Genetically Engineered Lymphocyte Therapy After Peripheral Blood Stem Cell Transplant in Treating Patients With High-Risk, Intermediate-Grade, B-cell Non-Hodgkin Lymphoma

• MTD based on Dose Limiting Toxicity (DLT) (Phase I) [ Time Frame: Within 30 days of T-cell infusion ] [ Designated as safety issue: Yes ]
  Tables will be created to summarize all toxicities and side effects by dose, course, organ, and severity. Determination of the full toxicity profile will include analyses of adverse events using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
  
  
• Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) detection above background [ Time Frame: 28 days after T cell infusion ] [ Designated as safety issue: No ]
  

• Rates of engraftment and persistence [ Time Frame: 28 days after T cell infusion ] [ Designated as safety issue: No ]
  Rates and associated 95% confidence intervals will be estimated.
  
  
• Failure to engraft [ Time Frame: Within 21 days after T-cell infusion ] [ Designated as safety issue: No ]
  Rates and associated 95% confidence intervals will be estimated.
  
  
• Progression-free survival [ Time Frame: Up to at least 15 years ] [ Designated as safety issue: No ]
  Estimated using the Kaplan-Meier methods.
  
  
• Overall survival [ Time Frame: Up to at least 15 years ] [ Designated as safety issue: No ]
  Estimated using the Kaplan-Meier methods.
  
  

PRIMARY OBJECTIVES: I. To assess the safety of cellular immunotherapy utilizing ex vivo expanded autologous TCM-enriched CD8+ T cells genetically-modified to express a CD19-specific chimeric antigen receptor (CAR) in conjunction with a standard myeloablative autologous hematopoietic stem cell transplantation (HSCT) for research participant(s) with high-risk intermediate grade B-lineage non-Hodgkin lymphomas who have relapsed after primary therapy, or who did not achieve complete remission with primary therapy. (Phase I) II. To determine the maximum tolerated dose (MTD) on dose limiting toxicities (DLTs) and to describe the full toxicity profile. (Phase I) III. To determine the rate of research participant(s) receiving TCM-enriched CD8+ T cells genetically-modified to express a CD19-specific CAR for which the transferred cells are detected in the circulation for at least 28 days(+/- 3 days)by woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) quantitative (Q)-polymerase chain reaction (PCR). (Phase II) SECONDARY OBJECTIVES: I. To determine the tempo, magnitude, and duration of engraftment of the transferred T cell product as it relates to the number of cells infused. (Phase II) II. To study the impact of this therapeutic intervention on the development of CD19+ B-cell precursors in the bone marrow as a surrogate for the in vivo effector function of transferred CD19-specific T cells. (Phase II) III. To describe the progression-free and overall survival of treated research participant(s) on this protocol. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of genetically engineered lymphocyte therapy followed by a phase II study. Patients receive standard salvage chemotherapy per standard practice and undergo standard mobilization for stem cell collection with G-CSF and/or plerixafor. Some patients may also receive rituximab intravenously (IV) within 4 weeks of transplantation. Patients receive standard myeloablative conditioning followed by autologous PBSCT. Patients then undergo infusion of ex vivo expanded autologous TCM-enriched CD8+ T cells expressing CD19-specific CAR on day 2 or 3 after transplantation.

After completion of study treatment, patients are followed up periodically for at least 15 years.