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

SIMPLE SUMMARY: Adoptive cell transfer (ACT) is a potentially robust treatment option for patients with advanced melanoma that is resistant to immune checkpoint inhibitors. The addition of cyclin-dependent kinase 4/6 inhibitors to combination BRAF-MEK inhibitors can also greatly improve the duration of response against melanoma. The aim of our study was to investigate adoptive cell transfer with combination BRAF-MEK and CDK4/6 inhibitors. We show triplet targeted therapy is highly efficacious against BRAF(V600) melanoma in YOVAL1.1 and the BRAFi resistant SM1WT1 model. Combination ACT with BRAF-MEK-CDK4/6i led to prolonged and deep anti-tumor responses in YOVAL1.1. This work provides additional evidence for BRAF-MEK-CDK4/6i in clinical trials and in combination with ACT. ABSTRACT: Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.