This proposal for OPD sponsorship applies autologous gene-modified T cells in a new type of immuno-gene therapy for gastric cancer. The investigators created chimeric IgTCR as molecular fusion products of a single chain humanized anti-CEA antibody (Ab) binding domain with the zeta signaling chain of the TCR. When expressed by gene therapy techniques in recipient T cells, the resulting """"""""designer T cells"""""""" combine the specificity of Ab with the cytotoxic potency of T cells. CEA is expressed at high levels on >80% of gastric cancers, with only minor expression on normal tissues, making CEA a suitable antigen (Ag) for targeting gastric carcinomas. Gastric cancer has a U.S. prevalence of 20,000 patients and takes 12,000 lives annually in the United States;no presently available therapy can cure patients with metastatic disease. Therefore, a cellular therapy against gastric cancer would offer a new therapeutic option to these patients. The investigators previously performed a Phase 1 trial with first generation designer T cells that yield Signal 1 (TCR) on tumor contact. This study showed adequate patient tolerance and yielded preliminary indications of efficacy, but of limited duration. In vitro correlates suggested that activation-induced cell death (AICD) contributed to lack of in vivo persistence of the infused T cells. This prompted a product redesign to add CD28 co-stimulation (Signal 2) on tumor contact via an IgCD28TCR. In preclinical tests, these second generation (2nd gen) designer T cells with Signal 1+2 resisted AICD, with improved survival on contact with CEA+ tumor targets, resulting in superior anti-tumor activity in vitro and in vivo in animal models.
Specific Aims are the following: (1) to conduct Phase 1 trial of 2nd gen designer T cells, a. to assess safety (toxicity/tolerance), and establish maximum tolerated dose/maximum practical dose (MTD/MPD);(2) to assess pharmacokinetics, pharmacodynamics and incidental measures of response. Phase 2 efficacy tests will follow in the post-award period. The hypothesis is that the addition of Signal 2 stimulation will improve the potency and duration of designer T cell action without serious treatment-related toxicities. The investigators anticipate that the survival advantage of these 2nd gen anti-CEA T cells will ultimately translate into extended clinical responses in patients with advanced gastric carcinomas.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project (R01)
Project #
5R01FD003020-03
Application #
7616713
Study Section
Special Emphasis Panel (ZFD1-OPD-L (C1))
Program Officer
Needleman, Katherine
Project Start
2006-02-01
Project End
2010-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
3
Fiscal Year
2009
Total Cost
Indirect Cost
Name
Roger Williams Hospital
Department
Type
DUNS #
625899281
City
Providence
State
RI
Country
United States
Zip Code
02908