Recent Study Findings in CAR T-Cell Therapy for Neoplastic Malignancies

Get Permission

Here is an update on two recent clinical trials focusing on chimeric antigen receptor (CAR) T-cell therapy for neoplastic malignancies. Highlighted are the findings from an early-phase study in refractory aggressive lymphoma and a study in chronic lymphocytic leukemia after failure of ibrutinib (Imbruvica).

Diffuse Large B-Cell Lymphoma

Study: Phase I ZUMA-1 trial, a multicenter study of KTE-C19 anti-CD19 CAR T-cell therapy in refractory aggressive lymphoma1

Key Findings: In the ZUMA-1 study, the investigators evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory diffuse large B-cell lymphoma (DLBCL). Patients received low-dose lymphodepleting conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days followed by KTE-C19 at a target dose of 2 × 106 CAR T cells/kg. The incidence of dose-limiting toxicity was the primary endpoint.

Seven patients were treated with KTE-C19, and one patient experienced a dose-limiting toxicity of grade 4 cytokine-release syndrome and neurotoxicity. Grade ≥ 3 cytokine-release syndrome and neurotoxicity were observed in 14% (n = 1 of 7) and 57% (n = 4 of 7) of patients, respectively. All other KTE-C19–related grade ≥ 3 events resolved within 1 month after administration.

The overall response rate was 71% (n = 5 of 7), and the complete response rate was 57% (n = 4 of 7). Three patients have an ongoing complete response (all at 12+ months). CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with an ongoing complete response. This regimen of KTE-C19 was safe for further study in phase II trial and induced durable remissions in patients with refractory DLBCL.

Clinical Implications: Despite the small numbers in this study, the overall and complete response rates were high and durable relative to historical controls. The durable efficacy of the KTE-C19 regimen was observed in patients with rigorously defined chemotherapy-refractory disease who had no viable treatment options. This multicenter study validated that centralized manufacturing is feasible and established the logistics for transportation of patient-specific product door to door within approximately 2 weeks. The results of this phase I study have led to the initiation of the pivotal ZUMA-1 phase II registration trial.

Chronic Lymphocytic Leukemia

Study: Durable molecular remissions in chronic lymphocytic leukemia (CLL) treated with CD19-specific CAR-modified T cells after failure of ibrutinib2

Key Findings: The investigators evaluated the safety and feasibility of anti-CD19 CAR-modified T-cell therapy in patients with CLL who had previously received ibrutinib. Twenty-four patients with CLL received lymphodepleting chemotherapy and anti-CD19 CAR T cells at one of three dose levels (2 × 105, 2 × 106, or 2 × 107 CAR T cells/kg). A total of 19 patients experienced disease progression while receiving ibrutinib, 3 were ibrutinib-intolerant, and 2 did not experience disease progression while receiving ibrutinib. Six patients were venetoclax (Venclexta)-refractory, and 23 had a complex karyotype and/or 17p deletion.

The durable efficacy of the KTE-C19 regimen was observed in patients with rigorously defined chemotherapy-refractory disease who had no viable treatment options.
— Syed A. Abutalib, MD

Tweet this quote

Four weeks after CAR T-cell infusion, the overall response rate (complete response and/or partial response) by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria was 71% (17 of 24 patients). A total of 20 patients (83%) developed cytokine-release syndrome, and 8 (33%) developed neurotoxicity, which was reversible in all but 1 patient with a fatal outcome. Of the 24 patients, 20 received cyclophosphamide and fludarabine lymphodepletion and CD19 CAR T cells at or below the maximum tolerated dose (≤ 2 × 106 CAR T cells/kg). In 19 of these patients who were restaged, the overall response rate by IWCLL imaging criteria 4 weeks after infusion was 74% (complete response, 4 of 19, 21%; partial response, 10 of 19, 53%), and 15 of 17 patients (88%) with marrow disease before CAR T cells had no disease by flow cytometry after CAR T cells. Twelve of these patients underwent deep immunoglobulin heavy chain gene (IGH) sequencing, and 7 (58%) had no malignant IGH sequences detected in marrow.

The absence of the malignant IGH clone in marrow of patients with CLL who responded by IWCLL criteria was associated with 100% progression-free and overall survival (overall survival; median 6.6 months of follow-up) after CAR T-cell immunotherapy. The progression-free survival was similar in patients with lymph node partial response or complete response by IWCLL criteria. CD19 CAR T cells are highly effective with manageable toxicity in patients with high-risk CLL, including those whose disease is refractory to ibrutinib.

Clinical Implications: This approach can achieve sustained molecular remissions and improve the poor prognosis of ibrutinib-refractory CLL. Of note, although bone marrow disease was highly responsive to CAR T cells, complete elimination of bulky nodal disease was less common, suggesting the malignant lymph node environment may impair CAR T-cell infiltration and/or function. The nodal and molecular complete response rates in advanced CLL might be improved if CAR T-cell immunotherapy is delivered when ibrutinib-induced mobilization of lymph node disease into the blood and/or marrow is still effective and before development of bulky lymphadenopathy. Such a strategy might be used by monitoring patients receiving ibrutinib for increasing prevalence of ibrutinib-resistance mutations. Future studies in patients who are likely to become refractory to ibrutinib on the basis of high-risk cytogenetics or early detection of mutations before relapse that confer ibrutinib resistance are warranted.■

Dr. Abutalib is Assistant Director in the Stem Cell Transplant & Cell Therapy Program at Cancer Treatment Centers of America in Chicago.

DISCLOSURE: Dr. Abutalib reported no conflicts of interest.


1. Locke FL, Neelapu SS, Bartlett NL, et al: Phase 1 results of ZUMA-1: A multicenter study of KTE-C19 Anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther 25:285-295, 2017.

2. Turtle CJ, Hay KA, Hanafi LA, et al: Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol 35:3010-3020, 2017.




By continuing to browse this site you permit us and our partners to place identification cookies on your browser and agree to our use of cookies to identify you for marketing. Read our Privacy Policy to learn more.