72IN - Which Systemic Therapies Should Be Combined to Immunotherapy?

Abstract

ABSTRACT Melanoma treatment by T cell checkpoint blockade (TcCB), e.g. anti-CTLA-4, PD-1, or PD-L1 mAbs, has largely contributed to the 2013 breakthrough of immunotherapy in medical science. In contrast to targeted therapies with high response rates, usually of short duration, immunotherapy benefits smaller groups of patients, but in case of response, these could be long-term and possibly curative. This raises the question whether and which systemic combination with TcCB can increase the response rate and subsequent the survival of melanoma patients. Several groups of systemic therapies have been tested/are currently tested in combination with TcCB: chemotherapy, angiogenesis inhibitors, targeted therapy, and immune modulators. Aside the reduction of tumor load (to bridge the time till onset of the immune response) several rationals have been postulated for the combination of TcCB with systemic therapies, e.g. induction of immunogenic cell death, synergistic breakdown of tumor vasculature, reduction of intra-tumor immune-inhibitory cells (Treg, MDSC), increased MHC and subsequent tumor antigen expression, reduced expression of T cell checkpoint molecules, and induction or broadening of the tumor specific T cell repertoire. So far most of the ideas are based on pre-clinical observations and are tested in phase 1/2 trials. Only the combination of DTIC and ipilimumab has been tested in a phase 3 trial. Unfortunately the missing comparator arm of single agent ipilimumab hampers the judgement of the net benefit of adding chemotherapy to CTLA-4 blockade. A phase 1 study testing the concurrent combination of selective BRAF inhibition (vemurafenib) and CTLA-4 blockade (ipilimumab) was closed for accrual due to unexpected toxicity. Testing combinations of targeting the MAPK pathway and TcCB inhibitiors at different schemes or with other compounds are currently underway, e.g. BRAF + /-MEK inhibition in combination with CTLA-4 blockade or BRAF inhibition in combination with PD-L1 blockade. In summary, TcCB is currently the most promising treatment approach in melanoma. Modulation of the tumor microenvironment, immunogenicity of the tumor cells itself, and the T cell repertoire will improve response rates and long-term outcome for patients treated with TcCB. Disclosure: C. Blank: Advisory role for BMS, MSD, Roche, Novartis, and GSK. Research funding from Novartis.