Novel Immunotherapies for the Treatment of Melanoma

Abstract

Immunotherapies are achieving clinical success for the treatment of many cancers. However, it has taken a long time to exploit the potential of the immune system for the treatment of human cancers. We cannot forget that this has been the consequence of very extensive work in basic research in preclinical models and in human patients. Thus, it is rather hard to compile all of it while giving a comprehensive view on this subject. Here we have attempted to give an overall perspective in immunotherapy of melanoma. A brief overview on current therapies is provided, followed by adoptive cell therapies. Gene engineering strategies to improve these therapies are also explained, finishing with therapies based on interference with immune checkpoint pathways.

PD1 signal transduction pathways in T cells

“…It is naturally assumed that PD-L1 expression in cancer cells would correlate with therapeutic outcome. However, the results from clinical trials differ on the usefulness of PD-L1 expression as a biomarker, as patients with PD-L1-positive and PD-L1-negative tumors may benefit from the treatment [ 1 ].…”

“…Anti-cancer immunotherapies are finally becoming clinically efficacious after many decades of intense research and development. Amongst these, antibody-mediated disruption of programmed death ligand 1 (PD-L1)/programmed death receptor 1 (PD1) interactions is one of the most efficacious with milder adverse effects than chemo- and radiotherapy [ 1 ]. However, this therapy is not successful for all patients and the mechanisms underlying anti-PD1 blockade need to be explored.…”

Molecular mechanisms of programmed cell death-1 dependent T cell suppression: relevance for immunotherapy

“…The co-stimulatory interaction between CD80 and CD28 reinforces T cell activation signaling. CD80-CD28 association recruits PI3K to CD28 intracytoplasmic domain and then gets activated producing phosphatidylinositol [3,4,5]-triphosphate (PIP 3 ) which is required for AKT and PKCƟ activation and therefore Bcl-x expression. AKT through the mTOR pathway rescues T cells from anergy (15), while PKCƟ activates NF-kβ and MKK7 required to Il-2 production.…”

“…An increasing number of clinical trials demonstrate that PDL1/PD1 blockade is remarkably more effective than conventional therapies in many cases, with durable clinical responses and milder side effects (5). This therapy enhances T cell responses toward cancer cells while surprisingly sparing non-transformed cells.…”

Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment

“…Until now, there are no approved therapeutic agents that specifically target PD-L2. In many clinical trials, PD-1/PD-L1 inhibitors showed superior efficacy and safety compared to the traditional chemotherapeutic agents [14,15]. However, the low response rates and the development of resistance are still among the major challenges encountered by this class of anticancer agents.…”