An Off-the-Shelf tumor cell vaccine with HLA-matching alleles for personalized treatment of advanced metastatic prostate cancer.

Briacell Therapeutics Corp, Philadelphia PA

Investigators

Abstract

SUMMARY Cancer vaccines have been shown capable of inducing strong and durable cancer-specific immune responses. Different types of cancer vaccines have been developed, including DNA/RNA-based, protein/peptide-based, dendritic cell-based, and whole cancer cell-based vaccines (allogeneic or autologous). 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, whereas autologous cellular vaccines entail costly personalized manufacturing. Thus, there remains an urgent and unmet need for new treatment regimens with greater impact on long-term survival. BriaCell Therapeutics is developing a novel whole-cell immunotherapeutic approach that acts through two complementary mechanisms of action that are unique and represent a significant advance over previous attempts to develop whole-cell cancer vaccines: 1) cross-presentation of cancer cell antigens and 2) direct immune cell activation. Our first-generation Bria-IMT product, a breast cancer cell line (SV-BR-1-GM) that secretes granulocyte-macrophage colony-stimulating factor (GM-CSF), functions as an antigen-presenting cell (APC), and activates CD4+ T cells, has demonstrated substantial tumor regression in patients with metastatic breast cancer, especially those who match Bria-IMT at two HLA alleles. Partially funded by a Phase I award, 1R43CA281555-01-A1, we have developed second- generation Bria-OTS+ cells as a personalized “off-the-shelf” cancer vaccine, consisting of engineered cancer 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. We generated and functionally validated four unique prostate (PC3) Bria-PROS+ cell lines (Bria-PROS1+, Bria-PROS2+, Bria-PROS3+, and Bria-PROS4+), each expressing two HLA-A and two HLA-DRB alleles. In addition, we also developed and characterized four unique breast cancer (SV-BR-1) Bria-OTS+ cell lines and are in the final stages of development and functionally characterizing two additional Bria-OTS+ collections for the treatment of melanoma (SK-MEL-24) and lung cancer (NCI-H2228). This Phase II renewal application will complete cGMP manufacture and Chemistry, Manufacture and Controls (CMC) characterization of all four Bria-PROS+ cell lines (Aim 1), followed by a Phase 1/2a study of HLA-matched cellular immunotherapy in patients with advanced metastatic prostate cancer (Aim 2). Patients will be treated with up to 5 escalating doses of Bria-PROS+ cells (5 to 60 M cells). Once safety has been established, patients will continue being dosed every three weeks for up to 20 cycles, and efficacy will be assessed by tumor responses (RECIST criteria), tumor markers, progression-free and overall survival, immune responses, patient and tumor characteristics, and quality of life.