Chimeric antigen receptor (CAR) T cell adoptive immunotherapy has shown great promise in clinical trials for the treatment of cancers, including acute lymphoblastic and chronic lymphocytic leukemia. CAR T cell therapies are comprised of the patients own T cells (autologous T cells) that have been genetically engineered to express a CAR. This receptor is comprised of an extracellular tumor-targeted binding moiety fused to intracellular domains with activation and signaling functionalities. Unfortunately, CART therapy has a complex, multi-step manufacturing process, and no standardized approach has been implemented among various institutions running the clinical trials. An efficient, cost-effective an standardized manufacturing process is critical to the broad application and ultimate success of CART therapy. The goal of this project is to develop stimuli-responsive reagent systems (SRRS) for cell isolations and activations that will help to streamline and improve the manufacturing process of adoptive cellular therapies like CAR T cell therapy. Magnetic beads are used to isolate and activate T cells in CAR T cell manufacturing. These beads have surface-bound antibodies, and they are either micro- (Dynal(r)) or nano- (Miltenyi Biotec) sized. Neither technology has been adopted universally in CAR T cell manufacturing processes because each approach has shortcomings. Nexgenia's magnetic nanoparticle (mNP) technology is designed to combine the favorable attributes of microbeads (rapid magnetic separation) and nanoparticles (rapid target binding), with the additional benefit of simple nanoparticle removal after cell manipulations. The key to achieving this ideal combination is the unique stimuli-responsive nature of the Nexgenia mNP. These mNP bear stimuli-responsive polymers, and they change from hydrophilic, monodispersed ~20 nm diameter particles to micron-sized aggregates in response to an environmental stimulus like a temperature change. Nexgenia's SRRS comprise mNP and antibodies conjugated to similar stimuli-responsive polymers. At low temperatures, polymer-antibody conjugates rapidly bind cell surface antigens. At higher temperatures, the polymer-antibody conjugates aggregate with the mNP, facilitating rapid magnetic isolation of target cells or cell activation. To achieve the project's goal, Nexgenia will develop a SRSS with a temperature response of ~15°C. The SRRS will be used to demonstrate the feasibility of isolating T cells from human peripheral blood mononuclear cells and its performance will be benchmarked against Dynal(r) CD3/28 beads. The SRRS will then be used to activate T cells, thereby mediating their expansion in vitro. A SRRS that isolates and then activates T cells can be readily integrated into cell therapy manufacturing processes and lead to more consistent and better- characterized therapeutics. An improved CAR T cell manufacturing process would help to realize the clinical and commercial success of adoptive cell therapies and ultimately, expand patient access to these promising therapeutics. Nexgenia's SRRS can address this area of great need.
Public Health Relevance Statement: Public Health Relevance: Nexgenia Project Narrative Adoptive cellular therapies with genetically modified autologous T cells (i.e., chimeric antigen receptor, or CAR T-cell therapy) have shown great promise in clinical trials for cancer, although the commercialization of cellular therapies is challenging due to complicated manufacturing processes. This project aims to develop a set of reagents to streamline the CAR T cell manufacturing process. These reagents will help to provide efficient, cost-effective and standardized methods that will support broad access to these promising therapeutics for cancer patients.
Project Terms: Acute; Address; Adopted; Adoptive Immunotherapy; Affinity; Amines; Antibodies; antibody conjugate; Architecture; Area; Autologous; base; Behavior; Benchmarking; Binding (Molecular Function); Blood; Caliber; cancer clinical trial; Cancer Patient; CD28 gene; CD3 Antigens; Cell Separation; Cell surface; Cell Survival; Cell Therapy; Cells; chimeric antigen receptor; Chronic Lymphocytic Leukemia; Clinical; Clinical Treatment; Clinical Trials; cold temperature; commercialization; Complex; cost; cost effective; crosslink; cytokine; design; Development; Engineering; Enzyme-Linked Immunosorbent Assay; Excision; extracellular; Flow Cytometry; Foundations; Generations; Genetic Engineering; Goals; High temperature of physical object; Human; improved; In Vitro; Institution; Lead; magnetic beads; Magnetic nanoparticles; Magnetism; Malignant Neoplasms; manufacturing process; Measurement; Measures; Mediating; Methods; Microspheres; nano; nanoparticle; Nature; novel; novel therapeutics; particle; Particle Size; Patients; Performance; Peripheral Blood Mononuclear Cell; Phase; Polymers; Process; Production; Property; public health relevance; Reagent; receptor; Receptor Aggregation; response; Response to stimulus physiology; Running; Signal Transduction; Small Business Innovation Research Grant; Specificity; Stimulus; Structure; success; Surface; Surface Antigens; System; T cell therapy; T-Cell Activation; T-Lymphocyte; Technology; Temperature; Therapeutic; tumor; Ursidae Family
