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

Phase 1, Open Label Study of CRISPR-CAR Genome Edited T Cells (PBLTT52CAR19) in Relapsed /Refractory B Cell Acute Lymphoblastic Leukaemia

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.

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