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Regimen-specific effects of RNA-modified chimeric antigen receptor T cells in mice with advanced leukemia.

ABSTRACT: Cytotoxic T lymphocytes modified with chimeric antigen receptors (CARs) for adoptive immunotherapy of hematologic malignancies have demonstrated activity in early phase clinical trials. While T cells bearing stably expressed CARs are efficacious and have potential long-term persistence, temporary expression of a CAR via RNA electroporation is also potentially efficacious in preclinical models. Temporary CAR expression using RNA presents a method of testing CARs clinically with additional safety where there may be concerns about possible chronic "on-target, off-tumor" toxic effects, as the degradation of RNA ensures complete removal of the CAR over time without relying on suicide induction systems. CD19-directed RNA CAR T cells were tested in vivo for efficacy and comparison to lentiviral vector (LV)-generated stable CAR T cells. We tested the hypothesis that multiple infusions of RNA CAR T cells preceded by lymphodepleting chemotherapy could mediate improved survival and sustained antitumor responses in a robust leukemia xenograft model. The saturation strategy using rationally designed multiple infusions of RNA CARs based on multiple model iterations approached the efficacy of a stable LV expression method. Two-color imaging revealed that relapse was a locoregional phenomenon in both the temporary and the stable expression models. In marked contrast to stably expressed CARs with retroviral or LV technology, the efficacy of RNA CARs appears independent of the costimulatory signaling endodomains likely because they more influence proliferation and persistence rather than short-term efficacy. The efficacy of the RNA CAR infusions may approach that of stably expressed CARs, offer theoretically safer initial clinical testing in addition to suicide systems, and allow for rapid and effective iterative preclinical modeling for the testing of new targets.

SUBMITTER: Barrett DM

PROVIDER: S-EPMC3746289 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Regimen-specific effects of RNA-modified chimeric antigen receptor T cells in mice with advanced leukemia.

Barrett David M DM Liu Xiaojun X Jiang Shuguang S June Carl H CH Grupp Stephan A SA Zhao Yangbing Y

Human gene therapy 20130801 8

Cytotoxic T lymphocytes modified with chimeric antigen receptors (CARs) for adoptive immunotherapy of hematologic malignancies have demonstrated activity in early phase clinical trials. While T cells bearing stably expressed CARs are efficacious and have potential long-term persistence, temporary expression of a CAR via RNA electroporation is also potentially efficacious in preclinical models. Temporary CAR expression using RNA presents a method of testing CARs clinically with additional safety ...[more]

PMID: 23883116

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Project description:Purpose We evaluated the safety and feasibility of anti-CD19 chimeric antigen receptor-modified T (CAR-T) cell therapy in patients with chronic lymphocytic leukemia (CLL) who had previously received ibrutinib. Methods 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). Nineteen patients experienced disease progression while receiving ibrutinib, three were ibrutinib intolerant, and two did not experience progression while receiving ibrutinib. Six patients were venetoclax refractory, and 23 had a complex karyotype and/or 17p deletion. Results Four weeks after CAR-T cell infusion, the overall response rate (complete response [CR] and/or partial response [PR]) by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria was 71% (17 of 24). Twenty patients (83%) developed cytokine release syndrome, and eight (33%) developed neurotoxicity, which was reversible in all but one patient with a fatal outcome. Twenty of 24 patients 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% (CR, 4/19, 21%; PR, 10/19, 53%), and 15/17 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 IGH sequencing, and seven (58%) had no malignant IGH sequences detected in marrow. Absence of the malignant IGH clone in marrow of patients with CLL who responded by IWCLL criteria was associated with 100% progression-free survival and overall survival (median 6.6 months follow-up) after CAR-T cell immunotherapy. The progression-free survival was similar in patients with lymph node PR or CR by IWCLL criteria. Conclusion CD19 CAR-T cells are highly effective in high-risk patients with CLL after they experience treatment failure with ibrutinib therapy.

Dataset Information

Regimen-specific effects of RNA-modified chimeric antigen receptor T cells in mice with advanced leukemia.

Publications

Regimen-specific effects of RNA-modified chimeric antigen receptor T cells in mice with advanced leukemia.

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