Nonviral RNA chimeric antigen receptor–modified T cells in patients with Hodgkin lymphoma

• Published in: Blood 2018-09, Vol.132 (10), p.1022-1026
• Main Authors: Svoboda, Jakub, Rheingold, Susan R., Gill, Saar I., Grupp, Stephan A., Lacey, Simon F., Kulikovskaya, Irina, Suhoski, Megan M., Melenhorst, J. Joseph, Loudon, Brandon, Mato, Anthony R., Nasta, Sunita Dwivedy, Landsburg, Daniel J., Youngman, Matthew R., Levine, Bruce L., Porter, David L., June, Carl H., Schuster, Stephen J.
• Format: Article
• Language: English
• Subjects: Adult; Female; Gene Transfer Techniques; Hodgkin Disease - genetics; Hodgkin Disease - immunology; Hodgkin Disease - therapy; Humans; Immunotherapy, Adoptive; Male; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - immunology; T-Lymphocytes - metabolism; Tumor Microenvironment - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-03-837609

Chimeric antigen receptor (CAR)–modified T cells are being investigated in many settings, including classical Hodgkin lymphoma (cHL). The unique biology of cHL, characterized by scant Hodgkin and Reed-Sternberg (HRS) cells within an immunosuppressive tumor microenvironment (TME), may pose challenges for cellular therapies directly targeting antigens expressed on HRS cells. We hypothesized that eradicating CD19+ B cells within the TME and the putative circulating CD19+ HRS clonotypic cells using anti-CD19–directed CAR-modified T cells (CART19) may indirectly affect HRS cells, which do not express CD19. Here we describe our pilot trial using CART19 in patients with relapsed or refractory cHL. To limit potential toxicities, we used nonviral RNA CART19 cells, which are expected to express CAR protein for only a few days, as opposed to CART19 generated by viral vector transduction, which expand in vivo and retain CAR expression. All 5 enrolled patients underwent successful manufacturing of nonviral RNA CART19, and 4 were infused with protocol-specified cell dose. There were no severe toxicities. Responses were seen, but these were transient. To our knowledge, this is the first CART19 clinical trial to use nonviral RNA gene delivery. This trial was registered at www.clinicaltrials.gov as #NCT02277522 (adult) and #NCT02624258 (pediatric). •Manufacturing CART19 by transfecting autologous T cells with messenger RNA is feasible.•Targeting CD19+ B cells in cHL using nonviral RNA CART19 was well tolerated and resulted in transient responses in a pilot study. [Display omitted]