This project is submitted under the R21 mechanism to support a focused, time limited effort to complete development and perform testing of a new therapy against colorectal carcinoma. The tumor associated marker, CEA is expressed in 60-94% of patients with advanced disease, and it has a profile of expression in normal tissues that will plausibly allow selective targeting of tumor expression of the antigen. T- cells can penetrate virtually every biologic space and have the power to dispose of normal or malignant cells as seen in viral and autoimmune diseases and in the rare spontaneous remissions of cancer. However, T cells are readily tolerant to self or tumor antigens, and """"""""immune surveillance"""""""" has manifestly failed in every cancer that is clinically apparent. It is the goal of these studies to supply the specificities and affinities to patient T cells without regard for their """"""""endogenous"""""""" T cell receptor repertoire, directed by antibody-defined recognition to kill malignant cells based on their expression of antigen. The applicant will achieve this by preparing chimeric IgTCR genes in mammalian expression vectors to yield """"""""designer T cells"""""""" from normal patient cells. Prior studies in model systems demonstrated that IgTCR could direct modified T cells to respond to antigen targets with IL-2 secretion, cellular proliferation, and cytotoxicity, the hallmarks of an effective, self-sustaining immune response. The applicant has prepared IgTCR constructs by molecular techniques to test several hypotheses pertinent to the optimal configuration for these applications in humans.
Specific aims for the two year period of the phase I study are: 1) to complete preclinical studies of chimeric anti-CEA IgTCR in human T cells; and 2) to conduct phase I studies of anti CEA IgTCR-modified T cells in colorectal cancer.
| Bernstein, Jonine L; Lapinski, Robert H; Thakore, Seema S et al. (2003) The descriptive epidemiology of second primary breast cancer. Epidemiology 14:552-8 |
