Transient TCR-based T cell therapy in a patient with advanced treatment-resistant MSI-high colorectal cancer.

Autor:	Maggadottir SM; Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway; Landspitali University Hospital, Reykjavik, Iceland., Dueland S; Department of Oncology, Oslo University Hospital, Oslo, Norway., Mensali N; Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Hamre H; Department of Oncology, Akershus University Hospital, Lørenskog, Norway., Andresen PA; Department of Pathology, Oslo University Hospital, Oslo, Norway., Myhre MR; Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Juul HV; Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Bigalke I; Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Lundby M; Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Hønnåshagen TK; Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Sæbøe-Larssen S; Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Josefsen D; Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Hagtvedt T; Department of Radiology, Oslo University Hospital, Oslo, Norway., Wälchli S; Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Kvalheim G; Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Inderberg EM; Translational Research Unit, Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway. Electronic address: elsin@rr-research.no.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Jun 05; Vol. 32 (6), pp. 2021-2029. Date of Electronic Publication: 2024 Apr 06.
DOI:	10.1016/j.ymthe.2024.04.009
Abstrakt:	We previously demonstrated the antitumor effectiveness of transiently T cell receptor (TCR)-redirected T cells recognizing a frameshift mutation in transforming growth factor beta receptor 2. We here describe a clinical protocol using mRNA TCR-modified T cells to treat a patient with progressive, treatment-resistant metastatic microsatellite instability-high (MSI-H) colorectal cancer. Following 12 escalating doses of autologous T cells electroporated with in-vitro-transcribed Radium-1 TCR mRNA, we assessed T cell cytotoxicity, phenotype, and cytokine production. Tumor markers and growth on computed tomography scans were evaluated and immune cell tumor infiltrate at diagnosis assessed. At diagnosis, tumor-infiltrating CD8+ T cells had minimal expression of exhaustion markers, except for PD-1. Injected Radium-1 T cells were mainly naive and effector memory T cells with low expression of exhaustion markers, except for TIGIT. We confirmed cytotoxicity of transfected Radium-1 T cells against target cells and found key cytokines involved in tumor metastasis, growth, and angiogenesis to fluctuate during treatment. The treatment was well tolerated, and despite his advanced cancer, the patient obtained a stable disease with 6 months survival post-treatment. We conclude that treatment of metastatic MSI-H colorectal cancer with autologous T cells electroporated with Radium-1 TCR mRNA is feasible, safe, and well tolerated and that it warrants further investigation in a phase 1/2 study. Competing Interests: Declaration of interests G.K., S.W., and E.M.I. are inventors of intellectual property (WO2017194555). (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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