From Co-Stimulation to Co-Inhibition: A Continuum of Immunotherapy Care Toward Long-Term Survival in Melanoma

Abstract

Harnessing the immune system with immune-checkpoint(s) blockade (ICB) has dramatically changed the treatment landscape of advanced melanoma patients in the last decade. Indeed, durable clinical responses and long-term survival can be achieved with anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and anti-Programmed cell Death-1 (PD-1) monoclonal antibodies (mAb) either alone or in combination. Despite these unprecedented results, due to intrinsic or acquired resistance to ICB-based immunotherapy, about half of metastatic melanoma (MM) patients neither respond to therapy nor experience durable clinical benefit or long-term survival. To improve the efficacy of ICB therapy among a larger proportion of MM patients, in addition to the targeting of immune-checkpoint(s) inhibitors (ICI) such as CTLA-4 or PD-1, several co-stimulatory molecules, such as Inducible T-cell COStimulator (ICOS), CD137 and OX40, have been investigated in MM, with initial signs of activity. Thus, a number of MM patients have been exposed to co-inhibitory and co-stimulatory mAb in the course of their disease. Being aware of the clinical outcome of such patients may pave the way to novel and more effective clinical approaches and therapeutic sequences for MM patients. Here we report a paradigmatic clinical case of a cutaneous MM patient who achieved multiple and durable complete responses, leading to an extraordinary long-term survival with sequential ICB therapies, suggesting the possibility to build a highly effective continuum of care with co-inhibitory and co-stimulatory therapeutic mAb.

The DC–T cell axis is an effective target for the treatment of non‐small cell lung cancer

“…75,76 Both positive and negative co-stimulatory molecules are important to initiate, regulate, and terminate the immune response effectively. 77 DCs, a third signal, secrete cytokines in response to signals from the MHC antigen TCR complex and sufficient costimulation. 78,79 In collaboration with T cells, DCs can secrete abundant IL-12 and IL-18.…”

“…On the contrary, CTLA‐4 competes with CD28 for the binding of CD80/86 on DCs, while PD‐1 binds to PD‐L1 on the surface of DCs, which inhibits the signals activating it 75,76 . Both positive and negative co‐stimulatory molecules are important to initiate, regulate, and terminate the immune response effectively 77 . DCs, a third signal, secrete cytokines in response to signals from the MHC antigen TCR complex and sufficient co‐stimulation 78,79 .…”