Cell and Gene Therapy, Clinical Manufacture and Monitoring Core

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CORE A: CELL AND GENE THERAPY CLINICAL MANUFACTURE AND MONITORING CORE Abstract This is the second revision of a Core that was initially reviewed favorably and rated Superior, but then was rated Satisfactory in the Al submission. The Core includes investigators with ample expertise in the regulatory filing and the conduct of investigator-initiated gene and cell therapy clinical trials. Relevant prior clinical trials conducted by Core A investigators include tumor infiltrating lymphocyte (TIL) gene marking using retrovirus, hematopoietic stem cell (HSC) genetic modification using retrovirus, and dendritic cell (DC)-based clinical trials both with tumor antigen peptide pulsing and adenoviral transduction. The generation of cell and gene therapy products is enabled by an existing and fully functional clinical Good Manufacturing Practices (GMP) suite, which includes both positive and negative pressure rooms for cellular and gene therapy product manufacture, respectively. Institutional oversight committees, Compliance Officers and auditors provide the adequate framework for the conduct of such investigator-initiated clinical trials. An important role of the Core is the analysis of immune responses in cancer immunotherapy. The Core has focused on assay standardization, use of quantitative measures and definition of changes from baseline parameters that are beyond the assay variability with high statistical confidence. These modern immune monitoring assays are fully implemented and routine in the Core, including MHC tetramer, ELISPOT, intracellular cytokine staining and intracellular phosphorylated signaling molecule flow cytometry. Based on this expertise, the Core will provide support for all projects of this Program Project Grant (PPG). In Aim 1 the Core will manage the two clinical grade vectors that will b^ used in the clinical trials proposed in Projects 1 and 3. In Aim 2 the Core will manufacture the cellular therapy products for the clinical trials proposed in Projects 1 and 3, including the genetically modified peripheral blood mononuclear cells (PBMC) and HSC. In Aim 3 the Core provides expertise in immune monitoring assays for all of this PPG. In this revised application we have detailed the information on the lot release testing of TCR transgenic cells, and we provide evidence that we can routinely gate and detect both CDS and CD4 cells expressing TCRs and intracellular staining for cytokine production using multicolor flow cytometry.