Abstract PO1-14-07: Programme of mast cell subsets to potentiate breast cancer immunotherapy: from bed to bench to bed (the phase 2 platform RENAISSANCE trial)

Abstract

Abstract Background: Immune checkpoint inhibitors (ICIs) have heralded a new era in breast cancer treatment; however, response rates remain limited, making precision immune-oncology a major unmet need. In addition to T cells, effective immune responses to ICIs rely on coordinated interactions between innate and adaptive immune cells. Mast cells are evolutionarily conserved, tissue-resident cells of importance to human health. Specific subsets of mast cells might be endowed with opposite roles in cancer treatment, yet the extent of mast cell heterogeneity and its clinical merit in immunotherapy remain undefined. Objective: We sought to comprehensively characterize mast cells in breast cancer, investigate their association with immunotherapy response with in-depth mechanistic insights, and identify actionable strategies to modulate mast cell functional states, thereby optimizing immunotherapy efficacy. Methods: We employed single-cell profiling on longitudinal breast cancer samples from three independent clinical trials (NCT04613674, NCT03197389 and GSE169246) to delineate mast cell heterogeneity in anti-PD-(L)1 therapy. By integrating multi-omic analyses, tissue characterization, preclinical experiments, transgenic mice, and high-throughput drug screening, we outlined the molecular features, underlying mechanisms, and clinical relevance of distinct mast cells to elicit ICI-responsive microenvironments. Subsequently, we launched RENAISSANCE (NCT05076682), a proof-of-concept, Bayesian adaptive, phase 2 platform trial, to evaluate the efficacy and safety of combining mast cell therapeutics with anti-PD-1 backbone therapy in metastatic triple-negative breast cancer (TNBC) patients who progressed after immunotherapy. The primary endpoint was the objective response rate (ORR) assessed using RECIST v1.1 criteria. Results: We identified a distinct population of mast cells termed antigen-presenting mast cells (APMCs), constituting approximately 30% of intratumoral mast cells and correlating with improved clinical benefit of anti-PD-(L)1 therapy in TNBC. APMCs displayed MHC-II and costimulatory molecules, and indicated the presence of tumor-reactive T cells and tertiary lymphoid structures. Using three immunocompetent mouse models, we confirmed the immunomodulatory capacity of APMCs in immunotherapy. Mechanistically, by employing Cpa3CreERT2Cd74fl/fl mice, we demonstrated that APMCs potentiate anti-PD-1 efficacy and antitumor T cell immunity through their antigen-presentation machinery. Interestingly, we identified cromolyn, an FDA-approved drug for allergy, as a potential therapeutic agent that elicited APMC-dependent CD8+ T cell cytotoxicity to synergize with anti-PD-1 therapy. Between February 2022 and March 2023, 10 patients with immunotherapy-refractory metastatic TNBC were enrolled to receive cromolyn plus camrelizumab backbone treatment. Given Bayesian predictive probability, this arm was “graduated” due to meeting the pre-specified efficacy boundary, with an ORR of 40.0% (4/10). The treatment was well tolerated with similar safety profiles of relevant drugs. Conclusions: Our findings provide crucial insights into the impact of mast cell heterogeneity on the clinical response to ICIs at a single-cell level, and pave the way for APMC-directed therapeutic interventions in cancer treatment. To our knowledge, this is the first prospective study in breast cancer of cromolyn plus anti-PD-1 backbone regimen after anti-PD-(L)1 immunotherapy failure, demonstrating significant antitumor activity and commendable tolerability. Consequently, we suggest a phase 3 randomized study to consolidate this finding, which might be an effective treatment in patients for whom there are few effective treatment options. Citation Format: Song-Yang Wu, Xi Jin, Yin Liu, Wen-Jia Zuo, Li Chen, Xiyu Liu, Lei Fan, Zhong-Hua Wang, Yan-Fei Liu, Yi-Zhou Jiang, Zhi-Ming Shao. Programme of mast cell subsets to potentiate breast cancer immunotherapy: from bed to bench to bed (the phase 2 platform RENAISSANCE trial) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-07.