Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia
By D. Porter, Wei-Ting Hwang, N. Frey, S. Lacey, Pamela A. Shaw, A. Loren, A. Bagg, K. Marcucci, Angela Shen, V. Gonzalez and 8 more. Science Translational Medicine, 2015
1,615 citations recorded by the source corpus.
CAR T cells persist and sustain remissions in advanced chronic lymphocytic leukemia. CAR T cells for the long haul Immunotherapy is one of the most promising avenues of cancer therapy, with the potential to induce sustained remissions in patients with refractory disease. Studies with chimeric antigen receptor (CAR)–modified T cells have paved the way in patients with relapsed and refractory chronic lymphocytic leukemia. Porter et al. now report the mature results from their initial CAR T cell trial. CAR T cell persistence correlated with clinical responses, and these cells were functional up to 4 years after treatment. No patient who achieved complete remission relapsed, and no minimal residual disease was detected, suggesting that in a subset of patients, CAR T cells may drive disease eradication. 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.
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Citations in the corpus
- FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‐Induced Severe or Life‐Threatening Cytokine Release Syndrome (2018, methodology): “Because the Penn Grading Scale was used for grading CRS in the CTL019 trials and the Lee Grading Scale was used in the KTE-019 trials, the two cohorts were assessed separately.”
- Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management (2018, background): “Toxicities are usually reversible and resolve on their own in most cases, though severe cases may require intensive care [7,9,14,15,20,25,41] and immunosuppressive therapy [7,8,11,25,30,41–43].”
- B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. (2019, methodology): “Expanand was grade 3–4 on the Penn grading scale (16) (Supplemental Table 1) in 8 (32%) subjects, all of whom were treated at the 1 × 108 to 5 × 108 dose.”
- Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor-Modified T Cells After Failure of Ibrutinib. (2017, background): “In a small study, CD19 CAR-T cells induced durable remissions in a subset of patients with CLL, few of whom had previously received ibrutinib.(14,17) Here, we report a high rate of elimination of marrow disease and molecular CR in patients with high-risk ibrutinib-refractory CLL after lymphodepletio”
- Toxicities of chimeric antigen receptor T cells: recognition and management. (2016, positive): “Systemic corticosteroids have been used effectively to abrogate CRSrelated toxicities.(4,6-8,11,54) Some evidence suggests that corticosteroids may inhibit CAR T-cell persistence and antimalignancy efficacy, as reported previously in ALL patients following anti-CD19 CAR T-cell infusion.”