Antitransgene Rejection Responses Contribute to Attenuated Persistence of Adoptively Transferred CD20/CD19-Specific Chimeric Antigen Receptor Redirected T Cells in Humans

• Published in: Biology of blood and marrow transplantation Vol. 16; no. 9; pp. 1245 - 1256
• Main Authors: Jensen, Michael C., Popplewell, Leslie, Cooper, Laurence J., DiGiusto, David, Kalos, Michael, Ostberg, Julie R., Forman, Stephen J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2010
• Subjects: Adoptive therapy; Adoptive Transfer - methods; Antigens, CD19 - biosynthesis; Antigens, CD19 - genetics; Antigens, CD19 - immunology; Antigens, CD20 - biosynthesis; Antigens, CD20 - genetics; Antigens, CD20 - immunology; Cellular immunotherapy; Clinical trial; Hematology, Oncology and Palliative Medicine; Humans; Immune Tolerance; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - therapy; Lymphoma, Follicular - immunology; Lymphoma, Follicular - therapy; Lymphoma, Large B-Cell, Diffuse - immunology; Lymphoma, Large B-Cell, Diffuse - therapy; Receptors, Antigen, T-Cell - biosynthesis; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; T lymphocyte; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - physiology; T-Lymphocytes, Cytotoxic - transplantation; Transfection; Transgenes - immunology; Clinical trial; Cellular immunotherapy; T lymphocyte; Adoptive therapy
• ISSN: 1083-8791; 1523-6536; 1523-6536
• DOI: 10.1016/j.bbmt.2010.03.014

Immunotherapeutic ablation of lymphoma is a conceptually attractive treatment strategy that is the subject of intense translational research. Cytotoxic T lymphocytes (CTLs) that are genetically modified to express CD19- or CD20-specific, single-chain antibody–derived chimeric antigen receptors (CARs) display HLA-independent antigen-specific recognition/killing of lymphoma targets. Here, we describe our initial experience in applying CAR-redirected autologous CTL adoptive therapy to patients with recurrent lymphoma. Using plasmid vector electrotransfer/drug selection systems, cloned and polyclonal CAR + CTLs were generated from autologous peripheral blood mononuclear cells and expanded in vitro to cell numbers sufficient for clinical use. In 2 FDA-authorized trials, patients with recurrent diffuse large cell lymphoma were treated with cloned CD8 + CTLs expressing a CD20-specific CAR (along with NeoR) after autologous hematopoietic stem cell transplantation, and patients with refractory follicular lymphoma were treated with polyclonal T cell preparations expressing a CD19-specific CAR (along with HyTK, a fusion of hygromycin resistance and HSV-1 thymidine kinase suicide genes) and low-dose s.c. recombinant human interleukin-2. A total of 15 infusions were administered (5 at 10 8cells/m 2, 7 at 10 9cells/m 2, and 3 at 2 × 10 9cells/m 2) to 4 patients. Overt toxicities attributable to CTL administration were not observed; however, detection of transferred CTLs in the circulation, as measured by quantitative polymerase chain reaction, was short (24 hours to 7 days), and cellular antitransgene immune rejection responses were noted in 2 patients. These studies reveal the primary barrier to therapeutic efficacy is limited persistence, and provide the rationale to prospectively define T cell populations intrinsically programmed for survival after adoptive transfer and to modulate the immune status of recipients to prevent/delay antitransgene rejection responses.