Ultrasmall PSMA-Targeted Particle Radiotherapy for Regulating the Immunosuppressive Prostate Cancer Tumor Microenvironment and Enhancing Treatment Efficacy
Abstract
Advanced prostate cancer (PCa) is the most common malignancy in Veterans and the fourth leading cause of cancer death in men worldwide. Despite advances in therapeutic options for metastatic and treatment-resistant disease, the average 5-year survival rate is less than 30%. Principal issues leading to treatment failure include resistance that often develops to standard-of-care therapy and an inherently cold tumor microenvironment (TME) that suppresses immune responses needed to fight the disease. The reversal of these suppressive activities remains a clinical challenge, as they are primarily driven by multiple inhibitory molecules and immune cells, as well as a relative lack of tumor-specific antigens and T cells needed to boost immune responses. As a result, most advanced PCa patients derive little benefit from immunotherapeutic (IT) agents. An important objective of this work is to therefore develop novel combination treatment strategies that not only enhance the activity of ITs, in this case, immune checkpoint blockade (ICB), but can substantially improve clinical outcomes. In this proposal, we introduce an emerging treatment strategy utilizing ultrasmall (sub-8 nanometer nm) fluorescent silica nanoparticles, Cornell prime dots (or C’ dots) that encapsulate fluorescent dye molecules for optical target visualization. Earlier generation C’ dots have previously been translated to the clinic for fluorescence image-guided surgery and, more recently, as a drug delivery vehicle for cancer therapy. Recently, we discovered that the base particle itself, in the absence of a drug, exhibits multiple inherent anti-cancer properties that can be used to alter the TME in a manner that potentially boosts responsiveness to IT. In PCa models, C’ dots have been found to significantly (i) reduce immune cell populations within the TME that can limit treatment effectiveness; (ii) activate anti-tumor immune cells, such as cytotoxic T cells; and (iii) induce cancer cell death programs that may synergize with IT. On this basis, we develop and assess the therapeutic capabilities of a novel ultrasmall targeted C’ dot radiotherapy (RT) that, combined with IT, can favorably reprogram the TME in a mouse model of PCa, the Hi-Myc model, that shares molecular features with human PCa. To realize these goals, we will first precision engineer C’ dots with varying numbers of molecules targeting prostate-specific membrane antigen (PSMA), a highly expressed marker on PCa cells. These newer generation PSMA-targeting C’ dots (or PSMAi-C’ dots) will be screened in Aim I to identify one (or more) lead probes that maximize cell kill, as well as biologic and immune-related properties relative to non-targeting C’ dots. In Aim II, lead probes will be adapted with an imaging radiolabel to identify candidates showing favorable whole-body distributions in the Hi-Myc model after intravenous injection using positron emission tomography (PET) imaging. In Aim III, we will identify novel combination treatment paradigms (i.e., lead PSMA-C’ dot RT plus ICB) that maximize anti-tumor immune responses and therapeutic efficacy in this same model over single-agent therapies. The contributions of this work and our projected outcomes support the overarching challenges of the Prostate Cancer Research Program. First, we have developed a novel treatment that has the potential to ultimately improve outcomes in men with advanced/lethal PCa. Specifically, we aim to advance a clinically translatable first-in-class sub-8-nm particle platform that selectively targets and delivers a PSMA-targeting and beta-emitting RT, 177Lu PSMAi-C’ dots to sites of disease. Second, we anticipate that radiation-induced tumor cell kill, augmented by the intrinsic therapeutic properties of the C’ dots itself, will minimize inhibitory TME activities and lead to efficacious anti-cancer responses. We also predict that 177Lu-PSMAi-C’ dots will further extend survival times relative to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310631
Entities
People
- Michelle Bradbury
Organizations
- United States Army
- Weill Cornell Medicine