This phase I trial studies the safety and feasibility of cytomegalovirus (CMV) specific CD19-chimeric antigen receptor (CAR) T cells in combination with the CMV-modified vaccinia Ankara (MVA) triplex vaccine following lymphodepletion in treating patients with intermediate or high grade B-cell non-Hodgkin lymphoma (NHL) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refectory). CAR T cells are a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added in the laboratory. The special receptor is called CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion. Vaccines such as CMV-MVA triplex are made from gene-modified viruses and may help the body build an effective immune response to kill cancer cells. Giving CMV-specific CD19-CAR T-cells plus the CMV-MVA triplex vaccine may help prevent the cancer from coming back.
Documented informed consent of the participant and/or legally authorized representative
Assent, when appropriate, will be obtained per institutional guidelines
Agreement to allow the use of archival tissue from diagnostic tumor biopsies
If unavailable, exceptions may be granted with study principal investigator (PI) approval
Prior allogeneic stem cell transplant unless the participant has recovered from transplantation and does not have active graft versus host disease (GVHD)
Growth factors within 14 days of enrollment
Platelet transfusions within 7 days of enrollment
Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of inhaled or topical steroids in standard doses is not exclusionary. Physiologic replacement of steroids (prednisone =< 5 mg/day, or equivalent doses of other corticosteroids) is allowed
Single group
Anti-CD19-CAR CMV-specific T-lymphocytes
Biological/VaccineGiven IV
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Computed Tomography
Procedure/SurgeryUndergo CT
Leukapheresis
Procedure/SurgeryUndergo leukapheresis per SOC
Lymphodepletion Therapy
Procedure/SurgeryUndergo lymphodepletion chemotherapy per SOC
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Multi-peptide CMV-Modified Vaccinia Ankara Vaccine
Biological/VaccineGiven IM
Positron Emission Tomography
Procedure/SurgeryUndergo PET
X-Ray Imaging
Procedure/SurgeryUndergo x-ray
Incidence of dose-limiting toxicity
Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0, and the revised American Society for Transplantation and Cellular Therapy (ASTCT) cytokine release syndrome (CRS) grading systems. Will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Incidence of adverse events
Will be assessed and graded according to the NCI CTCAE v5.0, and the ASTCT consensus grading for CRS and neurotoxicity associated with immune effector cells.
Feasibility as assessed by the ability to meet the required cell dose and product release requirement
Feasibility will be assessed by achieving the proposed dose of CMV-specific CD19-CAR T cells per product and meeting product release requirements for enrolled participants. The goal is to manufacture 10 x 10\^6 cells (this is a flat dose).
Short- and long-term cytomegalovirus (CMV)-specific CD19-chimeric antigen receptor (CAR) T cell expansion and persistence
Will be assessed longitudinally. Persistence is defined as detection of \>= 0.1% of CMV-specific CD19-CAR T cells in CD3+ cells in peripheral blood, 28 days after vaccine administration, by flow cytometry and Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element quantitative polymerase chain reaction (Q-PCR). Expansion is defined as an increase of 2-fold in CMV-specific CD19-CAR T cells after Triplex administration compared with pre-vaccination cell number. Response to Triplex will be assessed based on numbers of EGFR+, pp65-specific interferon gamma (IFNy)+ and CD137+T cells.
Clinically significant CMV reactivation
Clinically significant defined as \> 1250 IU/ml or 500 GC/mL) CMV reactivation requiring management treatment after CAR T cell infusion as assessed by PCR.
Disease response (complete response/minor response/partial response/disease progression/stable disease)
Will be assessed according to International Working Group consensus response evaluation criteria in lymphoma 2017. The specific time trend for CMV-specific CD19-CAR T cells will be assessed using linear mixed effects modeling. The overall fit of the model will be evaluated graphically by taking a scatter plot of data for the CAR T cells and applying an overlay of the line generated by the model. To assess changes over time, functional regression modeling will be used.
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City of Hope Medical Center
Lead sponsor
National Cancer Institute (NCI)
Collaborator
