CD19-CAR Immunotherapy for Childhood Acute Lymphoblastic Leukemia (ALL) (CD19TPALL)

University College London (UCL)

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Acute Lymphoblastic Leukemia

Treatments: Biological: Irradiated donor-derived Lymphoblastoid Cell Line; Genetic: donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta

Study type: Interventional

Funder types: Other

Identifiers

NCT01195480

UCL/09/0050

2007-007612-29 (EudraCT Number)

Details and patient eligibility

About

The aim of this clinical trial is to evaluate the feasibility, safety and biological effect of adoptive transfer of CD19ζ chimaeric receptor transduced donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTL) in patients with high-risk or relapsed B cell precursor ALL after allogeneic Haematopoietic Stem Cell Transplantation (HSCT).

Enrollment: 29 patients

Sex: All

Ages: Under 18 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria Pre-emptive arm

Children (18 years or younger) with CD19+ precursor B cell ALL fulfilling one of the following criteria who are undergoing an allogeneic stem cell transplant from an EBV-seropositive donor:

In first remission, if at least one of the following criteria are met:

• t(9;22) and MRD positive (BCR-ABL/ABL ratio > 0.01%) after HR3 block of EsPhALL or pre-HSCT or
• Infant ALL age < 6 months at diagnosis with MLL gene rearrangement and either presenting wcc >300 x 10^9/L or poor steroid early response (i.e circulating blast count >1x10^9/L following 7 day steroid pre-phase of Interfant 06) or
• Resistant disease (> 30% blasts at end of induction treatment day 28-33) in subsequent morphological CR or
• High level bone marrow MRD (> 1 in 1000) at week 12 ALL-BFM 2000/AIEOP BFM ALL 2009/EORTC 58951 protocols, week 12-15 of FRALLE A or at week 14 of UKALL2011

Relapsed patients if at least one of the following criteria are met:

• Very early (< 18 months from diagnosis) bone marrow or extramedullary relapse in second CR or
• Early (within 6 months of finishing therapy) isolated bone marrow relapse with bone marrow MRD > 1 in 100 at day 35 of reinduction in second CR or
• Early (within 6 months of finishing therapy) bone marrow or combined relapse with high level bone marrow MRD (> 1 in 1000) at the end of consolidation therapy (week 12-13 UKALL R3/INTREALL and COOPRALL protocols, prior to protocol M in BFM relapse protocol (ALL-REZ BFM 2002) and after Protocol II-IDA in AIEOP LLA Rec 2003)or
• Any relapse of infant or Philadelphia-positive ALL in morphological complete remission
• Any patient being transplanted in 3rd or greater CR

These patients have a high (> 50%) risk of relapse and will be monitored for evidence of MRD in bone marrow aspirates (monthly for months 1-6, 6 weekly months 7.5-12 post HSCT) for the first year post-transplant. Patients who become MRD +ve in the marrow at a level minimum 5 x 10-4 (or BCR-ABL/ABL ratio 0.05% in Ph+ve ALL patients with no IgH MRD marker) but are in morphological remission (<5% blasts in BM) will be eligible to be treated pre-emptively with CD19ζ transduced CTL

Prophylaxis arm

Additionally, any patient (≤ 18 years) with ALL relapsing in the bone marrow (isolated or combined) after myeloablative allogeneic HSCT who achieves morphological remission after re-induction and who is a candidate for second HSCT at one of the participating centres is eligible to receive CD19ζ transduced CTL prophylactically

• Stem cell donors must be EBV sero-positive and HLA-matched (8/8 HLA A,B,C and DR at medium resolution typing) or a single antigenic/allelic (7/8) mismatch with the recipient
• A life expectancy of at least 12 weeks
• Karnofsky score of >60% if >10 years old or Lansky performance score of >60 if ≤ 10 years old
• Patients must have transduced donor-derived EBV-specific CTLs with 15% or higher expression of CD19ζ determined by flow-cytometry which meet the specified release criteria
• Informed written consent indicating that patients are aware this is a research study and have been told of its possible benefits and toxic side effects

Exclusion Criteria

• Patients with CD19 negative precursor B cell ALL
• EBV seronegative or > single antigenic/allelic HLA-mismatched donor
• Active acute GVHD overall Grade 2 or higher or significant chronic GVHD requiring systemic steroids at the time of scheduled infusion of transduced CTL will be excluded until the patient is GVHD-free and off steroids
• Pre-existing severe lung disease (FEV1 or FVC < 50% predicted) pre-HSCT or an oxygen requirement of >28% O2 supplementation or active pulmonary infiltrates on chest X-ray at the time scheduled for transduced CTL infusion
• Serum bilirubin >3 times the upper limit of normal or an AST or ALT > 5 times the upper limit of normal
• Serum creatinine >3 times upper limit of normal
• Active severe intercurrent infection at the time of transduced CTL infusion (if present consult with Chief investigator).
• Patients in whom transduced donor-derived EBV-specific CTLs don't meet release criteria
• Serologically positive for Hepatitis B, C or HIV pre-HSCT
• Females of childbearing age with a positive pregnancy test
• Known allergy to DMSO

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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29 participants in 2 patient groups

Prophylaxis arm

Experimental group

Description:

Patients who have relapsed in the bone marrow after previous myeloablative HSCT and achieve remission after chemotherapy will be treated prophylactically with CD19-specific gene-engineered T cells after a second HSCT with reduced intensity conditioning.

Treatment:

Genetic: donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta

Biological: Irradiated donor-derived Lymphoblastoid Cell Line

Pre-emptive arm

Experimental group

Description:

In this arm, patients identified at high (\> 50%) risk of relapse will be eligible for generation of donor-derived EBV CTL immediately prior to HSCT. These patients will be monitored for evidence of MRD in regular bone marrow aspirates for the first year post-HSCT. MRD positivity post-HSCT is highly predictive of subsequent relapse. In those patients who become MRD+ in the marrow at a level of minimum 5 x 10-4, cryopreserved CTL that have been transduced with a retroviral vector carrying the CD19-zeta transgene will be thawed and administered to the patient pre-emptively.

Treatment:

Genetic: donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta

Biological: Irradiated donor-derived Lymphoblastoid Cell Line