222. AST-VAC2: An Embryonic Stem Cell-Derived Dendritic Cell Cancer Immunotherapy

Abstract

AST-VAC2 is a cancer immunotherapy product comprising embryonic stem cell-derived dendritic cells electroporated with an mRNA encoding a telomerase/lysosome-associated membrane protein 1 (LAMP hTERT) chimeric tumor antigen. Previous studies have shown that AST-VAC2 can elicit a telomerase-specific T-cell response from partially HLA-matched donor peripheral blood mononuclear cells. A related product (AST-VAC1), an autologous dendritic cell/LAMP hTERT cancer immunotherapy, has been tested in clinical trials on patients with prostate cancer or acute myeloid leukemia. The AST-VAC1 treatment was well tolerated and generated anti-telomerase immune responses. AST-VAC2 is being developed as an off-the-shelf allogeneic cancer vaccine for clinical testing in partially HLA matched patients with non-small cell lung carcinoma. The AST-VAC2 product is derived from the H1 human embryonic stem cell line. The stem cells are differentiated into mature dendritic cells in a multi-step process via embryoid bodies, prepared growth surfaces and specific growth factors. The differentiation process requires 34 days in culture. The cells are then electroporated with the LAMP hTERT mRNA and irradiated prior to cryopreservation. In preparation for clinical testing the manufacturing process has been scaled up from T-flasks to large surface area cell stacks. This has required a number of novel process modifications including large scale embryoid body filtration and flow-through electroporation. The final product will be rendered incapable of replication by gamma irradiation. The radiation dose required for halting replication while still preserving antigen presentation was determined using a combination colony formation/potency assay. It is anticipated that the proposed Phase 1/2a clinical trial will enroll approximately 30 patients and will include both a dose escalation and a broadening of inclusion criteria to permit an assessment of safety, toxicity and immunogenicity in patients with advanced disease. Asterias has recently partnered with Cancer Research United Kingdom (CRUK) and the University of Southampton for the GMP manufacturing and initial clinical testing of AST-VAC2 in the UK.