While the majority of anticancer therapeutic efforts are designed to directly target tumor cells, there is a strong rationale for targeting the tumor vasculature (TV) instead. The development of vascular-specific tools for therapy has been hindered by (a) the paucity of targets, (b) lack of reagents with optimal affinity and specificity, and (c) their short-lived action due to rapid clearance and/or development of neutralizing antibodies. This proposal aims to solve current limitations in the field of cancer vascular therapy and generate a novel powerful and personalized approach of autologous adoptive vascular disrupting lymphocyte immunotherapy applicable to most tumor types. T cells will be engineered with lentiviral vectors to express chimeric immunoreceptors (CIRs), fusion molecules comprising an extracellular single chain variable fragment (scFv) antibody domain and intracytoplasmic CD3, CD28 and 4-1BB signaling domains for robust T-cell activation. Patient-derived lymphocytes will be genetically reprogrammed to recognize, get activated by and destroy specifically the tumor vasculature. This approach combines the sensitivity and power of cytotoxic T cells with the specificity of scFv, and will unleash on the tumor vasculature the power of acute transplant rejection. Besides specificity and safety, this approach offers durability and long-term memory. CIRs already developed against the tumor vascular surface proteins TEM1, TEM7R and PSMA will be used to validate the approach, while scFv against additional tumor vascular targets identified by the PI's lab and others will be developed. The successful completion of the project will bring to the clinic combinations of modular CIRs for personalized vascular immunotherapy for most common and most recalcitrant tumors. Safety will be maximized by requiring simultaneous recognition of two distinct tumor vascular antigens for T cell activation, by physically separating CD3 from CD28/4-1BB domains in two distinct CIRs, each recognizing a different tumor vascular target. The likelihood of both targets to be co-expressed in normal tissues is negligible, thereby maximizing the therapeutic window. Additional safety will be provided by the integration of a suicide gene in engineered T cells, which will also allow developing PET imaging to track T cell trafficking in real time in vivo. The parallel development of PET imaging capable of visualizing the tumor vasculature targets with the same scFv used in CIR will enable us to select the appropriate combinations of CIRs for personalized therapy and to monitor therapy. The impact of this approach could be transforming, given the power of tumor vascular disruption and its applicability across a wide range of targets shared by most common cancer types. The proposed approach can feasibly reach the clinic to deliver highly personalized cancer therapy of unparalleled power.

Public Health Relevance

We propose a novel approach to image and destroy tumor vasculature with a high degree of specificity by combining T-cell therapy and PET imaging. This approach will help identify patients who are the best candidates for the treatment;kill the tumor vasculature without targeting normal tissues, and allow treatment to be followed by PET imaging in the same sitting. The relevance to public health is that our approach will create new opportunities in the area of cancer detection and personalized therapy and improve the quality of life for ovarian cancer patients and prolong their life span.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA156695-05
Application #
8712194
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Li, Chunsheng; Chacko, Ann-Marie; Hu, Jia et al. (2014) Antibody-based tumor vascular theranostics targeting endosialin/TEM1 in a new mouse tumor vascular model. Cancer Biol Ther 15:443-51
Melero, Ignacio; Rouzaut, Ana; Motz, Greg T et al. (2014) T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discov 4:522-6
Li, Chunsheng; Wang, Junying; Hu, Jia et al. (2014) Development, optimization, and validation of novel anti-TEM1/CD248 affinity agent for optical imaging in cancer. Oncotarget 5:6994-7012
Matthaiou, Efthymia-Iliana; Barar, Jaleh; Sandaltzopoulos, Raphael et al. (2014) Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer. Int J Nanomedicine 9:1855-70
Motz, Gregory T; Santoro, Stephen P; Wang, Li-Ping et al. (2014) Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 20:607-15
Chacko, Ann-Marie; Li, Chunsheng; Nayak, Madhura et al. (2014) Development of 124I immuno-PET targeting tumor vascular TEM1/endosialin. J Nucl Med 55:500-7
Motz, Greg T; Coukos, George (2013) Deciphering and reversing tumor immune suppression. Immunity 39:61-73