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Beyond PD(L)-1 Blockade in Microsatellite-Instable Cancers: Current Landscape of Immune Co-Inhibitory Receptor
Edoardo Crimini1,2, Luca Boscolo Bielo1,2, Pier Paolo Maria Berton Giachetti1,2
1Division of Early Drug Development, European Institute of Oncology, IRCCS, Via Giuseppe Ripamonti 435, 20141 Milan, Italy.
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.
Insights
High microsatellite instability (MSI-H) cancers, common in colorectal and endometrial types, show promise with new immune checkpoint inhibitor combinations. Further research is needed to identify biomarkers for personalized MSI-H cancer treatment strategies.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- High microsatellite instability (MSI-H) results from deficient DNA mismatch repair, leading to genomic hypermutability.
- Colorectal cancer (CRC) and endometrial cancer (EC) are frequently MSI-H.
- While anti-PD(L)-1 therapies are effective in some MSI-H cancers, a significant portion of patients do not respond, necessitating alternative treatments.
Purpose of the Study:
- To review emerging immunotherapeutic strategies and combination therapies for MSI-H cancers.
- To highlight the limitations of current treatments and the need for novel approaches.
- To discuss the ongoing research into various immune checkpoint inhibitors and other immunotherapies for MSI-H malignancies.
Main Methods:
- Review of clinical trial data and scientific literature on immunotherapies for MSI-H cancers.
- Analysis of approved and investigational immune checkpoint inhibitors (ICIs) targeting PD(L)-1, CTLA-4, TIM-3, LAG-3, TIGIT, BTLA, ICOS, and IDO1.
- Exploration of non-ICI immunotherapeutic strategies including vaccines, oncolytic viruses, and agonists.
Main Results:
- Anti-PD(L)-1 antibodies show agnostic efficacy in MSI-H cancers, but response rates vary.
- Ipilimumab (anti-CTLA4) in combination with nivolumab is approved for MSI-H CRC.
- Anti-TIM-3 antibody LY3321367 demonstrated clinical activity with anti-PDL-1 in treatment-naïve MSI-H patients. Clinical trials are ongoing for other ICIs.
- Various novel immunotherapies are under investigation for MSI-H cancers.
Conclusions:
- Combination therapies involving ICIs and novel strategies hold potential to transform MSI-H cancer treatment.
- Further research is crucial to develop reliable immune biomarkers for personalized therapeutic decisions in MSI-H patients.
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