Improved Adventitial Rapamycin Therapy for Peripheral Artery Restenosis

DESCRIPTION (provided by applicant): NexImmune is developing nanoparticles that stimulate immune responses against cancer and other diseases. This Artificial Immune Modulating (AIM(R)) platform is comprised of an artificial matrix to which various antigen-presenting and immune modulating proteins are attached, depending on the type of immune modulation desired. A number of published studies show the potential advantages of the AIM(R) platform over currently available immunotherapies in terms of product uniformity, reproducibility, cost, and sustained activity regardless of the disease state of the patient. The goal of this application is to develop AIM(R) particles based on an optimized, biocompatible matrix and to develop preclinical proof-of-concept data in a clinically- relevant model that will support beginning clinical development of the Company's first product, AIM101, for the treatment of melanoma. In Specific Aim #1, two biocompatible matrices - iron core beads and poly(lactic-co- glycolic acid) (PLGA) beads - will be produced and tested for protein binding, antigen-binding specificity, potency and functional responses of stimulated cells, and stability upon storage using FACS analyses of T cell numbers and intracellular cytokine production and T cellproliferation assays. In Specific Aim #2, particles on the different matrices will be tested for no-GLP toxicity by studying serum chemistries, gross examination and histopathological analyses of tissues from treated mice. Biodistribution will be determined using particles containing proteins that have been labeled with the near infrared imaging Cy5.5 dye to allow for optical imaging. In Specific Aim #3, in vivo efficacy studies will be conducted using the murine B16 F10 melanoma model. Mice will be treated with a three-antigen cocktail of AIM(R) nanobeads with or without cyclophosphamide, which acts as an immune adjuvant. Efficacy will be evaluated by following tumor growth and survival as well as assessment of surrogate markers of immune activation including pentamer staining and in vitro T cell responses. If successful, together with work being conducted separately to humanize our HLA-Ig and anti-CD28 constructs, we will have developed a clinically-compatible AIM101 for melanoma and obtained sufficientpreclinical proof-of-concept data to justify applying for a Phase II SBIR to support IND-enabling studies. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: NexImmune is developing an Artificial Immune Modulating (AIM(R)) platform to stimulate invivo immune responses against cancer and other diseases. AIM(R) particles are artificial matrices to which immune modulating proteins are attached. This grant application proposes to optimize the AIM(R) platform for clinical use by identifying a biocompatible and biodegradable matrix that will be validated in proof-of-concept tissue culture and tumor models for further development and testing of an AIM(R) product in clinical trials.