This phase I trial studies the side effects of NY-ESO-1 TCR engineered peripheral blood mononuclear cells (PBMC) and peripheral blood stem cells (PBSC) after melphalan conditioning regimen in treating participants with multiple myeloma that has come back or does not respond to treatment. The melphalan 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. Giving NY-ESO-1 TCR PBMC and PBSC after melphalan may work better at treating multiple myeloma.
PRIMARY OBJECTIVES: 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 melphalan 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 T-cell receptor (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). TERTIARY OBJECTIVES: 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 extramedullary disease sites. OUTLINE: G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of cells, participants undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem cells. Participants receive filgrastim subcutaneously (SC) on mobilization days 1-4 and up to mobilization day 8 and plerixafor SC starting on mobilization day 4 up to day 8. During mobilization, participants will undergo mobilized leukapheresis to obtain PBSC. Participants also undergo an unmobilized leukapheresis on day -5 before infusion of cells in order to obtain PBMC. CHEMOTHERAPY CONDITIONING REGIMEN: Participants receive melphalan intravenously (IV) on days -3 to -2. Participants receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, participants receive aldesleukin (interleukin-2 or IL-2) SC twice daily (BID) for up to 7 days. Participants receive the 18F-FHBG IV, and after 1 hour, undergo PET/computed tomography (CT) on days 30 and 90. After day 100, participants receive lenalidomide orally (PO) once daily (QD) for 21 days. Courses of lenalidomide repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up monthly after day 90 until disease progression and annually for up to 15 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Given IV
Given SC
LV-NYESO TCR /sr39TK PBSC and RV-NYESO TCR PBMC given IV
Undergo PET/CT
Given SC
Correlative studies
Given PO
Undergo leukapheresis
Given IV
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, then this dose level will have exceeded the 33% rate, and the study will be terminated.
Time frame: Up to 90 days
Feasibility of NY-ESO-1 TCR transgenic cells
The 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: Up to 1 month after transgenic cell adoptive transfer
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: 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: 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: Up to 2 years after transgenic cell adoptive transfer
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
Long term monitoring for replication competence of retrovirus (RCR) and lentivirus (RCL)
Will be assessed by polymerase chain reaction.
Time frame: Up to 12 months post cell administration
Immunological monitoring
Will be assessed by NY-ESO-1126-157/MHC 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 International Myeloma Working Group (IMWG) Response Criteria.
Time frame: Up to 15 years
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
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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