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Accession Number ADA570217
Title Targeting Breast Cancer with T Cells Redirected to the Vasculature. Addendum.
Publication Date Oct 2012
Media Count 11p
Personal Author G. Coukos
Abstract The overall objective of this project is to develop targeted therapy tools directed against the breast cancer vasculature. We aim to bypass many obstacles in the field by developing a treatment based on the targeting of tumor blood vessels with T cells bearing chimeric immune receptors (CIRs). We have constructed and tested first generation CIR lentiviral vectors targeting hTEM1, which were derived from a panel of scFvs of varying affinity. These constructs signal through CD3 but can be augmented by the addition of costimulatory molecules (CD28 and 4-1BB). In vitro, only T cells bearing the scFv78 CIR were activated upon co-culture with recombinant hTEM1 protein. However, no activation was observed when scFv78 CIR bearing T cells were co- cultured with cells expressing hTEM1 on the surface. Additional strategies, including hinge elongation and the utilization of loadable CIR bearing T cells, also failed to elicit a response against the hTEM1 bearing target cells. We engineered a new yeast-display scFv library from patients with ovarian cancer to isolate a second generation of anti-TEM1 scFvs. We validated a panel of multivalent antibodies for binding to recombinant proteins by ELISA assays.. We have generated CIRs against PSMA using scFv (PZ1) and T cells bearing PZ1 and CD28 produce a robust polyfunctional repertoire of cytokines. A tumor vascular mouse model expressing human TEM1 was developed and PET imaging with (124I)- MORAb-004 indicated TEM1-specific accumulation of antibody. We have established optimized HSV-tk as extra safety and tracer for PET imaging.
Keywords Blood vessels
Breast cancer
Cardiovascular system
Cir(Chimeric immune receptor)
Disease vectors
In vitro analysis
Ovarian cancer
T lymphocytes
Tumor vascular targeting

Source Agency Non Paid ADAS
NTIS Subject Category 57E - Clinical Medicine
Corporate Author Pennsylvania Univ., Philadelphia.
Document Type Technical report
Title Note Addendum to final rept. 15 May 2010-14 Sep 2012.
NTIS Issue Number 1314
Contract Number W81XWH-10-1-0277

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