Abstract 685: Engineering semi-allogeneic whole cancer vaccines with enhanced immunogenicity for the treatment of advanced solid tumors
Authors: Lopez-Lago Miguel A. , Bhardwaj Vikas , Zheng Xiaoyi , pachhal Sagarika , Cortez Renee , Wiseman Charles , Williams William 
Published: April 2023

Abstract
Background: Therapeutic cancer vaccines are designed to program a patient’s own immune system to recognize and eliminate tumor cells. We sought to harness gene-modified tumor cells as a vaccine platform and developed cancer vaccines composed of breast cancer cells expressing GM-CSF (SV-BR-1-GM). We have recently reported favorable clinical outcomes in patient populations that match SV-BR-1-GM at one or more HLA alleles. Mechanistically, SV-BR-1-GM cells can directly activate CD4+ T-cells in an antigen-specific HLA-restricted manner, as demonstrated by an in vitro antigen presentation assay (1). All these observations led us to hypothesize that semi-allogeneic cell-based cancer vaccines (partially matching host HLA genotype) would mount an enhanced immune response by forcing the host immune response to recognize tumor-associated antigens in the context of allogeneic HLA-I or II molecules or in proximity of strong non-self-antigens. Therefore, steps were taken to generate semi-allogeneic cancer cell lines expressing an extended repertoire of stimulatory molecules to induce optimal immune activation (Bria-OTS).
Methods: SV-BR-1 (Breast cancer), PC-3 (prostate cancer), SK-MEL-24 (Melanoma), and NCI-H2228 (Lung cancer) were selected for vaccine development. To generate semi-allogeneic cell lines matching &gt;99% of the population at least at 1 HLA allele, four cell lines (for each parental tumor cell line) were developed, each carrying two (2) HLA-A and two (2) HLA-DRB3/4/5 alleles, for a total of eight HLA-A and seven HLA-DRB3/4/5 alleles. We transduced selected co-stimulatory molecules and immune-modulatory cytokines. Next, the unique combinations of HLA-A and HLA-DRB3/4/5 alleles were transduced into the cells using lentiviral based vectors. Finally, functionality of the engineered cells was validated by using molecular and cellular based assays.
Preliminary data: Four cell lines (for each tumor type) that secreted GM-CSF, IFNα, IL12, IL7 and expressed CD80, CD86, 4-1BBL, and different combinations of both Class I and Class II HLA alleles were selected. Using cell-based assays - including mixed lymphocyte reaction assays -, we demonstrated that the generated cells stimulate naïve T-cells. Evaluation of the cells ability to present antigens in an HLA-restricted antigen-specific manner is also planned.
Discussion and conclusions: Different types of cancer vaccines have been developed with moderate success, often hampered by lack of strong immunogenicity and complex manufacturing. BriaCell’s Bria OTS provides a solution by increasing vaccine immunogenicity and decreasing manufacturing costs while personalizing the therapy based on matching the patient’s HLA type.1.Lacher MD et al, Front Immunol. 2018 May 15;9:776
Citation Format: Miguel A. Lopez-Lago, Vikas Bhardwaj, Xiaoyi Zheng, Sagarika pachhal, Renee Cortez, Charles Wiseman, William Williams. Engineering semi-allogeneic whole cancer vaccines with enhanced immunogenicity for the treatment of advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 685.