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Chimeric antigen receptor (CAR) T-cell therapy as a treatment option for patients with B-cell lymphomas: perspectives on the therapeutic potential of Axicabtagene ciloleucel.

ABSTRACT: Axicabtagene lisoleucel (Axi-cel) is the second approved gene-alterating cancer treatment and the first in aggressive lymphoma using the "chimeric antigen receptor" (CAR) technology. T-cells from patients were transfected with CARs and reinfused after a lymphodepleting chemotherapy. CAR T-cells are "living drugs" with the ability to persist and expand after a single infusion. Axi-cel is a "second generation" CAR product characterized by the use of a retroviral gene vector transfer and by CD28 as costimulatory domain. In a phase II trial with heavily pretreated patients with aggressive B-cell lymphoma, the overall response rate was 82% with an ongoing complete response rate of 40% after 6 months - with expectations of long-term remissions and cure, even though follow-up data are still limited. There are some prominent side effects like cytokine release syndrome (Grade 3-5: 13%) and neurotoxicity (Grade 3-5: 28%). Novel strategies for prediction, prevention and treatment of these critical side effects are warranted. There are new concepts to enhance the efficacy and prevent resistance in lymphomas. CAR T-cells represent an extremely evolving field with an inestimable potential in general and particularly in aggressive lymphoma. However, we are still learning how to use Axi-cel and other CAR-T cells compounds effectively to optimize the long-term results.

SUBMITTER: Viardot A

PROVIDER: S-EPMC6489634 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Chimeric antigen receptor (CAR) T-cell therapy as a treatment option for patients with B-cell lymphomas: perspectives on the therapeutic potential of Axicabtagene ciloleucel.

Viardot Andreas A Wais Verena V Sala Elisa E Koerper Sixten S

Cancer management and research 20190325

Axicabtagene lisoleucel (Axi-cel) is the second approved gene-alterating cancer treatment and the first in aggressive lymphoma using the "chimeric antigen receptor" (CAR) technology. T-cells from patients were transfected with CARs and reinfused after a lymphodepleting chemotherapy. CAR T-cells are "living drugs" with the ability to persist and expand after a single infusion. Axi-cel is a "second generation" CAR product characterized by the use of a retroviral gene vector transfer and by CD28 as ...[more]

PMID: 31114317

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Project description:BackgroundIn a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.MethodsIn this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.ResultsAmong the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.ConclusionsIn this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).

Project description:Axicabtagene ciloleucel is the first U.S. Food and Drug Administration-approved autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for the treatment of patients with relapsed or refractory large B-cell lymphoma after ≥2 prior systemic therapies. Although axicabtagene ciloleucel is administered only at authorized treatment centers, community oncologists play a critical role in the CAR T-cell treatment journey, recognizing potentially eligible patients for referral and then, after treatment, closely collaborating with treatment centers to monitor and manage patients long term. ZUMA-1, the pivotal, multicenter, phase I/II study of 108 patients treated with axicabtagene ciloleucel, resulted in an objective response rate of 83%, including 58% complete responses. With a 27.1-month median follow-up, 39% of patients had ongoing responses. CAR T-cell therapy is associated with the potentially life-threatening adverse events (AEs) of cytokine release syndrome and neurologic events, which generally occur early after treatment. In ZUMA-1, cytokine release syndrome and neurologic events were generally reversible and grade ≥3 cytokine release syndrome and neurologic events occurred in 11% and 32% of patients, respectively. Frequent prolonged AEs included hypogammaglobulinemia, B-cell aplasia, and cytopenias requiring supportive care until recovery of hematopoietic function. Rate of treatment-related mortality was low, at <2%. With appropriate management of common AEs, axicabtagene ciloleucel offers the potential for long-term durable responses in patients who otherwise lack curative treatment options. IMPLICATIONS FOR PRACTICE: Community oncologists should be familiar with key aspects of chimeric antigen receptor (CAR) T-cell indications and eligibility to help recognize and refer potential patients for this paradigm-changing treatment option at the appropriate time during the disease course. To ensure optimal long-term outcomes for patients who have been treated with CAR T-cell therapy, oncologists must also be familiar with common prolonged AEs and their monitoring and management.

Project description:PurposeAxicabtagene ciloleucel (axi-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Bridging therapy may be required for lymphoma control during the manufacturing interval between collection of autologous T cells and final CAR T product administration. The optimal bridging therapy is not known and patients are often chemorefractory. We present a case series of patients receiving radiation as a bridge to axi-cel.Methods and materialsBetween December 2017 and October 2018, 12 patients were intended to receive bridging radiation before axi-cel. The group was characterized by highly aggressive disease including 6 of 12 with "double hit" lymphoma and 6 of 12 with disease ≥10 cm in diameter. All patients received 2 to 4 Gy/fraction to a median dose of 20 Gy (range, 6-36.5 Gy). Half of patients received either 30 Gy in 10 fractions or 20 Gy in 5 fractions. Seven patients received concurrent chemotherapy. Eleven patients underwent axi-cel infusion and one did not. Median follow-up was 3.3 months (range, 1.1-12.0 months).ResultsNo significant toxicities were identified during bridging radiation, and no patient experienced in-field progression of disease before axi-cel infusion. One patient experienced abdominal pain, which resolved after dose reduction. Two patients had out-of-field progression of disease during the bridging period. After axi-cel infusion, 3 of 11 patients (27%) experienced severe cytokine release syndrome or neurotoxicity. At 30 days, the objective response rate was 81.8% (11 of 12 evaluable; 1 stable disease, 1 out-of-field progression), with complete response in 27% (3 of 11). At last follow-up, the best objective response rate was 81.8%, with a complete response attained in 45% (5 of 11). Lymphocyte counts decreased slightly in 10 of 12 patients during radiation (median, 0.25 k/uL).ConclusionsRadiation (with or without concurrent chemotherapy) can be safely administered as a bridge to axi-cel in high-risk lymphoma. Caution should be taken if irradiation is started before apheresis, and lymphocyte counts should be monitored closely throughout. Future investigation is warranted to optimize the use of bridging radiation before CAR T therapy.

Dataset Information

Chimeric antigen receptor (CAR) T-cell therapy as a treatment option for patients with B-cell lymphomas: perspectives on the therapeutic potential of Axicabtagene ciloleucel.

Publications

Chimeric antigen receptor (CAR) T-cell therapy as a treatment option for patients with B-cell lymphomas: perspectives on the therapeutic potential of Axicabtagene ciloleucel.

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