Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma
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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; Rana, Aynal Haque; Andersen, Rikke; Martinenaite, Evelina; Kongsted, Per; Pedersen, Magnus; Nielsen, Morten; Kjeldsen, Julie Westerlin; Kverneland, Anders Handrup; Lauss, Martin; Hölmich, Lisbet Rosenkrantz; Hendel, Helle; Met, Özcan; Jönsson, Göran; Donia, Marco; Marie Svane, Inge.
In: Journal for ImmunoTherapy of Cancer, Vol. 9, No. 7, e00270, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma
AU - Borch, Troels Holz
AU - Harbst, Katja
AU - Rana, Aynal Haque
AU - Andersen, Rikke
AU - Martinenaite, Evelina
AU - Kongsted, Per
AU - Pedersen, Magnus
AU - Nielsen, Morten
AU - Kjeldsen, Julie Westerlin
AU - Kverneland, Anders Handrup
AU - Lauss, Martin
AU - Hölmich, Lisbet Rosenkrantz
AU - Hendel, Helle
AU - Met, Özcan
AU - Jönsson, Göran
AU - Donia, Marco
AU - Marie Svane, Inge
N1 - Publisher Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - adoptive
KW - clinical trials as topic
KW - immunotherapy
KW - lymphocytes
KW - melanoma
KW - tumor-infiltrating
U2 - 10.1136/jitc-2021-002703
DO - 10.1136/jitc-2021-002703
M3 - Journal article
C2 - 34210820
AN - SCOPUS:85110357310
VL - 9
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
SN - 2051-1426
IS - 7
M1 - e00270
ER -
ID: 275772835