Sustained-Release STING Agonist Implants Activate Antitumor Immunity to Treat Advanced Breast Cancer in Combination with PARPi
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, with a higher risk of recurrence and worse prognosis after relapse than hormone receptor-positive cancers (median survival 12 to 18 months versus 50 to 60 months). Until recently, conventional treatment options for TNBC patients involve either a mastectomy or a lumpectomy followed by radiation and/or chemotherapy. When given the option for breast conservation therapy (BCT), 72% of patients preferred some form of BCT over surgical options, especially younger women. Poly (ADP-ribose) polymerase inhibitors (PARPi) have emerged as a promising therapy for these patients, however, resistance emerges and responses are not durable, necessitating research into quick translational strategies. Immune checkpoint blockade (ICB) has revolutionized the treatment of some cancer types but has demonstrated only modest benefit in TNBC as a monotherapy. ICB has been recently U.S. Food and Drug Administration (FDA)-approved for TNBC in combination with chemotherapy, however, the approval is only for PD-L1-positive metastatic TNBC, and while there are responses, the majority of the patients eventually progress. The limited response rates (5% to 20%) suggest that tumor-related immunosuppression cannot be fully overcome by ICB blockade alone. T cell infiltration and activation has been the focus of ICB, however, the largest population of infiltrating immune cells are tumor-associated macrophages (TAMs) that link innate and adaptive immunity. TAM-targeting strategies have been slow to be approved for clinical care, likely due to lack of clinical rationale and testing of appropriate combinations. Dr. Guerriero’s team recently demonstrated that PARPi drives development of a subset of suppressive TAMs that restrict antitumor T cell function. In the absence of tumorigenic TAMs, PARPi induce robust recruitment of cytotoxic T cells and durable antitumor responses. The breakthrough discovery by Dr. Guerriero’s team has set the stage for next-generation innate immune modulatory therapies to reprogram TAMs, specifically targeting of the cGAS/STING pathway with exogenous stimulator of interferon genes (STING) agonist. Dr. Guerriero’s team and others have recently shown that intratumoral STING agonists reprogram TAMs from protumor M2-like to anticancer M1-like phenotypes and synergize with PARPi, leading to 100% complete regression. Given that all cells have some degree of cGAS/STING sensing pathway, a key limitation to translation of STING agonist is the need for recurrent intratumoral injections to achieve high disease site drug dose and limit systemic toxicity. Chronic systemic activation of the STING pathway is linked to an autoinflammatory condition, STING-associated vasculopathy with onset in infancy (SAVI). Given the promising preliminary results of intratumoral STING agonist and PARPi, rapid clinical translation is necessary, however, hurdles of STING agonist delivery must be overcome. Sustained-release polymer-drug formulations are promising alternatives to recurrent intratumoral injections. Dr. Brown’s team has formulated sustained-release SMAART (Sustained Modulation and Activation of Anticancer Responses and Targets) implants from FDA-approved poly (lactic-co-glycolic) acid (PLGA) polymer that have linear release kinetics over 28 days and prolong duration of drug action. This partnering PI proposal will combine our expertise in drug delivery and nanoformulation (Brown), and immunology and breast tumor biology (Guerriero), to test the efficacy of sustained STING agonist implants to activate innate and adaptive immunity compared to periodic injections. This work will fill in gaps in knowledge about: (1) tumor immune microenvironment shifts following sustained versus periodic STING pathway activation (Aim 1); (2) how primary site cGAS/STING activation impacts the immune microenvironment at secondary, metastatic sites (Aim 2); and (3) the synerg
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310813
Entities
People
- Needa Brown
Organizations
- Northeastern University
- United States Army