TT52CAR19 Therapy for B-cell Acute Lymphoblastic Leukaemia (B-ALL)

• Status: Recruiting
• Trial end date: 2022-06-30
• Target enrollment: 0
• Participant gender: All

Summary

PBLTT52CAR19 modified T cells are allogenic engineered human T cells (defined as TT52CAR19 +TCRαβ-) prepared for the treatment of CD19+ B cell leukaemia. The cells are from healthy adult volunteer donors and are not HLA-matched. They have been transduced to express and anti-CD19 chimeric antigen receptor (CAR19) using a lentiviral vector that also incorporates CRISPR guides for genome editing of CD52 and TRAC loci in the presence of transiently provided Cas9.

Recognition by TT52CAR19 T cells mediates eradication of CD19+ leukaemia and other CD19+ B cells through T cell mediated cytotoxicity.

This study aims to apply PBLTT52CAR19 T cells to secure molecular remission in children with relapsed/refractory B-ALL ahead of programmed allogeneic stem cell transplantation. The cells are to be used in a time-limited manner for their anti-leukaemia effects and then depleted by standard pre- transplant conditioning.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
• Collaborator: University College, London

Criteria

Inclusion Criteria:

• Patients with relapsed (second or subsequent bone marrow relapse or bone marrow relapse after allo-SCT) or refractory (not achieving an initial complete response (CR) after 2 cycles of standard chemotherapy) CD19-positive B-acute lymphoblastic leukaemia

• Morphologically confirmed with leukemic blasts in the bone marrow or a quantifiable MRD load of 1x10-4 (by multiparameter flow cytometry and/or quantitative polymerase chain reaction)

• Eligible and fit for allogeneic hematopoietic stem cells transplantation with suitable donor available

• Estimated life expectancy ≥ 12 weeks

• Lansky (age < 16 years at the time of assent/consent) or Karnofsky (age ≥ 16 years at the time of assent/consent) performance status ≥ 50 Eastern Cooperative Oncology Group ECOG performance status < 2

Exclusion Criteria:

• Patients/parents unwilling to undergo a follow-up for 15 years

• Foreseeable poor compliance to the study procedures

• CD19-negative B-cell leukaemia

• Evidence of disease progression after cytoreduction

• Uncontrollable CNS leukaemia or neurological symptoms defined as CNS grade 3 (per National Comprehensive Cancer National guidelines). Patients developing grade 3 CNS disease at any time after enrolment will be excluded.

• Absence of suitable HLA matched or mismatched donor

• Weight < 6 kgs

• Presence of donor-specific anti-HLA antibodies directed against PBLTT52CAR19

• GvHD requiring systemic therapy

• Systemic steroid therapy prednisolone >0.5mg/kg/day

• Known hypersensitivity to any of the test materials or related compounds

• Active bacterial, fungal, or viral infection not controlled by a standard of care anti-microbial or anti-viral treatment. Uncontrolled bacteraemia/ fungaemia is defined as the ongoing detection of bacteria/fungus on blood cultures despite antibiotic or anti-fungal therapy.

• Uncontrolled viraemia is defined as rising viral loads on two consecutive occasions despite antiviral therapy.

• Risk of pregnancy or non-compliance with contraception (if applicable). Girls of childbearing potential must have been tested negative in a pregnancy test within 14 days prior to inclusion.

• Lactating female participants unwilling to stop breastfeeding

• Intrathecal methotrexate within 4 weeks or intrathecal chemotherapy (e.g Ara-C) within 2 weeks of lymphodepletion

• Less than 2 half-lives from prior therapy with immune checkpoint pathway modifiers to lymphodepletion

• Prior CAR19 therapy known to be associated with ≥Grade 3 cytokine release syndrome (CRS) or ≥Grade 3 drug-related CNS toxicity