"Phase II/Pilot Study of 2nd Generation Anti-CEA Esigner T Cells in Adenocarcinomas"
"Phase II/Pilot Study of 2nd Generation Anti-CEA Esigner T Cells in Adenocarcinomas"
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 remis-sions of cancer. However, T cells are easily tolerized 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. We will achieve this by preparing chimeric IgCD28TCR genes in mammalian expression vectors to yield "designer T cells" from normal patient cells. This extends the approach of Anderson, Rosenberg and co-workers to introduce or augment expression of genes in patients' T cells in a therapeutic setting.
Prior studies in model systems demonstrated that recombinant IgCD28TCR could direct modified T cells to respond to antigen targets with IL2 secretion, cellular proliferation, and cytotoxicity, the hallmarks of an effective, self-sustaining immune response. It therefore becomes of paramount interest to extend these studies to a human system of widespread clinical relevance to explore the clinical potential of this new technology. The target antigen for these studies is carcinoembryonic antigen (CEA) which is predominantly expressed on tumors of the colon and rectum, breast, pancreas and other sites.
CEA is perhaps the most prominent tumor marker among malignancies of epithelial origin: colorectal carcinoma, with 60-94% of tumors positive in patients with advanced disease; breast carcinoma, with 30-60% of metastatic cases positive for CEA; and cancers of the lung, liver, pancreas, head and neck, bladder, cervix and prostate with 30% or more with CEA+ tumors.
The application of these therapies in the four Phase II/Pilot clinical sub studies listed below proceed after collecting patient lymphocytes by leukapheresis, which are then modified by transfer of the chimeric gene for Ig-CD28-TCRzeta. Cells are selected in culture with amplification and activation of the now-specific anti-tumor T cells. These are then re infused into the patients, with IL2 supplementation, and toxicity and response are monitored.
There are four sub studies embedded within this Phase II Study of Second Generation Designer T Cells in CEA-expressing Adenocarcinomas. The embedded studies are:
A total of 12 subjects per protocol or a total of 48 subjects will be enrolled combining the enrollment of the 4 CEA-expressing protocols.
Inclusion Criteria:
Where preserved tumor tissue is available, direct immuno¬histochemical staining of tumor is obtained to demonstrate CEA expression on tumor cells.
Patient must be at least 18 years of age.
Patient able to understand and sign informed consent.
Patient with a life expectancy of greater than four months.
Patient failed standard potentially curative therapy.
Patient with performance status of 0 to 1 (ECOG).
Patient with adequate organ function as defined by:
A normal cardiac stress test for inducible ischemia or arrhythmia within 12 weeks prior to enrollment for all patients over 50 years old or those with abnormal EKG or any history or symptoms suggestive of cardiac disease.
-- No serious, symptomatic obstructive or emphysematous lung disease, or asthma requiring intravenous medications within the past 12 months; no serious lung disease associated with dyspnea at normal activity levels grade III) or at rest (grade IV), due to any cause (including cancer metastases and pleural effusions). The patient will be ineligible if PFTs show an FEV1 <1.3 liters or a DLCO <50% within 12 weeks of study entry.
Exclusion Criteria: