Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia

Abstract

Patients with multiply relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. Chimeric antigen receptor (CAR)–modified T cells targeting CD19 have the potential to improve on the low complete response rates with conventional therapies by inducing sustained remissions in patients with refractory B cell malignancies. We previously reported preliminary results on three patients with refractory CLL. We report the mature results from our initial trial using CAR-modified T cells to treat 14 patients with relapsed and refractory CLL. Autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector were infused into patients with relapsed/refractory CLL at doses of 0.14 × 108 to 11 × 108 CTL019 cells (median, 1.6 × 108 cells). Patients were monitored for toxicity, response, expansion, and persistence of circulating CTL019 T cells. The overall response rate in these heavily pretreated CLL patients was 8 of 14 (57%), with 4 complete remissions (CR) and 4 partial remissions (PR). The in vivo expansion of the CAR T cells correlated with clinical responses, and the CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR. No patient in CR has relapsed. All responding patients developed B cell aplasia and experienced cytokine release syndrome, coincident with T cell proliferation. Minimal residual disease was not detectable in patients who achieved CR, suggesting that disease eradication may be possible in some patients with advanced CLL.

Recent advances in T‐cell immunotherapy for haematological malignancies

“…Recently, the investigators published a detailed follow-up on this study in 14 extensively treated adults (median of 5 prior therapies), observing objective responses in 8, including 4 patients who attained CR with minimal residual disease (MRD) negativity by deep sequencing analyses. (Porter et al 2015) None of the patients with CR relapsed (with a median follow-up of 40 months), although all patients with PRs subsequently progressed. (Porter et al 2015)…”

“…(Porter et al 2015) None of the patients with CR relapsed (with a median follow-up of 40 months), although all patients with PRs subsequently progressed. (Porter et al 2015)…”

CART‐cells merge into the fast lane of cancer care

“…Genetically modified autologous T cells expressing an Anti-CD19 CAR have shown great promise in a number of different clinical trials [1][2][3][4][5][6]. Unprecedented remission rates of 67%-90% have been observed in adult and pediatric patients with relapsed and refractory acute lymphoblastic lymphoma (ALL).…”

“…Remissions have been sustained in many patients without subsequent therapy, a phenomenon often correlating with CAR T-cell persistence [1,3,4]. In other CD191 malignancies including chronic lymphocytic leukemia (CLL) and B cell Non-Hodgkin Lymphomas (NHL), response rates of 50%-80% have been observed even in heavily pretreated and refractory patients [2,6]. Cytokine release syndrome (CRS), an inflammatory process correlating with the in vivo activation and expansion of CD19-CAR T-cells, is the most significant treatment related toxicity.…”

“…Cytokine release syndrome (CRS), an inflammatory process correlating with the in vivo activation and expansion of CD19-CAR T-cells, is the most significant treatment related toxicity. Neurologic toxicity with encephalopathy and seizures is another important side effect [1][2][3][4][5][6]. On target, off tumor effects of CD19-CAR Tcells are fortunately limited to B-cells and B-cell aplasia occurs in patients with CAR T-cell persistence [4,6].…”