CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant

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.

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) < 80 or > 200

- DONOR: Heart rate < 50 or > 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