T Cells Expressing Fully-human Anti-CD19 and Anti-CD20 Chimeric Antigen Receptors for Treating B-cell Malignancies and Hodgkin Lymphoma

Background: * Improved treatments for a variety of treatment-resistant malignancies including B-cell lymphomas, and chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma 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-cluster of differentiation 19 (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 cluster of differentiation 20 (CD20), but expression of CD19 and CD20 can be lost or diminished. * The malignant cells of Hodgkin lymphoma, Hodgkin Reed-Sternberg cells, originate from B cells, which is the rationale for treating Hodgkin lymphoma with T cells targeting CD19 and CD20. * 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 cluster of differentiation 28 (CD28) domain and a fully-human anti-CD20 CAR with a 4-1BB (cluster of differentiation 37) domain. * T cells expressing this CAR construct, called Hu1928-Hu20BB, 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, 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. Objectives: Primary -Determine the safety and feasibility of administering T cells expressing a novel fully-human anti- CD19 and anti-CD20 CAR construct to patients with advanced B-cell malignancies and Hodgkin lymphoma. Exploratory * Evaluate serum cytokine levels and associations with anti-malignancy efficacy and toxicity * Evaluate clinical predictors of anti-lymphoma responses and toxicity. * Evaluate phenotype of infused CAR T cells and CAR T cells from the blood of patients. Eligibility: * Patients must have any B-cell lymphoma, or CLL/small lymphocytic lymphoma (SLL), Gray-zone lymphoma, nodular lymphocyte-predominance Hodgkin lymphoma, or classical Hodgkin lymphoma with any CD19 or CD20 expression on Reed-Sternberg cells. Lower grade lymphomas transformed to diffuse large B-cell lymphoma (DLBCL) are potentially eligible as is primary mediastinal B-cell lymphoma and all other subtypes of DLBCL. Burkitt and mantle cell lymphoma are potentially eligible. * Patients must have malignancy that is measurable on a computed tomography (CT) scan or by flow cytometry of bone marrow or blood. * Patients must have a creatinine of 1.5 mg/dL or less and a normal cardiac ejection fraction. * An Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 is required. * No active infections are allowed including hepatitis B or hepatitis C. * Absolute neutrophil count\>=1000/mL, platelet count\>=50,000/mL, hemoglobin\>=8g/dL * Serum alanine aminotransferase (ALT) and aspartate aminotransferase (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. Thirty days must elapse from therapy with antibodies targeting CD19 or CD20 and CAR T-cell infusion. * The patient's malignancy will need to be assessed for CD19 and C20 expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (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, patients 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 patient. * For classical Hodgkin lymphoma only, a biopsy from any time from any institution that shows any CD19 or CD20 expression on Reed-Sternberg cells is adequate for eligibility. CD19 or CD20 expression on the Reed-Sternberg cells that is weak or only present on some Reed-Sternberg cells by immunohistochemistry is compatible with protocol eligibility. * For all lymphoma types except for classical Hodgkin lymphoma, 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. Antigen expression can be assessed by either immunohistochemistry or flow cytometry. Design: * This is a phase I dose-escalation trial * Patients will undergo leukapheresis * T-cells obtained by leukapheresis will be genetically modified to express the Hu1928-Hu20BB CAR construct. * Patients 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 squared daily for 3 days and fludarabine 30 mg/m squared daily for 3 days. Fludarabine will be given on the same days as the cyclophosphamide. * Two days after the chemotherapy ends, patients 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, 16 days (neurologic checks), 21 days (neurologic checks) 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.