@article{f5e8a29543f1451d93fb1c27093b8af2,
title = "MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial",
abstract = "Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18\%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18\% of patients with dose-dependent {\textquoteleft}on-target, off-tumor{\textquoteright} toxicity and a maximum tolerated dose of 1.0 × 108 cells.",
keywords = "MART-1, T-cell receptor gene therapy, adoptive cell therapy, immunotherapy, melanoma, uveal",
author = "Rohaan, \{M. W.\} and R. Gomez-Eerland and \{van den Berg\}, \{J. H.\} and \{Geukes Foppen\}, \{M. H.\} and \{van Zon\}, M. and B. Raud and I. Jedema and S. Scheij and \{de Boer\}, R. and Bakker, \{N. A. M.\} and \{van den Broek\}, D. and Pronk, \{L. M.\} and Grijpink-Ongering, \{L. G.\} and A. Sari and R. Kessels and \{van den Haak\}, M. and Mallo, \{H. A.\} and M. Karger and \{van de Wiel\}, \{B. A.\} and Zuur, \{C. L.\} and Duinkerken, \{C. W.\} and F. Lalezari and \{van Thienen\}, \{J. V.\} and S. Wilgenhof and Blank, \{C. U.\} and Beijnen, \{J. H.\} and B. Nuijen and Schumacher, \{T. N.\} and Haanen, \{J. B. A. G.\}",
note = "Funding Information: RGE is stockholder in Neogene Therapeutics. JHvdB has received grants from NEON therapeutics, BMS and Medimmune. DvdB declares to have received compensation (paid to the institute) for advisory roles for Roche. CUB received compensation (all paid to the institute except TRV) for advisory roles for Bristol-Myers Squibb, Merck Sharp \& Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, received research funding (all paid to the institute) from Bristol-Myers Squibb, Novartis, NanoString and declares stockownership in Immagene BV, where he is co-founder. JHB is part-time employee and (in)direct stock holder of Modra Pharmaceuticals (small spin off company of the Netherlands Cancer Institute) and (partly) holds a patent on oral taxane formulations, which are clinically developed by Modra Pharmaceuticals. This is not related to the manuscript. TNS is advisor to and stockholder in Allogene Therapeutics, Asher Bio, Merus, Neogene Therapeutics and Scenic Biotech and consultant to Third Rock Ventures. JBAGH received compensation (all paid to the institute except for Neogene Therapeutics) for advisory roles for Achilles Therapeutics, BioNTech, BMS, Gadeta, Immunocore, Instil Bio, Iovance Biotherapeutics, Ipsen, MSD, Merck Serono, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Third Rock Ventures and T-knife, and has received grants (all paid to the institute) from Amgen, Asher Bio, BioNTech, BMS, MSD, Novartis and Neogene Therapeutics. All other authors have declared no conflicts of interest. Funding Information: This work was supported by ZonMw [grant number 431-00-005] and the Dutch Cancer Society (project number AVLZ 2013-5924). Funding Information: The authors thank all co-workers from the Netherlands Cancer Institute for making this trial run successfully. We especially kindly acknowledge the nursing staff and medical team of the nursing ward for excellent patient care and crucial support. Furthermore, we thank the departments of surgery, radiology, pulmonology, dermatology, intensive care unit, clinical laboratory and ophthalmology (external centers) for their clinical expertise and patient care. In addition, the Quality Assurance and Quality Control departments of the Hospital Pharmacy, the Clinical Chemistry Laboratory and Pathology are kindly acknowledged for their generous support. We also thank the Flow Cytometry Facility and Genomic Core Facility for their contributions to this trial. Lastly, we express our appreciation to the blood bank Sanquin for working with us and preserving the material obtained from apheresis. This work was supported by ZonMw [grant number 431-00-005] and the Dutch Cancer Society (project number AVLZ 2013-5924). RGE is stockholder in Neogene Therapeutics. JHvdB has received grants from NEON therapeutics, BMS and Medimmune. DvdB declares to have received compensation (paid to the institute) for advisory roles for Roche. CUB received compensation (all paid to the institute except TRV) for advisory roles for Bristol-Myers Squibb, Merck Sharp \& Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, received research funding (all paid to the institute) from Bristol-Myers Squibb, Novartis, NanoString and declares stockownership in Immagene BV, where he is co-founder. JHB is part-time employee and (in)direct stock holder of Modra Pharmaceuticals (small spin off company of the Netherlands Cancer Institute) and (partly) holds a patent on oral taxane formulations, which are clinically developed by Modra Pharmaceuticals. This is not related to the manuscript. TNS is advisor to and stockholder in Allogene Therapeutics, Asher Bio, Merus, Neogene Therapeutics and Scenic Biotech and consultant to Third Rock Ventures. JBAGH received compensation (all paid to the institute except for Neogene Therapeutics) for advisory roles for Achilles Therapeutics, BioNTech, BMS, Gadeta, Immunocore, Instil Bio, Iovance Biotherapeutics, Ipsen, MSD, Merck Serono, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Third Rock Ventures and T-knife, and has received grants (all paid to the institute) from Amgen, Asher Bio, BioNTech, BMS, MSD, Novartis and Neogene Therapeutics. All other authors have declared no conflicts of interest. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = sep,
day = "1",
doi = "10.1016/j.iotech.2022.100089",
language = "English",
volume = "15",
journal = "Immuno-Oncology and Technology",
issn = "2590-0188",
publisher = "Elsevier Inc.",
}
SDG 3 Good Health and Well-being