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Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma

Borch, Troels Holz ; Harbst, Katja LU orcid ; Rana, Aynal Haque ; Andersen, Rikke ; Martinenaite, Evelina ; Kongsted, Per ; Pedersen, Magnus ; Nielsen, Morten ; Kjeldsen, Julie Westerlin and Kverneland, Anders Handrup , et al. (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.

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organization
publishing date
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
  • scopus:85110357310
  • pmid:34210820
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
2024-04-20 11:04:05
@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}},
}