Clinical Instructor
Division of Hematology & Oncology

Project title: Mechanistic Study of Combined Targeted Therapy and Immunotheray for Melanoma

Antoni Ribas, MD, PhD – UCLA
John Glaspy, MD, MPH – UCLA
Steven Dubinett, MD – UCLA

Multidisciplinary Expertise:
Tumor Immunology, Translational Cancer Research, Cell and Molecular Biology, Signaling Transduction, Clinical Trials.

Project Description:
Recent breakthrough of immune checkpoint inhibition has resulted in durable disease control of metastatic cancers in a small subset of patients, and BRAF and MEK inhibitors can induce highly frequent tumor responses in patients with BRAFV600E mutant melanoma, but of limited durability. BRAF and MEK inhibitors can sensitize the immune system to target tumors, providing the rationale to synergize with immunotherapy for durable response in majority of patients. Our pre-clinical studies using syngeneic BRAFV600E mutant melanoma mouse model showed significantly improved antitumor effect combining BRAF inhibitor dabrafenib and MEK inhibitor trametinib, with either pmel-1 adoptive cell transfer or anti-PD1 immunotherapy, with increased tumor infiltrating lymphocyte, preserved effector function, and favorable changes in the tumor milieu. Based on these results, three Phase I trials have been opened at UCLA testing the combination of BRAF and MEK inhibitors with anti-PD-1/L1 antibodies. I proposed to study the clinical relevance of the preclinical findings in paired pre- and post-dosing biopsies that we have been collecting in these trials.