Background:
Chronic lymphocytic leukemia (CLL),small lymphocytic lymphoma (SLL) and B-cell acute lymphoblastic leukemia or lymphoma (ALL) are blood cancers that affect certain white blood cells. Advanced forms of these diseases are difficult to treat. CD19 is a protein often found on the surfaces of these cancer cells. Researchers can modify a person's own immune cells (T cells) to target CD19. When these modified T cells are returned to the body-a treatment called anti-CD19 chimeric antigen receptor (CAR) T cell therapy-they may help kill cancer cells.
Objective:
To test anti-CD19 CAR T cell therapy in people with CLL or SLL and ALL.
Eligibility:
People aged 18 years and older with CLL or SLL and ALL that has not been controlled with standard drugs.
Design:
Participants will be screened. They will have imaging scans and tests of their heart function. If a sample of tissue from their tumor is not available, a new one may be taken; the sample will be tested for CD19.
Participants will receive a drug to reduce the leukemia cells in their blood. Then they will undergo apheresis: Blood will be taken from the body through a needle. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different needle. The collected T cells will be gene edited to make them attack cells with CD19.
Participants will take drugs to prepare them for treatment for 3 days. These drugs will start 5 days before the treatment. Then their own modified CAR T cells will be returned to their bloodstream. Participants will stay in the hospital for at least 9 days after the treatment.
Follow-up visits will continue for 5 years.
Malignancy criteria
Histologically confirmed participants with either CLL or SLL or B-cell acute lymphoblastic leukemia or lymphoma (ALL) via immunohistochemical or flow cytometry methods will be eligible. Participants with evidence of Richter s transformation of CLL/SLL are also eligible. Participants with Richter s transformation must have current or prior evidence of CLL, confirmed by review of a current or prior histological sample by NIH pathologists or confirmed by flow cytometry performed at the NIH.
Demonstration of CD19 expression on CLL/SLL or ALL, as assessed by the NCI Laboratory of Pathology or NIH Department of Laboratory Medicine Hematopathology section. For participants with pathologically confirmed Richter s transformation, the transformed cells must also have CD19 expression.
CD19 expression must be uniform meaning no populations of clearly CD19-negative CLL/SLL, Richter s or ALL cells are observed.
Participants who are receiving any other investigational agents.
Participants who have had prior CAR T-cell therapy.
Participants who have had a live-attenuated or viral vector-based vaccine in the last 60 days prior to pre-leukapheresis rituximab. Participants who plan to receive a live attenuated or viral vector-based vaccine within the first 100 days after CAR T-cell infusion.
Participants that require urgent therapy due to tumor mass effects or spinal cord compression.
Sequential
Autologous HuCD19 ( Anti-CD19)CAR T cells
Biological/Vaccine1.0x10\^6 CAR+T-cells - 12x10\^6 CAR+ T cells/kg (weight based dosing per cohort) infused on day 0
Cyclophosphamide
Drug500 mg/m\^2 IV infusion over 30 minutes on days -5, -4 and -3
Fludarabine
Drug30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3
Rituximab
Drug500 mg/m\^2 IV infusion over 30 minutes on day -5; 375 mg/m\^2 IV infusion over 30 minutes on days 2-9 prior to apheresis
Phase II: Determine the overall response rate (ORR) of T cells expressing an anti-CD19 CAR with a fully-human single chain variable fragment (scFv) to participants with advanced CLL/SLL or ALL.
Overall Response Rate will be evaluated using published criteria; these will be reported along with a 95% confidence interval
Phase I: Determine the safety of administering T-cells expressing a fully-human anti-CD19 CAR to participants with advanced CLL/ SLL orALL.
Adverse Events (AE) by type, grade, and frequency
Phase II: Determine the proportion of grade 3-4, and 5 adverse events at the Optimal Dose
Adverse Events (AE) by type, grade, and frequency
Phase I+II: Determine the ORR for re treatment with rituximab, chemotherapy and CAR T cells in eligible patients
Overall Response rate (ORR= CR + PR) for re-treatment with Rituximab will be recorded if ORR occurs at any response assessment time-point.
Phase I+II: Assess duration of responses
Duration of response from date of response will be measured for no more than 5 years after the last participant has been enrolled on the trial.
Phase I+II: Assess complete response rate
Complete Response rate (CR) in participants who receive subsequent infusion, up to 5 years after entry date for last participant
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