Dipeptidyl peptidase inhibitor BXCL701 synergizes with immunomodulatory agents in a preclinical model of colorectal cancer (CRC) by altering the function of various components of the immune system
| Autor: | Subhendu Seth, Veena R Agarwal, Nirmal keshava, Dimple Bhatia, Snigdha Gupta, Hemant Banga, John MacDougall, Zeenia Jagga |
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| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
biology Colorectal cancer business.industry Immune checkpoint inhibitors medicine.disease Dipeptidyl peptidase 03 medical and health sciences 0302 clinical medicine Immune system Oncology 030220 oncology & carcinogenesis medicine Cancer research biology.protein Tumor growth Antibody business Function (biology) 030215 immunology |
| Zdroj: | Journal of Clinical Oncology. 37:e14253-e14253 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2019.37.15_suppl.e14253 |
| Popis: | e14253 Background: The oral DPP8/9 and FAP inhibitor BXCL701 in combination with a checkpoint inhibitor anti-PD-1 antibody (aPD-1) has demonstrated inhibition of tumor growth as well as up-regulation of immuno-stimulatory cytokines and tumor-infiltrating immune cells in animal models [ASCO 2018]. In the present study, BXCL701 was evaluated for its potential to improve synergistically the survival of animals when combined with anti-CTLA-4 antibody (aCTLA-4), an immune checkpoint blocker, and galunisertib, a transforming growth factor (TGF) β type I receptor inhibitor that counteracts the immunosuppressive influence that TGF β signalling has in the tumor microenvironment. Methods: In vivo studies were conducted utilizing the syngeneic colon cancer model (MC38) in C57BL/6 mice. BXCL701 was administered at the dose of 20 µg qd, p.o, while aPD-1 and aCTLA-4 were administered at the dose of 5 and 10 mpk q2w, i.p. respectively. Finally, galunisertib was administered at 75 mpk bid. Dosing was carried out for 4 weeks and median survival of the animals was calculated. Results: BXCL701 demonstrated a significant improvement in the survival of animals when combined with aCTLA-4. The median survival of animals treated with combination of BXCL701 and aCTLA-4 was significantly increased to 51.5 days in comparison to 40 days observed in BXCL701-treated animals (p < 0.001). Furthermore, in a separate study, addition of BXCL701 to the double combination of aPD-1 and aCTLA-4 resulted in a median survival of 51 days in comparison to 37 days for aPD-1 and aCTLA-4-treated animals (p < 0.05). Similarly, addition of BXCL701 to the combination treatment of aPD-1 and galunisertib increased the median survival to 40.5 days in comparison to 28 days observed in animals treated with galunisertib and aPD-1 combination (p < 0.05). Conclusions: BXCL701, an innate immune activator, synergistically combines with aCTLA-4 and a combination of aPD-1 with galunisertib to improve survival response likely by turning cold tumors to hot tumors. The present study advocates for a clinical evaluation of BXCL701 in combination with these immunomodulators in solid tumors. |
| Databáze: | OpenAIRE |
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