Core B Summary Core B comprises two interrelated laboratories: the Clinical Cell and Vaccine Production Facility (CVPF), a GMP- compliant cell manufacturing facility, and an associated Antibody Development Laboratory (ADL) that is devoted to the discovery and design of novel CAR-T constructs for use by P01-proposed projects. The CVPF is a Foundation for the Accreditation of Cellular Therapy (FACT)-accredited facility and is the only GMP-compliant cell manufacturing facility on the University of Pennsylvania campus providing the university community with integrated scientific, technical, and regulatory expertise to support manufacturing of biologics for in-human Phase I and II clinical trials. The ADL is new to this P01 renewal application and will support the three scientific projects by developing novel chimeric antigen receptor binding domains to complement those that are currently available to the projects. Core B has four specific aims. In Aim 1, the CVPF will support Project 1 by providing 3-day manufacturing, validation, and cryopreservation of CRISPR-mediated knockout of CD5 in CD19-directed CAR- T cells for use in a clinical trial for relapsed/refractory CLL and NHL patients. In Aim 2, the CVPF will support Project 2 by manufacturing, validating, and cryopreserving CD45 base-edited CD34+ hematopoietic stem cells and CD45-directed CAR-T cells for use in a clinical trial for AML patients. In Aim 3, the CVPF will support Project 3 by manufacturing, validating, and cryopreserving BCMA-directed CAR-T cells from marrow infiltrating lymphocytes (MILs) for comparison with conventional peripheral blood-derived BCMA-directed CAR-T cells produced in parallel for use in a clinical trial for multiple myeloma patients. In Aim 4, the ADL will use antibody phage display technology to construct and screen libraries derived from llamas immunized with CD5, CD45, and BCMA in order to isolate single-domain VHH antibody fragments optimized with respect to affinity and other desired functional properties as needed for use in Projects 1, 2, and 3.