Trial of Anti-CD19 and Anti-CD20 Bicistronic Chimeric Antigen Receptor T Cells for Treating B-Cell Malignancies

Background:

• Improved treatments for a variety of treatment-resistant malignancies including B-cell lymphomas, and chronic lymphocytic leukemia (CLL) are needed.
• A particular need is development of new treatments for chemotherapy-refractory B- cell malignancies.
• 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. These results have established anti-CD19 CAR T- cells as an important therapy for relapsed lymphoma, but only about 40% of patients receiving anti-CD19 CAR T- cells have durable complete remissions.
• Most B-cell malignancies express CD19 and CD20, but expression of CD19 and CD20 can be lost or diminished.
• CD19 and CD20 are not expressed by normal cells except for B cells and some plasma cells.
• We have constructed a novel gene therapy construct that encodes a fully-human anti- CD19 CAR with a CD28 domain and a fully-human anti-CD20 CAR with a 4-1BB domain.
• T -cells expressing this CAR construct, called Hu1928-Hu20BB-Long, can specifically recognize CD19 and CD20-expressing target cells in vitro and eradicate CD19 or CD20-expressing tumors in mice.
• One CAR expressed in this CAR construct, Hu19-CD828Z has been tested in humans before. The other CAR in the total construct, Hu20-CD8BBZ-Long, has not been tested in humans before.
• 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.

Objective:

• Determine the safety of administering T-cells expressing a novel fully-human anti- CD19 and anti-CD20 CAR construct to participant with advanced B-cell malignancies.

Eligibility:

• Participant must have any B-cell lymphoma, or CLL/small lymphocytic lymphoma (SLL), or Gray-zone lymphoma. Lower grade lymphomas transformed to diffuse large B-cell lymphoma (DLBCL) are potentially eligible.
• Age >= 18 years of age and <=75 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 protocol-required leukapheresis or CAR T-cell infusion. In addition, sixty days must elapse from therapy with antibodies targeting CD19 or CD20 and CAR T-cell infusion, and at least 180 days must elapse since any prior CAR T-cell therapy or checkpoint therapy.
• The participant s malignancy will need to be assessed for CD19 and C20 expression by flow cytometry or immunohistochemistry performed at the NIH. If unstained, paraffin- embedded bone marrow or lymphoma tissue sections are available from prior biopsies, these can be used to determine CD19 and CD20 expression by immunohistochemistry; otherwise, Participant will need to come to the NIH for a biopsy to determine CD19 and CD20 expression. The sample for CD19 and CD20 expression must come from a biopsy obtained after any CD19 or CD20-targeted therapies such as monoclonal antibodies if such antibodies or CAR T-cell therapies have been received by the Participant.
• Either CD19 or CD20 expression must be uniform . Uniform CD19 or CD20 expression is defined as no obvious lymphoma population lacking antigen expression can be present.

Design:

• This is a phase I dose-escalation trial
• T-cells obtained by leukapheresis will be genetically modified to express the Hu1928- Hu20BB-Long CAR construct.
• Participants will receive a lymphocyte-depleting chemotherapy conditioning regimen with the intent of enhancing the activity of the infused CAR-expressing T- cells.
• 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 anti- CAR- expressing T- cells .
• The initial dose level of this dose-escalation trial will be 0.66x10^6 CAR+ T- cells/kg of recipient bodyweight.
• The cell dose administered will be escalated until a maximum tolerated 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.