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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA210181-02
Application #
9369033
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Zahir, Nastaran Z
Project Start
Project End
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Methodist Hospital Research Institute
Department
Type
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030
Nizzero, Sara; Ziemys, Arturas; Ferrari, Mauro (2018) Transport Barriers and Oncophysics in Cancer Treatment. Trends Cancer 4:277-280
Du, Wenting; Huang, Huocong; Sorrelle, Noah et al. (2018) Sitravatinib potentiates immune checkpoint blockade in refractory cancer models. JCI Insight 3:
Tang, Chad; Hobbs, Brian; Amer, Ahmed et al. (2018) Development of an Immune-Pathology Informed Radiomics Model for Non-Small Cell Lung Cancer. Sci Rep 8:1922
Liu, Haoran; Mai, Junhua; Shen, Jianliang et al. (2018) A Novel DNA Aptamer for Dual Targeting of Polymorphonuclear Myeloid-derived Suppressor Cells and Tumor Cells. Theranostics 8:31-44
Wang, Feng; Xia, Xiaojun; Yang, Chunying et al. (2018) SMAD4 Gene Mutation Renders Pancreatic Cancer Resistance to Radiotherapy through Promotion of Autophagy. Clin Cancer Res 24:3176-3185
Kojic, M; Milosevic, M; Kojic, N et al. (2018) Mass release curves as the constitutive curves for modeling diffusive transport within biological tissue. Comput Biol Med 92:156-167
Zhu, Motao; Ding, Xilai; Zhao, Ruifang et al. (2018) Co-delivery of tumor antigen and dual toll-like receptor ligands into dendritic cell by silicon microparticle enables efficient immunotherapy against melanoma. J Control Release 272:72-82
Du, Wenting; Brekken, Rolf A (2018) Does Axl have potential as a therapeutic target in pancreatic cancer? Expert Opin Ther Targets 22:955-966
Koay, Eugene J; Lee, Yeonju; Cristini, Vittorio et al. (2018) A Visually Apparent and Quantifiable CT Imaging Feature Identifies Biophysical Subtypes of Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 24:5883-5894
Koay, Eugene J; Owen, Dawn; Das, Prajnan (2018) Radiation-Induced Liver Disease and Modern Radiotherapy. Semin Radiat Oncol 28:321-331

Showing the most recent 10 out of 31 publications