Abstract 1939: BR101801, a first-in-class dual target inhibitor of DNA protein kinase (DNA-PK) and phosphoinositide 3-kinase delta (PI3Kδ), triggers antitumor immunity

Autor: Baek kyung Kim, Mi Kwon Son, Nam Hoon Kim, Byeongwook Jeon, Jin Sang Wang, Yeon seo Choi, Jayhyuk Myung, Bo Ram Lee, Dal-Hyun Kim
Rok vydání: 2018
Předmět:
Zdroj: Cancer Research. 78:1939-1939
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2018-1939
Popis: Introduction: Regulatory T cells (Tregs) and conventional T cells (Tconvs) are differentially regulated by PI3K isoforms. Tregs are dependent on the PI3Kδ isoform, whereas Tconvs are regulated by PI3Kα and PI3Kβ instead of PI3Kδ as a complementary pathway. Moreover, recent reports have indicated that DNA-PK inhibition reduced Tregs maintenance and function by blocking phosphorylation of Nr4a. Idelalisib, which is an approved PI3Kδ inhibitor, was shown to reduce the number of suppressive Tregs in the peripheral blood of chronic lymphocytic leukemia patients in duration- and patient age-dependent manners. As BR101801 is a first-in-class dual target inhibitor of DNA-PK and PI3Kδ, the efficacy of BR101801 as a candidate for cancer immunotherapy is presented in this study. Methods: BALB/c mice were subcutaneously inoculated into the abdomen on day 0 with 5x104 4T1 cells. BR101801 (50 mg/kg, once daily) or vehicle was administered by oral gavage from day -1. On day 30, mice were sacrificed, after which tumor tissue and spleen were extracted for ex vivo analysis. Human CD3+ lymphocytes were isolated from PBMCs using positive selection on magnetic beads. CD3+ lymphocytes stimulation was achieved with an anti-CD3/CD28 T cell activator. FACS analysis was performed using antibodies (CD4, CD25, Foxp3, PD-1, CTLA-4). Results: Administration of BR101801 led to significant suppression of 4T1 tumor growth (TGI : 50.48%) based on a similar pattern as the positive control PI3Kδ inhibitor (PI-3065). Interestingly, 4T1 cells did not express PI3Kδ at a detectable level. Indeed, BR101801 did not affect the growth of 4T1 cells up to 10 μM in vitro. These results mean that BR101801 induces immune-mediated tumor regression without a direct cytotoxic effect on 4T1 cells. Ex vivo analysis of the spleen showed that the population of Tregs decreased while that of CD8 lymphocytes increased upon BR101801 treatment, reciprocally. Immuno-oncological activity was confirmed in human PBMCs. BR101801 did not influence the viability of CD3+ lymphocytes and CD4+ lymphocytes but specifically decreased the population of Tregs. In addition, PD-1 and CTLA-4 expression in Tregs was reduced in a dose-dependent manner, and the results were better than those obtained using idelalisib and TGR-1202. Furthermore, the remaining effect of BR101801 was confirmed to be effective even up to 24 hours after drug removal. Conclusions: BR101801 has immunogenic potential to alter the balance of immune tolerance to anti-tumor immunity by encouraging antigen exposure, disrupting Tregs, and boosting CD8 cells. Therefore, this study suggests the potential of BR101801 to be used as a first chemical immune checkpoint inhibitor. Citation Format: Byeongwook Jeon, Jin Sang Wang, Baek kyung Kim, Bo Ram Lee, Mi kwon Son, Yeon seo Choi, Nam-Hoon Kim, Jayhyuk Myung, Dal-Hyun Kim. BR101801, a first-in-class dual target inhibitor of DNA protein kinase (DNA-PK) and phosphoinositide 3-kinase delta (PI3Kδ), triggers antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1939.
Databáze: OpenAIRE
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