CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Completed

Phase 2

Phase 1

Conditions

Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia

Recurrent Mantle Cell Lymphoma

Refractory Chronic Lymphocytic Leukemia

Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia

Recurrent Adult Immunoblastic Large Cell Lymphoma

Recurrent Adult Acute Lymphoblastic Leukemia

Recurrent Adult Diffuse Large Cell Lymphoma

Treatments

Biological: allogeneic cytomegalovirus-specific cytotoxic T lymphocytes

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01475058

NCI-2011-01819 (Registry Identifier)

2494.00 (Other Identifier)

P30CA015704 (U.S. NIH Grant/Contract)

R01CA136551 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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.

Enrollment

1 patient

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

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