Expanding The Therapeutic Potential Of Anti-Pd-1 And Anti-Ctla-4 Therapy With Innovative Fc Engineering And Rationale Combinations For The Treatment Of Solid Tumors

Immune checkpoint blockade (ICB) of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) have shown durable responses in cancer patients. However, responses have been limited to a small subset of patients, and resistance to ICB therapy continues to be a limiting factor to achieving broad and more durable clinical benefit. Considering the emerging hallmarks of response to ICB, we investigated how response to anti-PD-1 and anti-CTLA-4 therapy could be improved through antibody engineering and combination with other therapeutic approaches such as with novel immune checkpoint inhibitors (e.g. TIGIT, LAG-3), adoptive T cell therapy (ACT), cancer vaccines or focal radiation. In preclinical studies, we demonstrated that anti-CTLA-4 antibodies engineered to selectively enhance binding to human FcyRIIIA or mouse FcyRIV, respectively, significantly improve T cell effector function and tumor clearance in preclinical models that are known to have high immunogenicity and responsiveness to ICB single therapy such as MC-38 and CT-26. To identify novel T cell-intrinsic resistance mechanisms to current ICB therapies, we emulated a progressive anti-PD-1 refractory state in primary CD4- and CD8-positive NY-ESO-1 TCR-transduced T cells upon repeat co-culture with an antigen-expressing glioblastoma cell line. In this model, the addition of anti-CTLA-4, anti-LAG-3, or anti-TIGIT enhanced T cell cytotoxicity and killing of tumor target cells. Gene expression signatures associated with the anti-PD-1 refractory state in this system predicted anti-PD-1 response in melanoma patients. Combination therapy with anti-PD-1 was further validated in a PD-1 refractory mouse syngeneic tumor models demonstrating improved tumor control. Finally, to further address resistance mechanisms to ICB therapy, we evaluated the combination potential of anti-PD-1 and Fc-engineered anti-CTLA-4 with tumor targeted therapies in syngeneic tumor models such as B16 melanoma which are resistant to co-blockade of PD-1 and CTLA-4. In these studies, anti-PD-1 and Fc-engineered anti-CTLA-4, promoted significantly improved tumor control when combined together or with CD4 or CD8 ACT, low dose focal radiation (10 Gy), or an antigen-specific heat shock protein-based (HSC70) cancer vaccine as compared to either therapy alone. Our preclinical data suggest that the limited activity of anti-PD-1 can be addressed by combining with a Fc engineered anti-CTLA4 antibody or with select novel ICB. Furthermore, we have demonstrated that PD1-CTLA4 activity could be further improved when combined with conventional focal radiation or other immune-modulating targeted therapies such as ACT or vaccines to significantly enhance tumor antigenicity and overcome resistance to conventional ICB. Citation Format: Antoine J. Tanne, Sylvia Vincent, Benjamin Duckless, Elena Paltrinieri, Simarjot Pabla, Andrew Basinski, Sudesh Pawaria, Vidur Patel, Margaret Wilkens, Bishnu Joshi, Matthew Hancock, Daniel Levey, Thomas Horn, Cailin Joyce, David Savitsky, Cori Gorman, Jennifer Buell, Dhan Chand. Expanding the therapeutic potential of anti-PD-1 and anti-CTLA-4 therapy with innovative Fc engineering and rationale combinations for the treatment of solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 922.