Abstract A61: Engineered antigen presenting T cells for treatment of solid tumor cancers

Abstract

Ex vivo manipulation of primary cells has shown immense clinical potential with the advent of adoptive T cell therapies to stimulate CD8 cytotoxic T lymphocyte (CTL) responses for the treatment of cancer. CTLs stimulated by tumor-associated antigens can target and clear solid tumors, however ex vivo manipulation methods for adoptive T cell transfer can be prohibitively time intensive. SQZ’s approach harnesses the endogenous T cell expansion mechanisms stimulated by antigen presentation to produce a relevant CTL dose. Previous efforts using antigen presenting cells (APCs) to induce this response have failed due to the difficulty inherent in delivering antigen to the APC cytosol, a necessary step for CTL activation. Within an APC, antigen location in the cytosol or endosome dictates how antigens are processed, presented, and the resultant adaptive immune system reaction. For an effective CTL response the antigens must be presented on MHC class I (MHC-I) molecules, which only occurs for antigens located in the cytosol. Antigen delivery methods, such as endocytosis, electroporation, and nanoparticle-based systems, can result in low efficiency, accumulation of material in endosomal compartments, cytotoxicity, and/or off-target effects. Furthermore, these processes are not amenable to scalable deployment, limiting the number of patients able to be treated. To circumvent such issues, we can achieve direct delivery of antigens into the APC cytosol with CellSqueeze®, resulting in MHC-I antigen presentation and effective stimulation of CTL activity. CellSqueeze® is a vector-free microfluidic platform that causes temporary membrane disruption by rapid mechanical deformation, enabling delivery of cell-engineering materials to diffuse into the cytosol without disrupting normal cell function. The CellSqueeze® platform, developed at MIT, has demonstrated efficacious delivery of various challenging materials, such as peptides and proteins, to patient-derived cells including stem cells and primary immune cells. We are developing our platform to employ primary human T cells as APCs. Previous CTL stimulation efforts have attempted to deliver antigenic material to dendritic cells (DCs); however, they are much less numerous in the blood and differentiation from monocytes is time consuming. This work uses primary human T cells, which are highly abundant in the blood, as APCs. We have demonstrated that delivery of antigenic material to T cells with the CellSqueeze® technology effectively enables the T cell to present the antigen to stimulate a targeted CTL response. In vitro we have demonstrated effective CTL activation using human T cells as APCs. In vivo we have demonstrated effective prophylactic and therapeutic treatment of murine tumors using CellSqueeze®-processed murine T cells in combination with multiple adjuvant strategies. We have also been investigating checkpoint inhibitors in combination with our T cell APCs. We believe that the unique ability to deliver molecules directly to the cytosol of T cells, as well as multiple other cell types, will enable a new paradigm in cellular therapy for multiple cancer types. Citation Format: LeeAnn Talarico, Ildefonso Vicente-Suarez, Katarina Blagovic, Eritza Chong-Ng, Lauren Jones, Lucas Pomerance, Howard Bernstein. Engineered antigen presenting T cells for treatment of solid tumor cancers [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A61.