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.

Keywords:

• immunotherapy
• combinations
• anti-PD1
• anti-CTLA-4
• CD137 agonist
• ICOS agonist

Abbreviations

ICB, Immune Checkpoint Blockade; CTLA-4, Cytotoxic T-Lymphocyte Antigen 4; PD-1, Programmed cell Death 1; mAb, monoclonal Antibody; MM, Metastatic Melanoma; ICI, Immune Checkpoint Inhibitors; ICOS, Inducible T-cell COStimulator; PD-L1, Programmed cell Death Ligand 1; CT, Computed Tomography; DTIC, Dacarbazine; EAP, Expanded Access Program; FDG-PET, [¹⁸F] FluoroDeoxy-Glucose Positron Emission Tomography; PD, Progression of Disease; SD, Stable Disease; CR, Complete Response; TR, Treatment Related; TA, Tumor Assessment; irRC, immune-related Response Criteria; RECIST, Response Evaluation Criteria in Solid Tumors.

Ethics Approval and Informed Consent

No institutional approval was required to publish the case details.

Consent for Publication

Informed consent was obtained in both written and verbal forms from patient to publish this case report and any accompanying images.

Acknowledgments

The authors wish to acknowledge the patient who participated in this study and her family.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

AMDG has served as a consultant and/or advisor to Incyte, Pierre Fabre, Glaxo Smith Kline, Bristol-Myers Squibb, Merck Sharp Dohme, SunPharma, Novartis and Sanofi and has received compensated educational activities from Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre and Sanofi; MM has served as a consultant and/or advisor to Roche, Bristol-Myers Squibb, Merck Sharp Dohme, Incyte, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, Glaxo Smith Kline, Sciclone, Sanofi, Alfasigma, and Merck Serono; and owns shares in Epigen Therapeutics, Srl. ES, SC, MV, TS, MR have no conflict of interest to declare.