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
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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.
REFERENCES
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.
