Cancer immunotherapy has recently been demonstrated to be quite effective for the treatment of lung cancer and melanoma, but for other indications including breast and pancreatic cancers, its application remains to be determined, given the additional challenges posed by the latter cancers (low immunogenicity). We believe that optimizing the transport and penetration of drugs and immune cells, systemically and in the tumor microenvironment, would improve the immune response in these cancers. Thus, the impact of transport phenomena (physical spatio-temporal parameters and aberrations of tumors) on immunotherapeutic efficacy should be considered for the development of effective immunotherapies. The proposed Center for Immunotherapeutic Transport Oncophysics (CITO) is focused on determining these transport phenomena in breast and pancreatic tumor models, in order to improve the transport of immunotherapies through tissues and, ultimately, to enable the rational design of optimal immunotherapeutic regimens for patients as part of individualized therapy. To support the CITO and its 2 research projects [Project 1 for the transport of cancer Nano-dendritic (DC) vaccines; Project 2 for the biophysical barriers in the tumor microenvironment], the Transport Oncophysics Core (TOC) will provide imaging, analysis, quantification, and unique oncophysical computational tools to rationalize the delivery of immunotherapies, based on the oncophysical modeling framework Transport and Biodistribution Theory (TBT). The TBT moves boundaries from classical tools used to study pharmacokinetic and efficacy relations, and instead creates novel precision immunotherapeutic tools to rationally tailor individual treatments to patients. The overall hypothesis of the TOC is that the biophysical properties of tissues (as biological barriers) are determinants that govern biodistribution of immunotherapeutics, upstream of (but in synergy with) specific biological target recognition. The distribution affects efficacy, adverse effects, and resistance phenomena, and, ultimately - patient outcomes. The TOC will aggregate data from the two projects and then provide specific services to rationalize development of and to improve the delivery of immunotherapeutics. The TOC will offer three major services to the projects: imaging (PET, IVM), data analysis and quantification, and application of computational biodistribution and tumor growth models. The underlying logic is that in vivo and pathology imaging provides snapshots and time-lapses of the biodistribution of therapeutics. The quantification of individual time-points and transport dynamics will create time series of data for computational models to develop spatio-temporal biodistribution, which is a function of the tumor microenvironment, immunotherapeutic modality, and their transport properties at therapeutically relevant time-scales. Biodistribution of immunotherapy agents and the effects of adjuvants controlling transport of immunotherapies will be correlated to therapeutic outcomes and tumor growth.
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