Anti-CD19 Chimeric Antigen Receptor T-Cell Immunotherapy for Chronic Lymphocytic Leukemia (CLL)

Description

Background:

* Improved treatments for relapsed and refractory chronic lymphocytic leukemia (CLL) are needed.
* T cells can be genetically modified to express chimeric antigen receptors (CARs) that specifically target malignancy-associated antigens.
* Autologous T cells genetically modified to express CARs targeting the B-cell antigen CD19 have caused complete remissions in patients with leukemia or lymphoma. However, there is no FDA-approved CAR T-cell product for CLL. Responses to CAR T-cell therapy in CLL have historically been lower than in other B-cell malignancies.
* CD19 is uniformly expressed on CLL.
* CD19 is not expressed by normal cells except for B cells, follicular dendritic cells, and some plasma cells.
* We have constructed a novel gene therapy construct that encodes a fully-human anti-CD19 CAR.
* The conditioning regimen for this trial will include rituximab, fludarabine, and cyclophosphamide.
* Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and neurological toxicities. Elimination of normal B cells is probable, and unknown toxicities are also possible.

Primary objective, Phase I:

-Determine the safety of administering a novel conditioning regimen and T cells expressing the Hu19-CD828Z CAR to participants with advanced CLL.

Primary objective, Phase II:

-Determine the overall response rate (ORR) of a novel conditioning regimen and T cells expressing the Hu19-CD828Z CAR for participants with advanced CLL.

Eligibility:

* Participant must have CLL or small lymphocytic lymphoma (SLL).
* Age >= 18 years of age at time of enrollment
* Participant must have malignancy that is measurable on a CT scan or by flow cytometry of bone marrow or blood.
* Participant must have a creatinine of 1.5 mg/dL or less and a normal cardiac ejection fraction.
* An ECOG performance status of 0-1 is required.
* No active infections are allowed including hepatitis B or hepatitis C.
* Absolute neutrophil count >= 1000/microL, platelet count >= 50,000/microL, hemoglobin >= 8g/dL
* Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal unless liver involvement by malignancy is demonstrated.
* At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids) and the first dose of protocol-required rituximab. In addition, 60 days must elapse from therapy with antibody-based treatments targeting CD19 and CAR T-cell infusion.
* Prior CAR T-cell therapy is not allowed.
* Demonstration of CD19 expression by the CLL/SLL is required for eligibility.
* CD19 expression must be uniform . Uniform CD19 expression is defined as no obvious CD19-negative CLL/SLL being present.

Design:

* This is a phase I dose-escalation trial with an expansion cohort (Phase II portion)
* T cells obtained by leukapheresis will be genetically modified to express the Hu19-CD828Z CAR.
* Participants will receive 2 doses of rituximab and a lymphocyte-depleting chemotherapy conditioning regimen with the intent of decreasing the burden of CLL, which might reduce toxicity and improve anti-leukemia outcomes.
* Rituximab will be given in 2 doses, of 375 mg/m^2 for the first dose and 500 mg/m^2 for the second dose.
* The chemotherapy conditioning regimen is cyclophosphamide 500 mg/m^2 daily for 3 days and fludarabine 30 mg/m^2 daily for 3 days. Fludarabine will be given on the same days as the cyclophosphamide.
* Three days after the chemotherapy ends, participants will receive an infusion of CAR T cells.
* The initial dose level of this dose-escalation trial will be 1.0×10^6 CAR+ T cells/kg of recipient bodyweight.
* The CAR T-cell cell dose administered will be escalated until a maximum tolerated dose or an optimal dose is determined.
* Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to monitor for toxicity.
* Outpatient follow-up is planned for 2 weeks and 1, 2, 3, 4, 6, 9, and 12 months after the CAR T-cell infusion; less frequent follow-up is required more than 1 year after infusion. Long-term gene-therapy follow-up for a total of 15 years after infusion is required.