An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors

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SUMMARY Cancer vaccines hold promise as immunotherapy due to strong and durable cancer-specific immune responses. Different types of cancer vaccines have been developed, including DNA/RNA-based, protein/peptide-based, dendritic cell-, and whole cell-based vaccines. Allogeneic tumor cell vaccines are limited by the variability in HLA-restricted cellular responses they elicit, typically not matching the HLA alleles of the patient’s tumor, which reduce vaccine efficacy. Autologous cellular vaccines require costly personalized manufacturing. Thus, there remains an urgent and unmet need for new treatment regimens with greater impact on long-term survival. To address the need for new immunotherapeutic approaches to treat advanced solid tumors, BriaCell Therapeutics is developing a novel whole-cell immunotherapeutic approach that acts through two complementary mechanisms of action: 1) cross-presentation of cancer cell antigens and 2) direct T cell activation. This dual mechanism of action is considered unique and represents a significant advance over previous attempts to develop whole-cell cancer vaccines. Enhanced clinical response via direct T cell activation is achieved when a patient’s HLA molecules match those in the therapeutic cell line. Our first-generation Bria- IMT product has demonstrated substantial tumor regression in patients with metastatic breast cancer who match Bria-IMT with at least one HLA allele. Bria-IMT is a breast cancer cell line (SV-BR-1-GM) that secretes granulocyte-macrophage colony-stimulating factor and functions as an antigen-presenting cell (APC) and is able to directly activate CD4+ T cells. We completed a molecular analysis of SV-BR-1-GM cells by microarray gene expression profiling and identified a distinctive 22-gene immune signature consisting of HLA molecules, cytokines, and chemokines. Based on this unique immune signature, BriaCell has selected additional cell lines of different origins in addition to breast cancer: melanoma, prostate, and lung cancers, and will engineer cell lines that express a defined set of cytokines and co-stimulatory molecules as well as a discrete collection of HLA alleles that, collectively, will have the potential to treat almost 100% of the US population at the level of one HLA class I or II allele match with 90% matching at 2 HLA alleles. These cells (termed Bria-OTS, for “off-the-shelf”) will be used as a pre-manufactured and ready-to-use personalized immunotherapy for the treatment of advanced solid tumors. The goal of this Phase I proposal is to generate a collection of melanoma, breast, prostate, and lung cancer Bria-OTS cell lines that will match at least one HLA locus of the US population to cover a large proportion of cancer patients in dire need of an effective therapy. In addition to cell line engineering (Aim 1), this project will validate preclinical activity using cell-based assays to demonstrate the functionality of the Bria-OTS cells (Aim 2). Following a successful Phase I proposal, the novel cell lines will advance to IND enabling studies and subsequent first-in-human clinical trials.