This pilot phase I trial studies the side effects of taking ipilimumab after gene-modified T cells and vaccine therapy when treating patients with advanced cancer that has spread to other areas of the body and has not responded to standard therapies. This trial also will determine the best dose of Ipilimumab to use in this combination treatment. T cells are a special type of white blood cell (immune cell) that have the ability to kill cancer cells. T cells are taken from the blood and modified in the laboratory to recognize a specific protein expressed on cancer cells, called NY-ESO-1. This may allow the T cells to target and kill cancer cells that express that protein. Dendritic cells are another type of blood cell that can teach other cells in the body to look for cancer cells and attack them. Giving a dendritic cell vaccine with the NY-ESO-1 protein may help dendritic cells teach the immune system to target cancer cells expressing that protein, and further help the T cells attack cancer. Ipilimumab is a monoclonal antibody, a type of drug manufactured in the laboratory that is similar to antibodies made in the human body that fight off infection. Ipilimumab blocks a protein that turns down the immune system, so blocking this protein may make the immune system more active. This may increase the ability of immune cells to kill cancer cells and improve the effectiveness of the T cell transplant. Giving gene-modified T-cells, a dendritic cell vaccine, and ipilimumab together may teach the immune system to recognize and kill cancer cells that have the NY-ESO-1 protein.
PRIMARY OBJECTIVES: I. The safety of NY-ESO-1 T-cell receptor (TCR) transgenic adoptive cell transfer (ACT) has been reported. The current protocol includes the addition of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) blocking monoclonal antibody ipilimumab to NY ESO TCR ACT in a dose escalation scheme in two study cohorts at 1 and 3 mg/kg of ipilimumab intravenous (i.v.) every three weeks with a maximum of 4 doses (q3wx4). SECONDARY OBJECTIVES: I. To determine the feasibility of delivering the TCR transgenic cell dose and CTLA blockade to patients. II. To determine the persistence of NY-ESO-1 TCR-engineered peripheral blood mononuclear cells (PBMC) in serial peripheral blood samples and in biopsies of accessible metastatic lesions. III. To explore the use of positron emission tomography (PET)-based imaging using the PET tracer \[18F\] fluorodeoxy-glucose (\[18F\]FDG) with the goal of determining if the adoptively transferred NY-ESO-1 TCR-engineered PBMC when administered with ipilimumab home and expand in secondary lymphoid organs and tumor deposits. IV. Clinical antitumor activity recording objective response rate will be an exploratory endpoint in this pilot clinical trial. OUTLINE: This is a dose-escalation study of ipilimumab. CONDITIONING CHEMOTHERAPY REGIMEN: Patients receive cyclophosphamide IV on days -5 and -4 and fludarabine phosphate IV over 30 minutes daily on days -4 to -1. NY-ESO-1 TCR PBMC INFUSION: Patients receive NY-ESO-1 reactive TCR retroviral vector transduced autologous T cells IV on day 0. IPILIMUMAB ADMINISTRATION: Patients receive ipilimumab IV over 90 minutes before the NY-ESO-1 TCR PBMC infusion on day 0 or after the infusion on day 1. Treatment repeats every 3 weeks for up to 4 doses in the absence of disease progression or unacceptable toxicity. NY-ESO-1(157-165) PEPTIDE PULSED DENDRITIC CELL (DC) ADMINISTRATION: Patients receive NY-ESO-1(157-165) peptide pulsed DC vaccine intradermally (ID) on days 1, 14, and 30. LOW DOSE INTERLEUKIN-2 (IL-2) ADMINISTRATION: Patients receive aldesleukin (IL-2) subcutaneously (SC) twice daily (BID) on days 1-14. After completion of study treatment, patients are followed up periodically for 90 days, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
4
Given IV
Given IV
Given NY-ESO-1 reactive TCR retroviral vector transduced autologous T cells IV
NY-ESO-1157-165 peptide pulsed DC vaccine given ID
Given SC
Correlative studies
Correlative studies
Correlative studies
Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
Incidence of toxicity as defined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0
Simple descriptive statistics will be used to summarize toxicities observed after each TCR transgenic cell infusion in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by toxicity table) and nadir or maximum values for the laboratory measures, time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented, as well.
Time frame: Up to 5 years
Maximum tolerable dose (MTD) based on the number of subjects experiencing dose limiting toxicities (DLTs)
Adverse events are defined following the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3.0.
Time frame: 60 days
Feasibility of NY-ESO-1 TCR cells, determined by incidence of preparation not meeting the lot release criteria
Descriptive statistics including simple summary measures and plots appropriate for longitudinal data will be used. If appropriate, single group inferences of counts will be made with 2-sided confidence intervals.
Time frame: 1 month
Transgenic cell persistence, analyzed using immune monitoring and molecular techniques
Molecular analysis of the persistence of cells bearing the NY-ESO-1 TCR complementary deoxyribonucleic acid (cDNA) will be done by real time polymerase chain reaction (PCR) techniques using primers specific for the transgenes and retroviral vector sequences. Immunological monitoring will consist primarily of quantifying T cells bearing surface NY-ESO-1 TCR by NY-ESO-1 126-157/ major histocompatibility complex (MHC) tetramer or dextramer analysis. Descriptive statistics including simple summary measures and plots appropriate for longitudinal data will be used.
Time frame: Up to 5 years
NY-ESO-1 TCR transgenic cell tumor trafficking (imaging), assessed using 18F-FDG PET
Regional uptake of 18F-FDG within metastatic tumor sites and secondary lymphoid organs will be quantified by standard uptake value (SUV) normalized to the body weight of the patient. As an internal quality control, SUVs will also be determined for several normal organs, such as muscle, liver and lungs. Descriptive statistics including simple summary measures and plots appropriate for longitudinal data will be used. If appropriate, single group inferences of SUVs will be made with 2-sided confidence intervals.
Time frame: Up to 60 days after ACT
Antitumor activity, assessed using RECIST
Descriptive statistics including simple summary measures and plots appropriate for longitudinal data will be used.
Time frame: Up to day 90
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