Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas

Abstract

BACKGROUND Patients with diffuse large B-cell lymphoma or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have been reported with the use of T cells modified by chimeric antigen receptor (CAR) that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited. METHODS We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments. Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CTL019 cells in vivo, and immune recovery. RESULTS A total of 28 adult patients with lymphoma received CTL019 cells, and 18 of 28 had a response (64%; 95% confidence interval [CI], 44 to 81). Complete remission occurred in 6 of 14 patients with diffuse large B-cell lymphoma (43%; 95% CI, 18 to 71) and 10 of 14 patients with follicular lymphoma (71%; 95% CI, 42 to 92). CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow of patients who had a response and patients who did not have a response. Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86% of patients with diffuse large B-cell lymphoma who had a response (95% CI, 33 to 98) and 89% of patients with follicular lymphoma who had a response (95% CI, 43 to 98) had maintained the response. Severe cytokine-release syndrome occurred in 5 patients (18%). Serious encephalopathy occurred in 3 patients (11%); 2 cases were self-limiting and 1 case was fatal. All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction, with a sustained reappearance of B cells in 8 of 16 patients and with improvement in levels of IgG in 4 of 10 patients and of IgM in 6 of 10 patients at 6 months or later and in levels of IgA in 3 of 10 patients at 18 months or later. CONCLUSIONS CTL019 cells can be effective in the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. High rates of durable remission were observed, with recovery of B cells and immunoglobulins in some patients. Transient encephalopathy developed in approximately one in three patients and severe cytokine-release syndrome developed in one in five patients. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02030834.)

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

“…1-4 However, long-term immune surveillance can be further improved, as sometimes only temporary responses and delayed progression is observed. Improved clinical efficacy of adoptive T cell therapy could be reached by generating tumor-specific T cell products with an early differentiation state, as they show superior longevity and proliferative capacity.…”

“…1-4 Different strategies are applied to generate T cells for infusion, including the expansion of tumor-infiltrating lymphocytes (TIL), genetic modification of T cells with a tumor-reactive T cell receptor (TCR) or chimeric antigen receptor (CAR), or expansion of tumor-reactive T cells from the naïve repertoire. Since the success of adoptive T cell therapy is associated with infusion of a high cell number, 5 all strategies include ex vivo activation and expansion.…”

The efficacy of anti-CD19 chimeric antigen receptor T cells for B-cell malignancies

“…There was significant heterogeneity among the studies with an I 2 of 64, Q = 36 ( Figure 3). For lymphoma, RR of 68% [7,17,42,43,49]. There was significant heterogeneity among studies with an I 2 of 83, Q = 23 ( Figure 3).…”

Immunotherapy: Pancreatic Cancer and Extrahepatic Biliary Tract Cancer

“…Adoptive T-cell therapy has demonstrated impressive results in hematological B cell malignancies like B cell lymphoma [46-49] and acute lymphoblastic leukemia [46, 50]. …”