Abstract 663: A novel combination immunotherapy for p53 mutant metastatic breast cancer leveraging vulnerabilities in the DNA damage response

Metastatic breast cancer (MBC) is a life-threatening disease with the lowest 5-year survival rates seen in patients with metastatic triple-negative breast cancer (TNBC). MBCs, including TNBCs, commonly carry mutations in the tumor suppressor p53. Mutant p53 (p53Mut) drives cancer progression and metastasis, in part, by promoting the accumulation of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), major enforcers of immune suppression in the tumor microenvironment (TME). At present, there are no effective treatment options for p53mut MBC, while existing chemotherapy-based treatments exhibit low selectivity for p53mut status and frequent adverse side effects. To address this clinical challenge, we developed a novel therapeutic strategy for the selective targeting of p53mut tumors. This novel strategy employs two drugs, one acting as an inducer (TAS102) and the other as an amplifier (PARP inhibitor, PARPi), to achieve selective and potent damage to p53mut tumors. Thymidine nucleotide analogue TAS102 does not block DNA synthesis but activates post-replicative repair leading to DNA breaks, while PARPi blocks repair of these DNA lesions. Post-replicative DNA repair results in DNA breaks and G2-arrest in p53mut cells. In contrast, p53WT cells accumulate in G1-phase and efficiently remove thymidine analogues. Our two-drug strategy showed high efficacy, without adverse effects, in preclinical cancer models of MBC. In this study, we further investigated the impact of the two-drug TAS102-PARPi regimen on the immune landscape in preclinical models of metastatic TNBC. We observed that the TAS102-PARPi combination reduced tumor growth and metastases in the lungs and liver. The two-drug regimen reduced the levels of MDSCs and TAMs, increased the levels of lymphocytes in the TME, and promoted CD8+ T cell-mediated anti-tumor activity that was abrogated by cell depletion. Immunophenotyping showed that the dual agent therapy increased the frequency of intra-tumoral CD8+ T cells expressing the immune checkpoint receptors PD-1 and LAG3, suggesting that the regimen may cooperate with immunotherapies targeting these molecules. Indeed, combining the dual agent therapy with anti-PD-1 or anti-LAG3 antibodies showed a further reduction in tumor growth and metastases. Together, these results demonstrate that the two-drug TAS102-PARPi regimen can be combined with immune checkpoint blockade for effective treatment of MBC, and potentially other p53-mutant cancers, like colorectal and pancreatic cancers. Citation Format: Andrei V. Bakin, Ashley Guo, Priyanka Rajan, Mohammed Alruwaili, Joseph Barbi, Scott I. Abrams, Thomas Melendy, Christos Fountzilas. A novel combination immunotherapy for p53 mutant metastatic breast cancer leveraging vulnerabilities in the DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 663.