Abstract 6753: Bria-OTS immunotherapy platform: Harnessing gene-modified tumor cells to reinvigorate the cancer immunity cycle for precision anti-tumor responses
Authors: Lopez-Lago Miguel A. , Bhardwaj Vikas , Kesarwani Pravin , Zheng Xiaoyi , Pachhal Sagarika , Cournoo Patience , Cortez Renee , Wiseman Charles L. , Williams William V. 
Published: March 2024

Background: For an immune response to lead to an effective anti-tumor response, a series of stepwise events involving a complex network of iterative cellular and molecular interactions must take place. Cancer, however, often derails this immune cycle, prompting contemporary cancer immunotherapy approaches to seek its reinstatement. Despite significant advances, the inherent disruption of the cancer immunity cycle at multiple junctures, coupled with current therapeutic strategies focusing on isolated stages within this intricate process, has left the attainment of curative therapies as an aspirational goal. We believe that targeting multiple immune processes can restore natural anti-cancer immunity and yield sustained responses. To this end, BriaCell is utilizing gene-modified tumor cells as an immunotherapeutic platform. Our initial version, SV-BR-1-GM, a breast cancer cell line expressing GM-CSF, demonstrates promising clinical outcomes by directly activating CD4+ T-cells in an antigen-specific, HLA-restricted manner. Building on our findings, we hypothesize that tumor cells not only supply antigens but also directly stimulate the immune system. Presenting our second-generation platform, we enhance antigen cross-presentation and direct immune activation through the expression of cytokines, co-stimulatory factors, and HLA alleles.

Methods: To achieve this objective, we have developed Bria-OTS cell lines derived from various cancer types with the following genetic modifications: 1) Expression of costimulatory molecules (CD80, CD86, 4-1BBL, CD40) and immunomodulatory cytokines (GM-CSF, IFNα, IL-12 and IL-7). This modification aims to improve the cell's ability to present antigens and activate the host immune system. 2) Expanding HLA alleles to create semi-allogeneic cell lines matching at least one HLA allele across the population aims to enhance the host immune response, enabling recognition of tumor-associated antigens in the context of syngeneic HLA molecules

Results: We generated four cell lines for each tumor type, and these cell lines secreted GM-CSF, IFNα, IL12 & IL7, while also expressing CD80, CD86, CD40, and different combinations of both Class I and Class II HLA alleles. In functional assays, our cell lines demonstrated potent antigen presentation, effectively triggering anti-tumor immune responses across diverse immune populations, including T-, NK, and NKT cells.

Conclusions: The Bria-OTS cell lines will offer the following key features: 1) multimodal mechanisms of action including thwarting some mechanisms of cancer immune escape. 2) Precision Therapy; Bria-OTS will be precisely matched to individual patients based on their HLA alleles, encompassing over 99% of the U.S. population. 3) rapid, cost-effective treatment as our 'off-the-shelf' cell lines eliminate the need for personalized manufacturing.

Citation Format: Miguel A. Lopez-Lago, Vikas Bhardwaj, Pravin Kesarwani, Xiaoyi Zheng, Sagarika Pachhal, Patience Cournoo, Renee Cortez, Charles L. Wiseman, William V. Williams. Bria-OTS immunotherapy platform: Harnessing gene-modified tumor cells to reinvigorate the cancer immunity cycle for precision anti-tumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6753.