CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant

A Phase I/II Study of Cellular Immunotherapy With Donor Central Memory-derived Virus-specific CD8+ T-cells Engineered to Target CD19 for CD19+ Malignancies After Allogeneic Hematopoietic Stem Cell Transplant

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Refractory Chronic Lymphocytic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia
• Intervention / Treatment: Biological: allogeneic cytomegalovirus-specific cytotoxic T lymphocytes

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (T cell therapy); Patients undergo one IV infusion of donor-derived CD8+ central memory-derived CMV/CD19 or EBV/CD19 bi-specific T cells, at least 30 days after HCT.	Biological: allogeneic cytomegalovirus-specific cytotoxic T lymphocytes; Allogeneic CD19-specific chimeric antigen receptor-modified CD8+ central memory derived virus-specific T cells. Allogeneic CD19CAR-TCM cells given IV; Other Names: allogeneic CMV-specific CTLs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and toxicity assessment of study treatment	Incidence of grade >= 3 toxicity, as defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 occurring from the T cell infusion through day 42 after the T cell infusion. Analysis will be performed separately in patients in complete remission (cohort A) or with detectable disease (cohort B) at day 28 post-transplant (prior to the T cell infusion). Incidence of acute GVHD occurring from the T cell infusion through day 42 after the T cell infusion will be assessed.	Up to day 42 after the T cell infusion
Feasibility assessment of study treatment	If the prescribed T cell dose is delivered in more than 50% of the patients, this approach will be considered feasible for further study to reduce relapse after allogeneic HCT.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Anti-tumor efficacy and duration of persistence, migration, and function of adoptively transferred bi-specific effector cells	Up to 15 years

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Cameron Turtle, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Publications and helpful links

General Publications

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: November 10, 2011
• First Submitted That Met QC Criteria: November 16, 2011
• First Posted (Estimate): November 21, 2011

Study Record Updates

• Last Update Posted (Actual): February 15, 2017
• Last Update Submitted That Met QC Criteria: February 14, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, B-Cell; Lymphoma, B-Cell; Chromosome Aberrations; Translocation, Genetic; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Leukemia; Recurrence; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Large-Cell, Immunoblastic; Plasmablastic Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Philadelphia Chromosome
• Other Study ID Numbers: 2494.00 (Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); R01CA136551 (U.S. NIH Grant/Contract); NCI-2011-01819 (Registry Identifier: CTRP (Clinical Trial Reporting Program))