This phase I clinical trial evaluates the safety and feasibility of administering NY-ESO-1 TCR (T cell receptor)engineered peripheral blood mononuclear cells (PBMC) and peripheral blood stem cells (PBSC) after a myeloablative conditioning regimen to treat patients with cancer that has spread to other parts of the body. The conditioning chemotherapy makes room in the patient?s bone marrow for new blood cells (PBMC) and blood-forming cells (stem cells) to grow. Giving NY-ESO-1 TCR PBMC and stem cells after the conditioning chemotherapy is intended to replace the immune system with new immune cells that have been redirected to attack and kill the cancer cells and thereby improve immune system function against cancer.
PRIMARY OBJECTIVE: I. To determine the safety of administering the combination of autologous peripheral blood mononuclear cells (PBMC) and CD34+ peripheral blood stem cells (PBSC) following a reduced intensity conditioning regimen, both of which have been genetically modified to express NY-ESO-1 TCR. SECONDARY OBJECTIVES: I. To determine the feasibility of delivering the combination of TCR transduced autologous PBMC and CD34+ PBSC to patients. II. To determine the persistence of NY-ESO-1 TCR transduced PBMC and the progeny of TCR transduced PBSC in serial peripheral blood samples. III. Objective response rate (ORR). EXPLORATORY OBJECTIVE: I. To explore the use of positron emission tomography (PET)-based imaging using the PET tracer 9-4-\[18F\]fluoro-3-(hydroxymethyl)butylguanine (\[18F\]FHBG) with the goal of determining whether the adoptively transferred NY-ESO-1 TCR transduced PBSC home to bone marrow, differentiate into T cells and expand in secondary lymphoid organs and tumor deposits. OUTLINE: G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of cells, patients undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem cells. Patients receive G-CSF subcutaneously (SC) on mobilization days 1-8 and plerixafor SC on mobilization days 4-7, during mobilization, patients will undergo mobilized leukapheresis to obtain PBSC. Patients also undergo an unmobilized leukapheresis on day -5 before infusion of cells in order to obtain PBMC. CHEMOTHERAPY CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) on days -4 to -2 and fludarabine IV over 30 minutes on days -3 to -2. Patients receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and after approximately 24 hours, patients receive RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, patients receive aldesleukin (interleukin-2 (IL) or IL-2) SC twice daily (BID) for up to 7 days. Patients undergo blood collection for safety and immune monitoring on days 0, 1, 3, 5, 7, 14, 30, 60, 90, and 120. Patients receive the PET tracer 18F-FHBG IV, and after 1 hour, undergo PET/computed tomography (CT) on days 25 and 120. After completion of study treatment, patients are followed up every 2-3 months for 2 years, every 6 months for 5 years, and annually for 15 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
5
Given IV
Given SC
Given IV
Given LV-NYESO TCR/sr39TK PBSC IV and RV-NYESO TCR PBMC IV
Undergo PET/CT
Given SC
Given IV
Undergo leukapheresis
Given SC
Undergo PET/CT
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
Incidence of dose limiting toxicity
Safety will be assessed by monitoring and recording potential adverse effects of the treatment using the Common Toxicity Criteria at each study visit. Subjects will be monitored by medical histories, physical examinations and blood studies to detect potential toxicities from the treatment. If there are no dose limiting toxicities observed, the cohort will be expanded to 12 subjects. If 1/3 are observed, up to 6 subjects will be recruited. If less than 2/6 are observed, the cohort will be expanded to a total of 12 subjects. If a dose limiting toxicity is observed in 2 or more of 6 subjects, the
Time frame: Up to 90 days
Detection of replication competent retrovirus and replication competent lentivirus
Will be assessed by polymerase chain reaction.
Time frame: Up to 12 months post cell administration
Duration of overall complete response
Will evaluate duration of overall complete response.
Time frame: From the time measurement criteria has been first met for complete response until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years
Duration of overall response
Will evaluate duration of overall response.
Time frame: From the time measurement criteria is met for complete response/partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years
Persistence of transduced T cells
Analysis will be performed using immune monitoring techniques. The number of days until the percentage of cells expressing both NYESO- 1 TCR and CD3 drops below the baseline percentage.
Time frame: Time Frame: Up to 2 years after transgenic cell adoptive transfer
Engraftment and persistence of transduced progeny T cells
Analysis will be performed using immune monitoring techniques. The number of days until the vector copy number in the progeny T cells is undetectable.
Time frame: Time Frame: Up to 2 years after transgenic cell adoptive transfer
Engraftment and persistence of transduced T cells and progeny T cells
Analysis will be performed both using immune monitoring and molecular techniques. The number of days until the vector copy number in the T cells is undetectable.
Time frame: Time Frame: Up to 2 years after transgenic cell adoptive transfer
Feasibility of generation NY-ESO-1 TCR transgenic T cells and NY-ESO-1 TCR/sr39TK transgenic stem cells that meet the lot release criteria
Feasibility of manufacturing will be assessed as: The number of manufacturing products meeting the lot release criteria after an acceptable number of CD34+ cells have been obtained.
Time frame: Time Frame: Up to 1 month after transgenic cell adoptive transfer
Immunological monitoring will consist primarily of quantifying T cells bearing surface NY-ESO-1 TCR
Will be assessed by NY-ESO-1126-157/MHC (major histocompatibility complex) dextramer analysis. Functional assays like enzyme-linked immunosorbent assay, intracellular cytokine staining, and/or multicytokine array assays will complement the results. Immunological assays will be compared between 1) pre-infusion peripheral blood mononuclear cells and peripheral blood stem cells, 2) an aliquot of the engineered peripheral blood lymphocytes and stem cells at the time of infusion and 3) cells recovered from patients? peripheral blood after adoptive transfer.
Time frame: Up to 15 years
Objective response
Potential objective responses to this combinatorial immunotherapy will be recorded following Response Evaluation Criteria in Solid Tumors version 1.1 criteria.
Time frame: Up to 15 years
Persistence of TCR gene transduced cells
Will be assessed by semi quantitative deoxyribonucleic acid-polymerase chain reaction using primers specific for vector sequence.
Time frame: Up to 15 years
Time to disease progression
Will evaluate length of time until disease progression.
Time frame: Time from the date of cell infusion (day 0) to the date of progressive disease first documented, or death whichever occurs first, assessed up to 15 years
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