Adoptive Cellular Therapy for Follicular Lymphoma Using Genetically-Modified Autologous CD20-Specific T Cells.
Authors: Till Brian G. , Jensen Michael C. , Wang Jinjuan , Chen Eric Y. , James Scott , Raubitschek Andrew , Forman Stephen J. , Gopal Ajay K. , Pagel John M. , Lindgren Catherine G. , Greenberg Philip D. , Riddell Stanley R. , Press Oliver W. 
Published: October 2019

Follicular Lymphoma (FL) is the second most common type of non-Hodgkin’s Lymphoma (NHL) in the United States, accounting for approximately 20% of NHL cases. FL is considered incurable with conventional therapies, and novel therapies are therefore urgently needed. Long-term remissions using allogeneic stem cell transplantation and donor lymphocyte infusion suggest curability using cellular therapy, but these approaches are limited by significant toxicity. We have initiated a pilot Phase I clinical trial testing the feasibility, safety, and toxicity of treating patients with relapsed FL with autologous T lymphocytes that have been genetically modified to express a chimeric antigen receptor (CAR) recognizing the CD20 antigen present on B cell lymphomas. Nine patients have been registered to the protocol to date. Peripheral blood mononuclear cells were obtained from patients by apheresis, activated with anti-CD3 monoclonal antibody (OKT3) and interleukin-2 (IL-2) and transfected by electroporation with a plasmid encoding a CD20-specific scFvFc:ζ CAR as well as a neomycin-resistance selection gene. Transfectants were selected using G418 and expanded ex vivo. For the first 5 patients, cytotoxic CD8+ T cells were cloned by limiting dilution, but this process proved to be laborious and inefficient. Two patients’ clones failed to expand adequately and are off-study, and 2 additional patients received cell doses below the target level. Therefore, subsequent patients underwent oligoclonal expansion of T cells in bulk culture. T cells expressing the CAR and manifesting CD20-specific cytotoxicity were identified by flow cytometry and standard chromium release assays. Patients underwent three infusions of modified T cells at escalating doses (108, 109 and 3.3 × 109 cells/m2) over a period of 7–10 days. The 4 patients who received oligoclonal T cells also received 14 days of low-dose subcutaneous IL-2 injections (500,000 U/m2 twice daily) to prolong in vivo persistence. Seven patients underwent a total of 20 T cell infusions, and no significant toxicities attributable to the T cell infusions were observed. Cellular and immune response assays have not detected any immune responses to the genetically modified T cells in any of the treated patients, although the seventh patient has not yet been evaluated for immune responses. T cells expressing the CAR were detectable in the peripheral blood of patients by PCR for ∼14 days after infusions in the first three patients who received T cell clones, and 4–8 weeks in patients receiving oligoclonal T cells and IL-2 injections. One patient was maintained in complete remission for over a year after T cell infusions, and a second patient achieved a partial remission lasting three months. A third patient had a partial PET response. The remaining 3 patients maintained stable disease for 3–12 months. These results suggest that adoptive cellular therapy with genetically modified CD20-specific T cells is a safe and feasible approach to treating FL that warrants further investigation.