with AXAL + anti-CD137 mAb was associated with increased levels of tumor-infiltrating HPV-E7-specific CD8+ T cells compared to mice treated with either agent alone. To assess the durability of antitumor T cell responses, mice with complete tumor regression after AXAL + anti-CD137 mAb treatment were re-challenged in the opposite flank with HPV+ TC-1 tumor cells 16 weeks after primary tumor implantation. Of the 4 mice re-challenged, all remained tumor-free in both flanks for an additional 6 weeks, the time of study termination. High frequencies of HPV-E7-specific CD8+ T cells were detected in the blood of the 4 mice both before and after re-challenge. To test whether adding a checkpoint inhibitor to the AXAL + anti-CD137 mAb combination further enhances the synergistic antitumor effects of the combination, HPV+ TC-1 tumor-bearing mice were treated with AXAL + anti-CD137 mAb + anti-CTLA4 mAb or with AXAL + anti-CD137 mAb + anti-PD-1 mAb. Unexpectedly, neither of the triple combinations were more effective than AXAL + anti-CD137 mAb at controlling tumor growth or at prolonging animal survival. These preclinical data, demonstrating that AXAL and an agonistic anti-CD137 mAb synergize to provide durable antitumor immunity, support this combination as a potential new therapeutic strategy.
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