Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma
(2021) In Journal for ImmunoTherapy of Cancer 9(7).- Abstract
PURPOSE: Despite 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. METHODS: 12 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... (More)
PURPOSE: Despite 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. METHODS: 12 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. RESULTS: No 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. CONCLUSIONS: Priming 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.
(Less)
- author
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- adoptive, clinical trials as topic, immunotherapy, lymphocytes, melanoma, tumor-infiltrating
- in
- Journal for ImmunoTherapy of Cancer
- volume
- 9
- issue
- 7
- publisher
- BMJ Publishing Group
- external identifiers
-
- pmid:34210820
- scopus:85110357310
- ISSN
- 2051-1426
- DOI
- 10.1136/jitc-2021-002703
- language
- English
- LU publication?
- yes
- additional info
- P
- id
- 3b7a5845-040c-43da-8b93-d050ea3c29bc
- date added to LUP
- 2021-08-23 17:20:35
- date last changed
- 2024-07-13 17:27:05
@article{3b7a5845-040c-43da-8b93-d050ea3c29bc, abstract = {{<p>PURPOSE: Despite 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. METHODS: 12 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. RESULTS: No 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. CONCLUSIONS: Priming 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.</p>}}, author = {{Borch, Troels Holz and Harbst, Katja and Rana, Aynal Haque and Andersen, Rikke and Martinenaite, Evelina and Kongsted, Per and Pedersen, Magnus and Nielsen, Morten and Kjeldsen, Julie Westerlin and Kverneland, Anders Handrup and Lauss, Martin and Hölmich, Lisbet Rosenkrantz and Hendel, Helle and Met, Özcan and Jönsson, Göran and Donia, Marco and Marie Svane, Inge}}, issn = {{2051-1426}}, keywords = {{adoptive; clinical trials as topic; immunotherapy; lymphocytes; melanoma; tumor-infiltrating}}, language = {{eng}}, number = {{7}}, publisher = {{BMJ Publishing Group}}, series = {{Journal for ImmunoTherapy of Cancer}}, title = {{Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma}}, url = {{http://dx.doi.org/10.1136/jitc-2021-002703}}, doi = {{10.1136/jitc-2021-002703}}, volume = {{9}}, year = {{2021}}, }