Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma
| Autor: | Marco Donia, Evelina Martinenaite, Lisbet Rosenkrantz Hölmich, Katja Harbst, Özcan Met, Troels Holz Borch, Anders Handrup Kverneland, Aynal Haque Rana, Magnus Pedersen, Helle W. Hendel, Rikke Fredslund Andersen, Göran Jönsson, Julie Westerlin Kjeldsen, Per Kongsted, Inge Marie Svane, Martin Lauss, Morten Nielsen |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oncology lymphocytes Male Cancer Research Adoptive cell transfer medicine.medical_treatment T-Lymphocytes Priming (immunology) 0302 clinical medicine Immunology and Allergy Vemurafenib RC254-282 clinical trials as topic Melanoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens hemic and immune systems Middle Aged Chemotherapy regimen Cytokine medicine.anatomical_structure 030220 oncology & carcinogenesis Molecular Medicine Female immunotherapy Immunotherapy medicine.drug Adult Proto-Oncogene Proteins B-raf medicine.medical_specialty Adolescent T cell Immunology chemical and pharmacologic phenomena adoptive 03 medical and health sciences Young Adult Internal medicine medicine melanoma Humans Protein Kinase Inhibitors Aged Pharmacology Immune Cell Therapies and Immune Cell Engineering business.industry tumor-infiltrating medicine.disease 030104 developmental biology business |
| Zdroj: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 9, Iss 7 (2021) Borch, T H, Harbst, K, Rana, A H, Andersen, R, Martinenaite, E, Kongsted, P, Pedersen, M, Nielsen, M, Kjeldsen, J W, Kverneland, A H, Lauss, M, Hölmich, L R, Hendel, H, Met, Ö, Jönsson, G, Donia, M & Marie Svane, I 2021, ' Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma ', Journal for ImmunoTherapy of Cancer, vol. 9, no. 7, e00270 . https://doi.org/10.1136/jitc-2021-002703 |
| ISSN: | 2051-1426 |
| Popis: | PurposeDespite impressive response rates following adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, improvement is needed to increase the efficacy and broaden the applicability of this treatment. We evaluated the use of vemurafenib, a small-molecule BRAF inhibitor with immunomodulatory properties, as priming before TIL harvest and adoptive T cell therapy in a phase I/II clinical trial.Methods12 patients were treated with vemurafenib for 7 days before tumor excision and during the following weeks until TIL infusion. TILs were grown from tumor fragments, expanded in vitro and reinfused to the patient preceded by a lymphodepleting chemotherapy regimen and followed by interleukin-2 infusion. Extensive immune monitoring, tumor profiling and T cell receptor sequencing were performed.ResultsNo unexpected toxicity was observed, and treatment was well tolerated. Of 12 patients, 1 achieved a complete response, 8 achieved partial response and 3 achieved stable disease. A PR and the CR are ongoing for 23 and 43 months, respectively. In vitro anti-tumor reactivity was found in TILs from 10 patients, including all patients achieving objective response. Serum and tumor biomarker analyses indicate that baseline cytokine levels and the number of T cell clones may predict response to TIL therapy. Further, TCR sequencing suggested skewing of TCR repertoire during in vitro expansion, promoting certain low frequency clonotypes.ConclusionsPriming with vemurafenib before infusion of TILs was safe and feasible, and induced objective clinical responses in this cohort of patients with checkpoint inhibitor-resistant metastatic melanoma. In this trial, vemurafenib treatment seemed to decrease attrition and could be considered to bridge the waiting time while TILs are prepared. |
| Databáze: | OpenAIRE |
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