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

Abstract

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.

Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma

“…In the clinic, the targeted therapy triplet of BRAF-MEK-CDK4/6i could be employed in combination with TIL ACT. BRAFi have been combined with TIL ACT in small pilot studies with encouraging activity and safety [ 31 , 32 , 33 ]. In two trials, the BRAFi vemurafenib was commenced after excision of melanoma metastases for ACT production and briefly withheld during the pre-conditioning chemotherapy regimen for five days [ 32 , 33 ].…”

Barriers to immune cell infiltration in tumors

“…The mechanism for this transient increase in T cells is unclear, but may be due to lysis of tumor cells and disruption of the tumor-associated barriers to infiltration Short-term blockade of mutated BRAF has been combined with adoptive T cell therapy for advanced melanoma, with an encouraging 75% objective response rate, but median progression-free survival of <6 months. 104 There is rationale for combining immune therapies with targeted therapy or cytotoxic chemotherapies that may overcome tumor-associated barriers to immune infiltration. Such combinations will be enhanced by a deeper understanding of the barriers and how to overcome them on a long-term basis.…”

Molecular patterns of resistance to immune checkpoint blockade in melanoma

“…All patients resistant to anti-CTLA4 were naïve to PD1 blockade and instead, the majority of anti-CTLA4 resistant patients had received prior IL-2 treatment. Seven patients had also relapsed on BRAF inhibitor (BRAFi) and twelve anti-PD1 resistant samples were taken at day 7 during treatment with the BRAFi vemurafenib according to a study protocol 34 . Most patients displayed primary resistance to ICB, except six cases that clinically had acquired resistance.…”

“…ICB resistant melanoma patients were referred to CCIT, Denmark for enrollment in three different clinical trials on adoptive cell therapy 34,56,57 1.…”