Dataset Information

Chimeric antigen receptor T-cell therapy targeting a MAGE A4 peptide and HLA-A*02:01 complex for unresectable advanced or recurrent solid cancer: protocol for a multi-institutional phase 1 clinical trial.

ABSTRACT:

Introduction

Adoptive cell transfer of genetically engineered T cells is a promising treatment for malignancies; however, there are few ideal cancer antigens expressed on the cell surface, and the development of chimeric antigen receptor T cells (CAR-T cells) for solid tumour treatment has been slow. CAR-T cells, which recognise major histocompatibility complex and peptide complexes presented on the cell surface, can be used to target not only cell surface antigens but also intracellular antigens. We have developed a CAR-T-cell product that recognises the complex of HLA-A*02:01 and an epitope of the MAGE-A4 antigen equipped with a novel signalling domain of human GITR (investigational product code: MU-MA402C) based on preclinical studies.

Methods and analysis

This is a dose-escalation, multi-institutional, phase 1 study to evaluate the tolerability and safety of MU-MA402C for patients with MAGE A4-positive and HLA-A*02:01-positive unresectable advanced or recurrent solid cancer. Two dose cohorts are planned: cohort 1, MU-MA402C 2×10⁸/person; cohort 2, MU-MA402C 2×10⁹/person. Prior to CAR-T-cell infusion, cyclophosphamide (CPA) and fludarabine (FLU) will be administered as preconditioning chemotherapy. Three evaluable subjects per cohort, for a total of 6 subjects (maximum of 12 subjects), will be recruited for this clinical trial. The primary endpoints are safety and tolerability. The severity of each adverse event will be evaluated in accordance with Common Terminology Criteria for Adverse Events V.5.0. The secondary endpoint is efficacy. Antitumour response will be evaluated according to Response Evaluation Criteria in Solid Tumours V.1.1.

Ethics and dissemination

This clinical trial will be conducted in accordance with the current version of Good Clinical Practice. The protocol was approved by the Clinical Research Ethics Review Committee of Mie University Hospital (approval number F-2021-017). The trial results will be published in peer-reviewed journals and/or disseminated through international conferences.

Trial registration number

jRCT2043210077.

SUBMITTER: Okumura S

PROVIDER: S-EPMC9664294 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Chimeric antigen receptor T-cell therapy targeting a MAGE A4 peptide and HLA-A*02:01 complex for unresectable advanced or recurrent solid cancer: protocol for a multi-institutional phase 1 clinical trial.

Okumura Satoshi S Ishihara Mikiya M Kiyota Naomi N Yakushijin Kimikazu K Takada Kohichi K Kobayashi Shinichiro S Ikeda Hiroaki H Endo Makoto M Kato Koji K Kitano Shigehisa S Matsumine Akihiko A Nagata Yasuhiro Y Kageyama Shinichi S Shiraishi Taizo T Yamada Tomomi T Horibe Keizo K Takesako Kazuto K Miwa Hiroshi H Watanabe Takashi T Miyahara Yoshihiro Y Shiku Hiroshi H

BMJ open 20221114 11

<h4>Introduction</h4>Adoptive cell transfer of genetically engineered T cells is a promising treatment for malignancies; however, there are few ideal cancer antigens expressed on the cell surface, and the development of chimeric antigen receptor T cells (CAR-T cells) for solid tumour treatment has been slow. CAR-T cells, which recognise major histocompatibility complex and peptide complexes presented on the cell surface, can be used to target not only cell surface antigens but also intracellular ...[more]

PMID: 36375974

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Project description:Afamitresgene autoleucel, an HLA-restricted autologous specific peptide enhanced affinity receptor (SPEAR) T-cell therapy targeting MAGE-A4, was developed to treat HLA-A*02 positive patients with MAGE-A4 expressing solid tumors. A multicenter, dose-escalation, Phase 1 trial (NCT03132922) was conducted evaluating afamitresgene autoleucel in patients with relapsed or refractory (≥1 prior line of therapy) metastatic solid tumors. The primary endpoint was safety. The secondary endpoint was anti-tumor activity including overall response rate, best overall response, time to response, duration of response, duration of stable disease, progression-free survival and overall survival. Thirty-eight patients were treated with afamitresgene autoleucel across 9 tumor types, including 16 with synovial sarcoma (SS). Overall, afamitresgene autoleucel was well tolerated. The most common adverse events were cytopenias. Cytokine release syndrome occurred in 55% of all patients with severity grade ≤2 in 90% of reported cases. Overall response rate (ORR) was 24% and disease control rate (DCR) was 74% with objective responses in 7 patients with SS, 1 patient with non-small cell lung cancer, and 1 patient with head and neck squamous cell carcinoma. ORR in patients with SS, all prior treated with ifosfamide chemotherapy, was 44%, and DCR was 94%. Median progression-free survival and overall survival were 20.4 weeks (95% CI: 10.0, 52.1) and 58.1 weeks (95% CI: 36.3,-), respectively, for patients with SS and 12.3 weeks (95% CI: 10.857, 19.1) and 42.9 weeks (95% CI: 20.7, -), respectively, for the overall population. Translational findings demonstrated that afamitresgene autoleucel infiltrates into tumors, has an IFNγ-driven mechanism-of-action, and triggers adaptive immune responses. Overall, afamitresgene autoleucel has an acceptable safety profile with early and durable responses in HLA-A*02 positive patients with MAGE-A4 expressing solid tumors, especially in patients with metastatic SS. The recommended treatment regimen for Phase 2 evaluation involves lymphodepleting chemotherapy consisting of cyclophosphamide 600 mg/m2 x 3 days and fludarabine 30 mg/m2 x 4 days followed by afamitresgene autoleucel at a dose range of 1 to 10 billion transduced T-cells.

Dataset Information

Chimeric antigen receptor T-cell therapy targeting a MAGE A4 peptide and HLA-A*02:01 complex for unresectable advanced or recurrent solid cancer: protocol for a multi-institutional phase 1 clinical trial.

Introduction

Methods and analysis

Ethics and dissemination

Trial registration number

Publications

Chimeric antigen receptor T-cell therapy targeting a MAGE A4 peptide and HLA-A*02:01 complex for unresectable advanced or recurrent solid cancer: protocol for a multi-institutional phase 1 clinical trial.

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