Gene Therapy Using Anti-CEA Cells to Treat Metastatic Cancer

Background:

• We have constructed a single retroviral vector that contains both the alpha and beta chains of a T cell receptor (TCR) that recognizes the carcinoembryonic antigen (CEA), which can be used to mediate genetic transfer of this TCR with high efficiency (greater than 30%) without the need to perform any selection.
• In co-cultures with HLA-A2 and CEA positive tumors, anti-CEA TCR transduced T cells secreted significant amounts of interferon-gamma (IFN-gamma) with high specificity.

Objectives:

Primary objectives:

• To evaluate the safety of the administration of anti-CEA TCR engineered peripheral blood lymphocytes in patients receiving the non-myeloablative conditioning regimen and aldesleukin.
• To determine if the administration of anti-CEA TCR engineered peripheral blood lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer that expresses CEA.
• To determine the in vivo survival of TCR gene-engineered cells.

Secondary objective:

• To determine the in vivo survival of TCR gene-engineered cells.

Eligibility:

Patients who are HLA-A*0201 positive and 18 years of age or older must have

• metastatic cancer whose tumors express the CEA antigen where the life limiting component of the disease is hepatic metastases;
• previously received and have been a non-responder to or recurred to standard care for metastatic disease;

Patients should not have:

• contraindications for high dose aldesleukin administration.

Design:

• Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis (approximately 5 times 10(9) cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth.
• Transduction is initiated by exposure of approximately 10(8) to 5 times 10(8) cells to retroviral vector supernatant containing the anti-CEA TCR genes.
• Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of ex vivo tumor reactive, TCR gene-transduced PBMC plus IV aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses). Patients will receive CD8-enhanced anti-CEA TCR transduced cells.
• Patients will undergo complete evaluation of tumor with physical examination, computed tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has stable disease (SD) or tumor shrinkage, repeat complete evaluations will be performed every 1-3 months. After the first year, patients continuing to respond will continue to be followed with this evaluation every 3-4 months until off study criteria are met.
• The study will be conducted using a Phase I/II optimal design. The protocol will proceed in a phase 1 dose escalation design, with six cohorts. Should a single patient experience a dose limiting toxicity (DLT) at a particular dose level, three more patients would be treated at that 3 dose to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the next higher level. If a level with 2 or more DLTs in 3-6 patients has been identified, three additional patients will be accrued at the next-lowest dose, for a total of 6, in order to further characterize the safety of the maximum tolerated dose (MTD) prior to starting the phase II portion. If a DLT occurs in the first cohort, that cohort will be expanded to 6 patients. If 2 DLTs are encountered in this cohort, patients will be accrued to the de-escalation cohort.
• Once the MTD has been determined, the study then would proceed to the phase II portion. Patients will be entered into two cohorts based on histology: cohort 1 will include patients with metastatic colorectal cancer, and cohort 2 will include patients with other types of metastatic cancer that express CEA.
• For each of the 2 strata evaluated, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled in that stratum.
• The objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-CEA TCR-gene engineered lymphocytes is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% partial response (PR) + complete response (CR) rate (p1=0.20).