Inclusion Criteria:

• Age 18 years or older.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Relapsed or refractory CD19-positive B-ALL defined as one of the following:
  • Primary refractory disease (not achieving CR after two cycles of induction chemotherapy);
  • First relapse if first remission ≤ 12 months;
  • Relapsed or refractory disease after two or more lines of systemic therapy;
  • Relapsed or refractory disease after allogeneic transplant provided AUTO1 infusion occurs at least 3 months after stem cell transplant.
• Patients with Philadelphia chromosome positive ALL (Ph+ ALL) are eligible if they are intolerant to or have failed two lines of any tyrosine kinase inhibitor (TKI) or one line of second-generation TKI, or if TKI therapy is contraindicated.
• Documentation of CD19 expression on leukaemic blasts in the BM, peripheral blood, or cerebrospinal fluid (CSF) by flow cytometry within 1 month of screening. In patients treated with blinatumomab, testing should be undertaken after blinatumomab therapy has been stopped.
• Phase Ib:
  • Primary Cohort IA: Presence of ≥ 5% blasts in BM at screening.
  • Exploratory Cohort IB: MRD-positive defined as ≥ 10-4 and < 5% blasts in the BM at screening.
• Phase II:
  • Cohort IIA: Presence of ≥ 5% blasts in BM at screening.
  • Cohort IIB: Patients with B-ALL in ≥ 2nd (CR) or (CRi) with MRD- positive disease (≥ 10-4 and < 5% blasts in the BM) by local assessment (NGS/PCR/Flow Cytometry) at screening.
    • Note: A bone marrow sample must be available at time of screening to quantify the MRD by NGS. An archival tumor sample from the time of initial diagnosis or last morphological relapse must be available to calibrate the NGS MRD assay.
  • Cohort IIC (Exploratory): Isolated extramedullary (EM) disease, (including CNS disease), with or without MRD.
• Adequate renal, hepatic, pulmonary, and cardiac function defined as:
  • Serum alanine aminotransferase/aspartate aminotransferase ≤ 2.5 x upper limit of normal (ULN);
  • Creatinine clearance (as estimated by Cockcroft Gault) ≥ 50 cc/minute;
  • Total bilirubin ≤ 1.5 x ULN, except in patients with Gilbert’s syndrome who must have normal direct bilirubin;
  • Left ventricular ejection fraction (LVEF) ≥ 45% (or ≥institutes lower limit of normal) confirmed by echocardiogram (ECHO) or multigated acquisition (MUGA) in patients with history of coronary artery disease or cardiovascular disease or those with history of low LVEF;
  • Baseline oxygen saturation > 92% on room air.

Exclusion Criteria:

• Phase Ib (Cohort IA and Cohort IB) and Phase II Cohort IIA and Cohort IIB: B-ALL with isolated EM disease.
• Diagnosis of Burkitt’s leukaemia/lymphoma according to World Health Organisation (WHO) classification or chronic myelogenous leukaemia lymphoid in blast crisis.
• History or presence of clinically relevant CNS pathology such as epilepsy, paresis, aphasia, stroke within 3 months prior to consent, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or psychosis.
• Presence of CNS 3 disease or CNS 2 disease with neurological changes. Patients developing CNS 3 disease or symptomatic CNS 2 disease at any time after consent will also be excluded until they no longer meet these criteria.
• Presence of active or uncontrolled fungal, bacterial, viral (including COVID-19), or other infection requiring systemic antimicrobials for management.
• Active or latent Hepatitis B virus or active Hepatitis C virus.
• Human Immunodeficiency Virus (HIV), human T-cell lymphotropic virus (HTLV)-1, HTLV-2, or syphilis positive test.
• Patients who have received a prior stem cell transplant: less than 3 months prior to AUTO1 infusion. Active significant (overall Grade ≥ II, Seattle criteria) acute graft versus host disease (GVHD) or moderate/severe chronic GVHD (National Institutes of Health [NIH] consensus criteria) requiring systemic steroids or other immunosuppressants within 4 weeks of consent.
• Prior CD19 targeted therapy other than blinatumomab. Patients who have experienced Grade 3 or higher neurotoxicity following blinatumomab.
• The following medications are excluded:
  • Steroids: Therapeutic doses of corticosteroids (greater than 10 mg daily of prednisone or its equivalent) within 7 days of leukapheresis or 72 hours prior to AUTO1 administration. However, physiological replacement, topical, and inhaled steroids are permitted;
  • Immunosuppression: Immunosuppressive medication must be stopped ≥ 2 weeks prior to leukapheresis and AUTO1 infusion;
  • Allogeneic cellular therapy: any donor lymphocyte infusions must be completed > 2 weeks prior to leukapheresis and not repeated thereafter;
  • Graft versus host disease therapies: any drug used for GVHD must be stopped > 2 weeks prior to leukapheresis and not reinitiated thereafter;
  • Chemotherapy should be stopped 1 week prior to leukapheresis or starting pre-conditioning chemotherapy.  TKIs for Ph+ ALL should be stopped >72 hours prior to pre-conditioning chemotherapy;
  • Treatment with any T cell lytic or toxic antibody (e.g., alemtuzumab) within 6 months prior to leukapheresis, or treatment with clofarabine or cladribine within 3 months prior to leukapheresis;
  • Live vaccine ≤ 4 weeks prior to leukapheresis;
  • Intrathecal therapy within 2 weeks prior to starting pre-conditioning chemotherapy;
  • Use of blinatumomab after leukapheresis. 

Eligibility last updated 5/12/22. Questions regarding updates should be directed to the study team contact.