CD19/22 CAR T Cells (AUTO3) for the Treatment of Diffuse Large B Cell Lymphoma
CD19/22 CAR T Cells (AUTO3) for the Treatment of Diffuse Large B Cell Lymphoma
The purpose of this study is to test the safety and efficacy of AUTO3, a CAR T cell treatment
 targeting CD19 and CD22 followed by limited duration of anti-PD1 antibody in patients with
 DLBCL
The study will consist of 2 phases, a Phase I or dose escalation and expansion phase, and a
 Phase II. Patients with relapsed or refractory DLBCL will be enrolled in both phases of the
 study. Eligible patients will undergo leukapheresis in order to harvest T cells, which is the
 starting material for the manufacture of the autologous CAR T product AUTO3 which is a CD19
 and CD22 dual targeting CAR T cell product. Following pre-conditioning by a chemotherapeutic
 regimen, the patient will receive AUTO 3 intravenously as a single dose and in addition a
 limited duration of treatment with an anti-PD1 antibody (either as part of the
 pre-conditioning regimen or consolidation). Patients will then enter a 24-month follow-up
 period.
Inclusion Criteria:

 1. Male or female, aged ≥18 years.

 2. Willing and able to give written, informed consent.

 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.

 4. Histologically confirmed DLBCL and large B cell lymphoma (at last relapse) subsets,
 including:

 Phase I and Phase II Cohort 1:

 1. DLBCL, not otherwise specified (NOS), per World Health Organisation
 classification and DLBCL with MYC and BCL2 and/or BCL6 rearrangements
 (double/triple hit).

 2. Transformed DLBCL from FL.

 3. High-grade B cell lymphoma with MYC expression (excluding Burkitt's lymphoma)

 Phase I and Phase II Cohort 2:

 4. Transformed DLBCL from other indolent lymphomas (excluding Richter's
 transformation).

 5. Primary mediastinal large B cell lymphoma.

 5. Chemotherapy-refractory disease, defined as one or more of the following:

 1. Stable disease (≤12 months) or progressive disease as best response to most
 recent chemotherapy containing regimen. Refractory disease after frontline
 chemo-immunotherapy is allowed.

 2. Disease progression or recurrence in ≤12 months of prior autologous
 haematopoietic stem cells transplantation (ASCT).

 OR

 6. Relapse after ≥two lines of therapy or after ASCT. At a minimum:

 1. Patients must have received rituximab or another anti-CD20 monoclonal antibody
 (unless Investigator determines that tumour is CD20-negative) and an
 anthracycline-containing chemotherapy regimen.

 2. Patients must have either failed ASCT, or be ineligible for or not consenting to
 ASCT.

 3. Patients with transformed DLBCL must have received at least one line of therapy
 after transformation to DLBCL.

 7. PET-positive disease per Lugano classification.

 8. For females of childbearing potential, a negative serum or urine pregnancy test must
 be documented at screening, prior to pre-conditioning and confirmed before receiving
 the first dose of study treatment.

 For females who are not postmenopausal or surgically sterile, highly effective methods
 of contraception must be used during the treatment period and for at least 12 months
 after the last dose of study treatment.

 9. For males, it must be agreed that that two acceptable methods of contraception are
 used.

 10. Adequate renal, hepatic, pulmonary, and cardiac function defined as:

 1. Creatinine clearance ≥40 cc/min.

 2. Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x ULN.

 3. Total bilirubin ≤1.5 x ULN, except in subjects with Gilbert's syndrome.

 4. LVEF ≥50% (by ECHO or MUGA) unless the institutional lower limit of normal is
 lower.

 5. Baseline oxygen saturation >92% on room air and ≤Grade 1 dyspnoea.

 11. Patient has adequate BM function without requiring ongoing blood product or
 granulocyte-colony stimulating factor support and meets the following criteria:

 1. Absolute neutrophil count ≥1.0 × 109/L.

 2. Absolute lymphocyte count ≥0.3 × 109/L (at enrolment and prior to leukapheresis).

 3. Haemoglobin ≥80 g/L.

 4. Platelets ≥75 × 109/L

 12. No contra-indications for leukapheresis.

 Exclusion Criteria:

 1. Prior allogeneic haematopoietic stem cell transplant.

 2. Females who are pregnant or lactating.

 3. History or presence of clinically relevant CNS pathology such as epilepsy, paresis,
 aphasia, stroke within prior 3 months, severe brain injuries, dementia, Parkinson's
 disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or
 psychosis.

 4. Patients with active CNS involvement by malignancy. Patients with history of CNS
 involvement with malignancy may be eligible if CNS disease has been effectively
 treated and provided treatment was at least 4 weeks prior to enrolment (at least 8
 weeks prior to AUTO3 infusion).

 5. Clinically significant, uncontrolled heart disease or a recent (within 12 months)
 cardiac event.

 1. Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial
 fibrillation are not excluded).

 2. Evidence of pericardial effusion

 6. Patients with a history (within 3 months) or evidence of deep vein thrombosis or
 pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of
 pre-conditioning.

 7. Patients with active gastrointestinal bleeding.

 8. Patients with any major surgical intervention in the last 3 months.

 9. Active bacterial, viral or fungal infection requiring systemic treatment. Active or
 latent hepatitis B infection or hepatitis C infection. Testing positive for human
 immunodeficiency virus, human T cell lymphotropic virus (HTLV1 and 2) or syphilis.

 10. History of autoimmune disease resulting in end organ injury or requiring systemic
 immunosuppression/systemic disease modifying agents within the last 24 months.

 11. Patients with a known history or prior diagnosis of optic neuritis or other
 immunologic or inflammatory disease affecting the CNS.

 12. Evidence of active pneumonitis on chest computed tomography (CT) scan at screening or
 history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising
 pneumonia, or idiopathic pneumonitis.

 13. History of other malignant neoplasms unless disease free for at least 24 months
 (carcinoma in situ, non-melanoma skin cancer, breast or prostate cancer on hormonal
 therapy allowed).

 14. Prior treatment with PD1, PD-L1, or cytotoxic T lymphocyte-associated
 protein-4-targeted therapy, or tumour necrosis factor (TNF) receptor superfamily
 agonists within 6 weeks prior to AUTO3 infusion.

 15. Prior treatment with investigational or approved gene therapy or cell therapy products
 until a dose level has treated at least three patients and has been declared safe.

 16. Prior CD19 or CD22 targeted therapy.

 17. The following medications are excluded:

 1. Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or
 72 hours prior to AUTO3 administration. However, physiological replacement,
 topical, and inhaled steroids are permitted.

 2. Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior to
 leukapheresis or AUTO3 infusion.

 3. Cytotoxic chemotherapies within 2 weeks of AUTO3 infusion and 1 week prior to
 leukapheresis (2 weeks for lymphodepleting chemotherapy).

 4. Antibody therapy use including anti-CD20 therapy within 2 weeks prior to AUTO3
 infusion, or 5 half-lives of the respective antibody, whichever is shorter.

 5. Granulocyte-colony stimulating factor less than 10 days prior to leukapheresis.

 6. Live vaccine ≤4 weeks prior to enrolment.

 7. Prophylactic intrathecal therapy: Methotrexate within 4 weeks and other
 intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to starting
 pre-conditioning chemotherapy.

 18. Prior limited radiation therapy within 4 weeks of AUTO3 infusion or within 24 weeks
 for definitive radiation to chest.

 19. Research participants receiving any other investigational agents, or concurrent
 biological, chemotherapy, or radiation therapy.

 20. Known allergy to albumin, dimethyl sulphoxide (DMSO), cyclophosphamide or fludarabine,
 pembrolizumab or tocilizumab.

 21. Any contraindications to receive anti-PD1 antibody pembrolizumab will be excluded from
 cohorts requiring administration of pembrolizumab.

 22. Patients, who in the opinion of the Investigator, may not be able to understand or
 comply with the safety monitoring requirements of the study.

 23. Any other condition that in the Investigator's opinion would make the patient
 unsuitable for the clinical trial.

 Phase I outpatient cohort:

 24. Subjects who do not have caregiver support (in line with institutional outpatient
 transplant guidelines) for outpatient/ambulatory care setting.

 25. Subjects who are staying greater than 60 minutes (or whatever is permissible per
 institutional outpatient transplant guidelines) from the clinical trial site at the
 time of treatment.

 For AUTO3 Infusion: Patients meeting any of the following exclusion criteria must not be
 treated with AUTO3 or have treatment delayed until they no longer meet these criteria:

 1. Severe intercurrent infection.

 2. Requirement for supplementary oxygen or active pulmonary infiltrates.

 3. Clinical deterioration of organ function (renal and hepatic) exceeding the criteria
 set at study entry.