Radio-immunotherapy dose-painting (RAID) treatment for hormonal resistant prostate cancer

ABSTRACT Prostate cancer, rather indolent by nature, has specific subtypes present with aggressive locoregional disease that are quickly becoming hormonal resistant. Patients with castrate-resistant disease (CRPC) are generally younger and non-Caucasian, and many suffer from local progression, edema, and pain. Radiotherapy (RT) is offered but limited by the extent, former exposure, and resistance of disease. Sequential multiple chemotherapy or RT treatments, offered as standard of care, are hard to comply to, especially in low-resource populations. Treatment of this symptomatic population is often terminated prematurely, or never started, due to financial and time restrictions. Innovative, shorter more efficient treatments are needed, especially to reduce disparities in compliance and outcomes of global cancer care. In extensive preclinical work, the combination of RT with immunogenic smart radiotherapy materials (iSRBs), addressed as radio-immunotherapy dose-painting (RAID) technology, brings intra-tumoral slow-release antiCD40 payload in the target that gets irradiated and has shown to prime the immune system and create sustainable tumor control by in situ-vaccination, even after different therapeutic options have failed. Moreover, this combination treatment can improve quality of life (QoL) fast by a short simple intervention with fewer side effects, having an antiCD40 payload far smaller than needed in intravenous (IV) immunotherapy. The overall goal of this project - proposed by Nanocan Therapeutics Corporation in collaboration with John Hopkins Medicine, Dana-Farber Cancer Institute and Northwell Health - is to bridge preclinical work to the first clinical trial with the innovative RAID technology and confirm its potential for in situ-vaccination that can extend the use of radiotherapy (RT) from palliative local treatment to systemic disease control in one session. The iSRBs are as seed-like fiducial markers administered directly in the prostate tumor by ultrasound guided needles. The iSRBs create contrast on CT and KV imaging making RT set-up fast; iSRBs slowly release (20mcg per unit over 15 days) anti-CD40 payload directly the target which gets irradiated, triggering in situ-vaccination. The purpose of this project is to translate extensive safety and efficacy data from small animal studies of single fraction RT combined with slow released intra-tumoral antiCD40 delivery to a first human trial for CRPC patients. The first part will be used to optimize iSRBs into a cGMP product, and confirmation of larger volume testing in monkeys to confirm safety, immunogenicity, and pharmacokinetics already performed in extensive small animal work. Milestones will complete IND filling by Nanocan Therapeutics. After FDA approval, second part of the project will encompass the Phase 1 single arm open label clinical trial seeking confirmation of safety and number of iSRBs as well as RT dose needed in CRPR patients. This project can provide all needed data for planned Phase II clinical work in aims offering a novel treatment paradigm for CRPR patients.NARRATIVE Prostate cancer is the most common male cancer and although rather indolent by nature, has specific subtypes present with aggressive locoregional disease that become hormonal resistant fast. Patients with castrate-resistant disease are generally younger and non-Caucasian, and many suffer from local progression, edema, and pain. Overall compliance to standard of care long-course chemotherapy and/or radiation is poor due to toxicity and costs, in this research project, we aim sustainable tumor control by in situ vaccination combining intra-tumoral insertion of immune-promoting nanoparticles with radiotherapy in a one-day treatment.