Modified White Blood Cells That Secrete IL-2 and Express a Protein That Targets the ESO-1tumor Protein for Metastatic Cancer

Background:

• In prior trials we have shown that adoptive transfer of lymphocytes, transduced with a T cell receptor (TCR) that recognizes the NY-ESO-1 antigen, can mediate regression of metastatic cancer, though responses are often transient, and complete responses are rare.
• Interleukin-12 (IL-12) is an important immunostimulatory cytokine. We have constructed a retroviral vector that contains an inducible single chain IL-12 driven by an NFAT responsive promoter which can be used to mediate transfer of this gene into anti-tumor lymphocytes. This construct enables the secretion of IL-12 following stimulation of the TCR.
• Transduction of the IL-12 gene into mouse anti-tumor lymphocytes results in a profound increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice. These cells have a profound advantage in inducing anti-tumor responses because very few cells are needed and there is no requirement for the concomitant administration of interleukin-2 (IL-2) as is the case for conventional cell transfer immunotherapies.
• Based on these studies we have now used a retrovirus that encodes an inducible human single chain IL-12 driven by an NFAT responsive promoter and a retrovirus that encodes an anti-NY-ESO-1 TCR to cotransduce autologous lymphocytes for the treatment of patients with metastatic cancer that expresses the NY-ESO-1 antigen.

Objectives:

Primary objectives:

• To evaluate the safety of the administration of IL-12 and anti-NY-ESO-1 engineered lymphocytes in patients receiving a non-myeloablative conditioning regimen.
• To determine if the administration of the transduced lymphocytes to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer.

Secondary objective:

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

Eligibility:

Patients who are 18 years of age or older must have

• Metastatic cancer whose tumors express the ESO antigen;
• ECOG performance status 0 or 1;

Design:

• Autlogous lymphocytes will be cotransduced with retroviral vectors, encoding IL-12 and anti- NY-ESO-1 TCR.
• Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12/anti-ESO TCR gene-transduced lymphocytes.
• Patients will undergo complete evaluation of tumor with physical examination, CT of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has 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. Initially, the protocol will enroll 1 patient in each of the first 3 dose cohorts unless that patient experiences a dose limiting toxicity (DLT). Following cohort 3, all subsequent cohorts will proceed in a phase 1 dose escalation design, with 5 cohorts of n=3. Should a single patient experience a DLT due to the cell transfer at a particular dose level, additional patients would be treated at that 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, the study will be terminated.
• Once the MTD has been determined, the study then will proceed to the phase II portion using a phase II optimal design where initially 21 evaluable patients will be enrolled in each of 2 cohorts. 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.
• The objective will be to determine if the combination of lymphocyte depleting chemotherapy, and IL-12/ESO TCR gene engineered lymphocytes is associated with a complete response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).