This phase I trial tests the safety, side effects, and best dose of intracerebroventricularly (ICV) administered CD19-chimeric antigen receptor (CAR) T cells in treating patients with central nervous system (CNS) lymphoma. CAR T cell therapy is 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, CD19, on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. ICV is an injection technique that delivers the CD19-CAR T cells directly into the cerebrospinal fluid (which flows in and around the hollow spaces of the brain and spinal cord, and the thin layers of tissue that cover and protect the brain and spinal cord) in the brain, through a surgically placed catheter. Giving CD19-CAR T cells ICV may be more effective at treating patients with CNS lymphoma than giving them via other methods.
Participant must have the ability to understand and the willingness to sign a written informed consent
Note: For research participants who do not speak English, a short form consent may be used with a City of Hope (COH) certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated full consent is processed. However, the research participant can proceed with lymphodepletion (if applicable) and CAR T cell infusion only after the translated full consent form is signed
Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable exceptions may be granted with study principal investigator (PI) approval
Age >= 18 years
Participant has not yet recovered from toxicities of prior therapy
Presence of systemic lymphoma
Participant with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of signing the screening and leukapheresis consent
Participant with known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, including seizure disorder
Single group
Aspiration
Procedure/SurgeryUndergo CSF aspiration
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Catheterization
Procedure/SurgeryUndergo catheterization
CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem T-lymphocytes
Biological/VaccineGiven ICV
Computed Tomography
Procedure/SurgeryUndergo CT
Cyclophosphamide
DrugGiven IV
Fludarabine
DrugGiven IV
Leukapheresis
Procedure/SurgeryUndergo leukapheresis
Lumbar Puncture
Procedure/SurgeryUndergo lumbar puncture
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Positron Emission Tomography
Procedure/SurgeryUndergo PET
Incidence of adverse events
Will be assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0, particularly dose-limiting toxicities (DLTs), cytokine release syndrome (CRS) based on the revised CRS grading system by American Society for Transplantation and Cellular Therapy Consensus Criteria, and all other toxicities. Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated for participants experiencing DLTs, each type of cytopenia, disease response and progression free survival (PFS) at 6 months. All toxicities and side effects will be summarized in tables by period, organ, severity and attribution.
Disease response
Will be assessed per International Primary Central Nervous System Lymphoma Collaborative Group criteria.
Chimeric antigen receptor (CAR) T and endogenous T cell levels and phenotype
Detected in peripheral blood (PB) and cerebral spinal fluid (CSF) when available, (absolute number per uL by flow). CAR T cell level and cytokines will be interrogated if CRS or neurotoxicity attributed at the probable level to CAR T cells are observed. Statistical and graphical longitudinal methods will be used to describe the profile of the CAR T cells, and endogenous immune cell populations including B cells through one-year post T cell infusion. Regression analysis will be used to assess the relationship between CAR T cell levels and B cells levels.
Cytokine levels
Measured in PB, and CSF, when available. CAR T cell level and cytokines will be interrogated if CRS or neurotoxicity attributed at the probable level to CAR T cells are observed. Cytokine levels (PB and CSF) will be described using longitudinal statistical and graphical methods over the study period.
B cell level
Measured in PB. CAR T cell level and cytokines will be interrogated if CRS or neurotoxicity attributed at the probable level to CAR T cells are observed. Statistical and graphical longitudinal methods will be used to describe the profile of the CAR T cells, and endogenous immune cell populations including B cells through one-year post T cell infusion. Regression analysis will be used to assess the relationship between CAR T cell levels and B cells levels.
Anemia, neutropenia, thrombocytopenia, and hypogammaglobulinemia lasting longer than 60 days or deemed medically significant
Measured in PB. Rates and associated 90% Clopper and Pearson Binomial confidence limits will be estimated for each type of cytopenia.
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City of Hope Medical Center
Lead sponsor
National Cancer Institute (NCI)
Collaborator
