Beyond PD(L)-1 Blockade in Microsatellite-Instable Cancers: Current Landscape of Immune Co-Inhibitory Receptor Targeting
Author:
Crimini Edoardo12, Boscolo Bielo Luca12, Berton Giachetti Pier Paolo Maria12ORCID, Pellizzari Gloria12ORCID, Antonarelli Gabriele12ORCID, Taurelli Salimbeni Beatrice1, Repetto Matteo3, Belli Carmen1ORCID, Curigliano Giuseppe12ORCID
Affiliation:
1. Division of Early Drug Development, European Institute of Oncology, IRCCS, Via Giuseppe Ripamonti 435, 20141 Milan, Italy 2. Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy 3. Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Abstract
High microsatellite instability (MSI-H) derives from genomic hypermutability due to deficient mismatch repair function. Colorectal (CRC) and endometrial cancers (EC) are the tumor types that more often present MSI-H. Anti-PD(L)-1 antibodies have been demonstrated to be agnostically effective in patients with MSI-H cancer, but 50–60% of them do not respond to single-agent treatment, highlighting the necessity of expanding their treatment opportunities. Ipilimumab (anti-CTLA4) is the only immune checkpoint inhibitor (ICI) non-targeting PD(L)-1 that has been approved so far by the FDA for MSI-H cancer, namely, CRC in combination with nivolumab. Anti-TIM3 antibody LY3321367 showed interesting clinical activity in combination with anti-PDL-1 antibody in patients with MSI-H cancer not previously treated with anti-PD(L)-1. In contrast, no clinical evidence is available for anti-LAG3, anti-TIGIT, anti-BTLA, anti-ICOS and anti-IDO1 antibodies in MSI-H cancers, but clinical trials are ongoing. Other immunotherapeutic strategies under study for MSI-H cancers include vaccines, systemic immunomodulators, STING agonists, PKM2 activators, T-cell immunotherapy, LAIR-1 immunosuppression reversal, IL5 superagonists, oncolytic viruses and IL12 partial agonists. In conclusion, several combination therapies of ICIs and novel strategies are emerging and may revolutionize the treatment paradigm of MSI-H patients in the future. A huge effort will be necessary to find reliable immune biomarkers to personalize therapeutical decisions.
Subject
Cancer Research,Oncology
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