Table 3 Preclinical DDRi and ICB combination studies with immune read-outs in solid cancer
DDR inhibitors | DDR agent | Immune checkpoint inhibitors | Murine tumor model | Immunological effects | References |
|---|---|---|---|---|---|
PARP inhibitors | Talazoparib (BMN673) | Anti-PD-L1 | ID8 (ovarian cancer), CT26 (colorectal cancer) | PARPi increased percentages of CD8+ T cells and PD-L1+ cells; targeting PD-1/PD-L1 pathway potentiates therapeutic efficacy of PARPi | [150] |
Olaparib, talazoparib | Anti-PD-L1 | MDA-MB-231, BT549, SUM149 (breast cancer) | PARPis increased PD-L1 expression and decreased tumor-infiltrated cytotoxic CD8+ T-cell population, the addition of anti-PD-L1 restored the cytotoxic CD8+ T-cell population | [97] | |
Rucaparib (CO-338) | Anti-PD-1/PD-L1 | BRCA1 mutant BrKras (ovarian cancer) | The combination of rucaparib with PD-1 or PD-L1 inhibition improved survival, immune profiling studies are ongoing | [106] | |
Olaparib | Anti-PD-1 | PBM (Trp53−/−, Brca1−/−, c-Myc) (ovarian cancer) | Olaparib increased PD-L1, Tim-3, and Lag-3, number of intratumoral effector CD4+ and CD8+ T cells, immune cell (CD45+) infiltration, derived a STING-dependent type I IFN signal, IFNγ and TNFα production, reduced MDSCs, the addition of PD-1 blockade overcome limits of PARPi effectiveness and prolonged survival | [102] | |
Niraparib | Anti-PD-1 | MDA-MB-436 (BRCA1 mutant triple-negative breast cancer), SK6005 (skin tumor), BrKras (BRCA1-deficient ovarian tumor), KLN205 (lung squamous cancer) | Niraparib enhanced the infiltration of CD8+ cells and CD4+ cells and activated interferon pathway, combination with pembrolizumab established immune memory | [107] | |
ABT-888 (Veliparib) | Anti-CTLA-4, Anti-PD-1/PD-L1 | BRCA1−ID8 (epithelial ovarian cancer) | PARPi in combination with CTLA-4 antibody, but not PD-1/PD-L1 antibody, increased proportion of CD8 cells with an effector/memory phenotype among T cells and enhanced Th1 T-cell response in the peritoneal tumor environment | [109] | |
ATR inhibitors | BAY1895344 | Anti-PD-1/PD-L1 | A20 (lymphoma), MC38 and CT26 (CRC) | ATR inhibitors depends on CD8+ T cells to exert the anti-tumor activity | [113] |
CHK1 inhibitors | Prexasertib, olaparib | Anti-PD-L1 | mTmG (SCLC) | DDRi enhanced PD-L1, CXCL10 and CCL5 mRNA, combination DDRi with anti-PD-L1 enhanced CD3+ total T-cell or CD8+ cytotoxic T-cell, CD44+ memory/effector T-cell, reduced tumor-infiltrating PD-1+/TIM3+ exhausted CD8+ T, CD25+/FOXP3+CD4+ T-regulatory cells, CD62L+ naïve T-cell, and CD4+ helper T-cell infiltration | [151] |