Abstract B70: Modification of hematopoietic stem cells with CD19-specific chimeric antigen receptors as a novel approach for cancer immunotherapy

Abstract

Abstract Pediatric patients with recurrent B-lineage hematological malignancies have less than 50% of chance of cure, despite intensive therapy. Chimeric Antigen Receptors (CARs) redirect immune cells to tumor-associated antigens. CD19 is proposed as target because its B-lineage restriction and expression in the majority of hematological malignancies. Current clinical trials use CD19-specific CAR-modified T-cells, but the effector cells are only transiently present. The main hypothesis is that modification of hematopoietic stem cells (HSCs) with anti-CD19 CAR will generate persistent anti-leukemic activity through production of multilineage effectors. Gene transfer did not impair HSC differentiation and proliferation when transduced at 1-2 copies/cell. CAR-bearing myeloid and NK cells specifically lysed CD19-positive targets, with second-generation CAR including CD28 domains being more efficient in NK cells. CAR-modified human HSCs engrafted in NSG mice, producing functional cell progenies. Furthermore, ex vivo leukocytes presented antigen-specific target lysis, and animals engrafted with CAR-modified cells presented inhibition or elimination of CD19-positive tumors, and consequent survival advantage. First-generation CAR did not present tumor development inhibition or survival advantage when compared to non-modified HSCs, confirming that the addition of co-stimulatory moieties to the CAR construct is necessary for effectiveness. This approach is untested in cancer immunotherapy, implies the use of a patient's own cells, and can be applied to different cancers just by adjusting the target specificity. It bears the possibility of decreased morbidity and mortality, being desirable for vulnerable populations such as children, and offers alternative treatment for patients with no available HLA-matched sources for bone marrow transplantation, benefiting ethnic minorities. Citation Format: Satiro N. De Oliveira, Christine Ryan, Jennifer Wherley, Andy Tu, David Elashoff, Laurence JN Cooper, Roger P. Hollis, Donald B. Kohn. Modification of hematopoietic stem cells with CD19-specific chimeric antigen receptors as a novel approach for cancer immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B70.