Abstract 2327: Same day transduction and in vivo expansion of chimeric antigen receptors and synthetic driver constructs for adoptive cellular therapy

Abstract

Abstract Adoptive cellular therapy (ACT) using ex vivo expanded chimeric antigen receptor (CAR) modified T cells to target cancer cells expressing CD19 has been very successful in the treatment of hematologic malignancies and the clinical application of this technology for solid tumor malignancies is a major focus of several research and development programs. Despite the clinical success of these products, there are several obstacles that currently limit widespread deployment of CAR-T. Current autologous CAR-T manufacturing approaches are complex, requiring centralized manufacturing facilities and extensive logistical control over the receipt and delivery of individually patient matched products. Several weeks are required to prepare and release CAR-T cells using current manufacturing processes from apheresis to genetic modification and expansion before the cell product is reinfused into the patient. However, recent studies suggest that limiting the ex vivo expansion time results in less differentiated CAR-T products with enhanced effector function. Successful engraftment and persistence for current autologous CAR-T cell products require the depletion of normal lymphocytes in patients with cytotoxic drugs (primarily cyclophosphamide, fludarabine or combinations) prior to administration of CAR-T cells. Although the use of non-myeloablative lymphodepleting regimens prior to CAR-T infusion significantly enhances the successful in vivo homeostatic expansion and persistence of administered CAR-T cells, non-myeloablative chemotherapy also requires significant supportive care. The development of a point of care approach to ACT has the potential to reduce the complexity of CAR T-cell immunotherapy and broaden access to a substantially greater number of cancer patients and address many of the limitations discussed above. The most ideal system would allow for rapid genetic modification of patient’s cells next to the patient, thereby eliminating chain of custody risks, combined with successful in vivo expansion and engraftment of cells in the patient to achieve therapeutic cellular levels without preconditioning through lymphodepletion. Here we describe and provide data demonstrating initial proof of concept for a novel point of care approach for CAR-T using engineered lentivirus vectors and resting human PBMC. Resting human PBMC were isolated from blood and successfully transduced within a four hour exposure to engineered lentivirus particles encoding a synthetic lymphoproliferative element. These modified cells expanded in vivo upon administration in mice. The entire process of PBMC isolation, genetic modification and dosing was completed within twelve hours vein to vein and represents a significant step forward in advancing the development of CAR-T therapies with point of care potential expanding upon patient accessibility and deployment. Citation Format: Frederic Vigant, Jianfang Hu, Laurence Jadin, Benjamin Lopez, Tiffany Lam, Hiba Shaban, Anirban Kundu, Timothy Mayall, Gregory Schreiber, Farzad Haerizadeh, James Onuffer, Gregory Frost. Same day transduction and in vivo expansion of chimeric antigen receptors and synthetic driver constructs for adoptive cellular therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2327.