Combination TIGIT blockade with Listeria-based immunotherapy enhances antigen-specific antitumor immunity
Daniel O Villarreal1, Susan Armington1, Andrew L'Huillier1, Cristina Mottershead1, Kimberly Ramos1, Elena V Filippova1, Dipti M Kelkar1, Brandon D Coder1, Robert G. Petit1, Michael F Princiotta1 1Advaxis Immunotherapies, Princeton, NJ, 08540 USA
Tumor progression is facilitated immunologically by mechanisms that include low antigen expression, lack of co-immunostimulatory signals, upregulation of co-inhibitory molecules, and the presence of Treg cells, all contributing to impaired anti-tumor effector T cell function. It may be possible to overcome these conditions by a combination of modulatory immunotherapy agents and tumor-antigen targeting to activate and drive effective T cell responses. TIGIT (T cell immunoreceptor with Ig and ITIM domains) has been described as an inhibitory receptor which blocks CD8+ T cell-mediated anti-tumor immune responses. In addition, modified Listeria monocytogenes (Lm) have been used to develop cancer therapeutic vaccines to express specific tumor-associated antigens to enhance T cell-mediated tumor control. Here, we report that an anti-TIGIT (aTIGIT) mAb can synergize with a Listeria-based immunotherapeutic vaccine (Lm-Vax). We demonstrate that aTIGIT therapy can augment the expansion and function of antigen-specific CD8+ T cells, as evidenced by increased levels of splenic Antigen-specific IFNg ELISpot responses and polyfunctional effector CD8+ T cell responses in a non-tumor bearing model. Consequently, in a tumor-bearing model, the combination Lm-Vax/aTIGIT therapy significantly delayed tumor growth and prolonged mouse survival in the murine CT26 colon carcinoma model as compared to controls and single agents alone. This response was associated with increased expansion and functionality of infiltrating tumor-specific CD8+ T cells and the reduced the frequency of CD4+Foxp3+ regulatory T cells within the tumor microenvironment. These findings support the concept that combining aTIGIT therapy with a Listeria-based immunotherapy may be an effective and promising approach for the treatment of cancer.
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