cd19 car t cells for b cell malignancies after allogeneic transplant

Conditions: Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia

Summary: this phase i/ii trial studies the safety and toxicity of post-transplant treatment with donor t cells engineered to express a chimeric antigen receptor (car) targeting cd19 in patients who have had a matched related allogeneic hematopoietic stem cell transplant for a cd19+ b cell malignancy.

primary objectives: i. to assess the safety and feasibility of pre-emptive adoptive t cell therapy using ex vivo expanded cytomegalovirus (cmv)- or epstein-barr virus (ebv)-specific t cells derived from donor cd62l+ central memory (tcm) cells and genetically modified to express a cd19-specific chimeric antigen receptor (car) in patients in complete remission after human leukocyte antigen (hla)-matched related donor hematopoietic stem cell transplantation (hct) for cd19+ b cell malignancies at high risk of post-hct relapse. (cohort a) ii. to assess the safety and feasibility of adoptive t cell therapy using ex vivo expanded cmv- or ebv-specific t cells derived from donor cd62l+ tcm cells and genetically modified to express a cd19-specific car in patients with persistent, progressive or relapsed disease after hla-matched related donor hct for cd19+ b cell malignancies. (cohort b) secondary objectives: i. to determine the duration of in vivo persistence of adoptively transferred bi-specific cd8+ t cells, and the phenotype of persisting t cells. ii. to determine if adoptively transferred bi-specific cd8+ t cells traffic to the bone marrow and function in vivo. iii. to determine if adoptively transferred bi-specific cd8+ t cells proliferate in allogeneic hct recipients that reactivate cmv or ebv. iv. to determine if the adoptive transfer of bi-specific cd8+ t cells eliminates cd19+ tumor cells in the subset of patients with a measurable tumor burden prior to t cell transfer. outline: at least 30 days after hct, patients will receive one intravenous (iv) infusion of cmv/cd19 or ebv/cd19 bi-specific cd8+ t cells. after completion of study treatment, patients are followed up periodically for 15 years.

Eligibility criteria:
inclusion criteria: * patients with cd19+ b cell malignancy who have persistent, relapsed or progressive disease after hematopoietic stem cell transplant from an human leukocyte antigen (hla)-matched related donor or patients with cd19+ b cell malignancy who are planned for or have had a hematopoietic stem cell transplant from an hla-matched related donor and are at risk of relapse after hct defined by any one of the disease-specific criteria listed below: * philadelphia chromosome negative acute lymphoblastic leukemia: * beyond first complete remission (cr) at the time of pre-transplant evaluation * required \> 1 cycle of induction chemotherapy to achieve cr * first morphologic cr but with evidence of minimal residual disease by flow cytometry, conventional cytogenetics, fluorescence in situ hybridization (fish) or polymerase chain reaction (pcr) * first cr with poor risk cytogenetics (t(4:11), t(8;14), hypodiploidy, near triploidy or \> 5 cytogenetic abnormalities) at diagnosis * planned for or have had a reduced intensity conditioned or non-myeloablative transplant * philadelphia positive acute lymphoblastic leukemia * not in cr at the time of pre-transplant evaluation * in cr with the following features: * intolerant or unwilling to use a tki after hct * current or previous detection of cytogenetic abnormalities in addition to t(9;22) by conventional karyotyping, fish or molecular methods * chronic lymphocytic leukemia, or low grade b cell lymphomas: * failed or ineligible for prior immunochemotherapy that included a purine analog and anti-cd20 monoclonal antibody and a lymph node \>= 5 cm at the time of pre-transplant evaluation * mantle cell lymphoma: * failed or ineligible for autologous transplant and a lymph node \>= 2 cm at the time of pre-transplant evaluation * diffuse large b cell lymphomas, large b cell transformation of an indolent lymphoma or other aggressive b cell lymphomas * failed or ineligible for autologous transplant and not in cr at the time of pre-transplant evaluation * confirmation of tumor diagnosis and expression of cd19 after review by university of washington medical center (uwmc) or seattle cancer care alliance (scca) pathology services * the patient has signed the informed consent form for this study * donor: genotypic or phenotypic hla-identical family members * donor: express one or more of the following combinations of viral serostatus and hla allele: * cmv seropositive and hla-a\*0101 positive * cmv seropositive and hla-a\*0201 positive * cmv seropositive and hla-b\*0702 positive * cmv seropositive and hla-b\*0801 positive * ebv seropositive and hla-a\*0201 positive * ebv seropositive and hla-b\*0801 positive * donor: hematocrit \>= 35% at enrollment * donor: age \>= 18 years * donor: the donor has signed the informed consent form for the study exclusion criteria: * known central nervous system (cns) tumor (cns2 or cns3) that is refractory to intrathecal chemotherapy and/or cranio-spinal radiation; patients with a history of cns disease that has been effectively treated to cns1 or lower evidence of disease will be eligible * human immunodeficiency virus (hiv) seropositive * significant medical or psychological conditions that would make them unsuitable candidates for t cell therapy * fertile patients unwilling to use contraception during and for 12 months after protocol enrollment * pregnant or breast-feeding * donor: g-csf administered within one month prior to the blood draw for t cell collection * donor: unable for any reason to provide a 400 ml blood draw * donor: inadequate peripheral veins for blood collection * donor: hiv-1, hiv-2, human t-lymphotropic virus (htlv)-1 or htlv-2 seropositive * donor: active hepatitis b or hepatitis c virus infection * donor: positive serologic test for syphilis * donor: aberrant cd45ra isoform expression on all t cells * donor: systolic blood pressure (bp) \ 200 * donor: heart rate \ 120, if considered due to cardiac disease * donor: oxygen (o2) saturation \< 88% on room air * donor: serum creatinine (cr) \> 3.0 * donor: aspartate aminotransferase (ast) or alanine aminotransferase (alt) \> 4 x the upper limit of normal * donor: unable to provide informed consent to participate * donor: significant medical conditions (e.g. immunosuppressive therapy) that would make them unsuitable t cell donors * donor: pregnant or nursing