Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Single Arm, Open-label, Multi-centre, Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO3, a CAR T Cell Treatment Targeting CD19 and CD22 With Anti PD1 Antibody in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma
Brief Summary: 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


Options:
A: 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.
B: Inclusion Criteria:

* Histologically diagnosed as DLBCL according to the NCCN non-Hodgkin's lymphoma Clinical Practice Guidelines (3rd edition 2016)
* Refractory DLBCL
* All subjects must have received adequate prior therapy including anti-CD20 monoclonal antibody (unless tumor is CD20-negative) and an anthracycline containing chemotherapy regimen. The standardized treatment regimens reference to NCCN non-Hodgkin lymphoma Clinical Practice Guidelines (2016 Version 3)
* At least one measurable lesion per revised IWG Response Criteria (the longest diameter of the tumor ≥ 1.5 cm)
* Age 18-70 years old, male or female
* Expected survival ≥ 12 weeks
* ECOG score 0-1
* Subject's left ventricular ejection fraction (LVEF) is ≥ 50% and no evidence of pericardial effusion as determined by an ECHO
* At least 4 weeks from receiving previous treatment (radiotherapy, chemotherapy, monoclonal antibody therapy or other treatments)
* No contraindications of peripheral blood apheresis
* Female subjects in childbearing age, their serum or urine pregnancy test must be negative, and must agree to take effective contraceptive measures during the trial measures
* Volunteered to participate in this study and signed informed consent

Exclusion Criteria:

* Have a history of allergy to cellular products
* Used any genetically modified T cell therapy
* History of allogeneic hematopoietic stem cell transplantation
* Severe active infection (uncomplicated urinary tract infections, bacterial pharyngitis allowed) or currently receiving intravenous antibiotic therapy and received intravenous antibiotic therapy within one week. Prophylactic antibiotic, antiviral and antifungal treatment is permissible
* Hepatitis B or hepatitis C virus infection (including carriers), as well as acquired, congenital immune deficiency diseases, including but not limited to HIV-infected persons
* Patients with class III and IV heart failure according to the NYHA Heart Failure Classifications
* A history of QT prolongation
* A history of epilepsy or other central nervous system disorders
* The patient had a history of other primary cancers, with the following exceptions: Excisional non-melanoma such as cutaneous basal cell carcinoma; Cured in situ carcinoma such as cervical cancer, bladder cancer or breast cancer
* Subjects with any autoimmune disease or any immune deficiency disease or other disease in need of immunosuppressive therapy
* Used of systemic steroids within two weeks (using inhaled steroids is an exception)
* Women who are pregnant or lactating or have breeding intent in 6 months
* Participated in any other clinical trial within three months
* The investigators believe that any increase in the risk of the subject or interference with the results of the trial
C: * INCLUSION CRITERIA:

Inclusion Criteria: Recipient

1. Recipients (patients with B-cell malignancy) must have received an HLA-identical or 9/10 matched sibling allogeneic hematopoietic stem cell transplant, a 1-antigen mismatched related transplant, or a greater than or equal to 9/10-matched unrelated donor (URD) alloHSCT for any CD19+ B-cell malignancy. Patients with any CD19+ B-cell malignancy that is persistent or relapsed after all of the following interventions are eligible:

   1. Donor T cell engraftment after alloHSCT (\>50% donor chimerism of the T cell compartment and a peripheral blood T cell number from the NIH, CC clinical lab of at least 50 CD3+ cells/uL).
   2. A trial of withdrawal of immunosuppressive therapy.

   Exception: Prior (DCI) DLI is not an eligibility requirement for patients with ALL, Burkitt lyphoma, ALL like high-grade lymphomas, or diffuse large B-cell lymphoma.

   At least 28 days weeks must have elapsed since the latest trial of withdraw of immunosuppression or DLI until the patient can be deemed to have persistent disease.
2. CD19 expression must be detected on the majority of the malignant cells by immunohistochemistry or by flow cytometry in the Laboratory of Pathology, CCR, NCI, NIH. Definition of which cells are malignant must be determined for each patient by the Laboratory of Pathology using techniques to demonstrate monoclonality such as kappa/lambda restriction (other techniques can be used to determine monoclonality at the discretion of the Laboratory of Pathology). The choice of whether to use flow cytometry or immuohistochemistry will be determined by what is the most easily available tissue sample in each patient. Immunohistochemistry will be used for lymph node biopsies and bone marrow biopsies. Flow cytometry will be used for peripheral blood, fine needle aspirate, and bone marrow aspirate samples.
3. Patients must be 18-75 years of age.
4. Performance status: ECOG less than or equal to 2
5. Either no evidence of GVHD or minimal clinical evidence of acute GVHD and chronic GVHD while off of systemic immunosuppressive therapy for at least 28 days. Minimal clinical evidence of acute GVHD is defined as grade 0 to I acute GVHD. Minimal evidence of chronic GVHD is defined as chronic GVHD with no organ site with a score exceeding 1, except for the skin, for which a score of 1 or 2 will be allowable (as defined by the 2005 NIH consensus project) or no chronic GVHD. Subjects with disease that is controlled to stage I acute GVHD or chronic GVHD meeting the above criteria with local therapy only, e.g., topical cutaneous steroids, will be eligible for enrollment.
6. Ability to give informed consent.
7. Prior Therapy: Therapy with monoclonal antibodies and/or chemotherapy must be stopped at least 7 days prior to anti-CD19 CAR-transduced T cell infusion, and recovery of treatment-associated toxicity to less than or equal to grade 2 is required prior to infusion of cells. For patients that have received prior DLI, the last dose must be at least 28 days prior to anti-CD19 CAR-transduced T cell administration. Note that patients can be enrolled on this study at any time after or during therapy, but at least 14 days must elapse from the time of prior monoclonal antibody administration or chemotherapy until anti-CD19 CAR-transduced T cells are infused, and at least 28 days must elapse from the time of withdraw of immunosuppression, or DLI, or other immunomodulatory therapies such as lenalidomide until anti-CD19 CAR-transduced T cells are infused. Systemic immunosuppression given for graft versus host disease must be stopped at least 28 days prior to protocol entry. There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such.
8. Recipients of unrelated donor transplants from a National Marrow Donor Program (NMDP) Center must sign a release of information form to authorize NMDP transfer of information to the NIH.
9. Previous allogeneic donor must be willing and available to donate again.
10. Patients of childbearing or child-fathering potential must be willing use an effective method of contraception while being treated on this study and for 4 months after the last cell infusion.
11. Normal left ventricular function as evaluated by echocardiograph within 4 weeks of anti- CD19-CAR-transduced T cell infusion

Inclusion Criteria: Donor

1. Donors greater than or equal to 18 years of age must be the same individual whose cells were used as the source for the patient s original stem cell transplant.
2. Adequate venous access for peripheral leukapheresis, or consent to use a temporary central venous catheter for leukapheresis.
3. Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C antibody negative.
4. Ability to give informed consent.
5. Donor selection will be in accordance with NIH/CC Department of Transfusion Medicine (DTM) criteria and, in the case of an unrelated donor from a Transplant Center, the National Marrow Donor Program (NMDP) standards. When a potentially eligible recipient of an unrelated donor product from an NMDP Center is identified, the recipient will complete an NMDP search transfer request to allow NIH NMDP staff to contact the NMDP Coordinating Center, who will, in turn, contact the donor s prior Donor Center. The NMDP Policy for Subsequent Donation Requests will be followed and the appropriate forms (Subsequent Donation Request form) and Therapeutic T Cell Collection Prescription will be submitted as required.

EXCLUSION CRITERIA:

Exclusion Criteria: Recipients

1. Active infection that is not responding to antimicrobial therapy.
2. Sero positive for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune -competence and thus are less responsive to the experimental treatment and more susceptible to its toxicities.)
3. Sero positive for hepatitis B antigen, positive hepatitis B tests can be further evaluated by confirmatory tests (HBV DNA), and if confirmatory tests are negative, the patient can be enrolled.
4. Sero positive for hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then patients must be tested for the presence of RNA by RT-PCR and be HCV RNA negative.
5. Active psychiatric disorder which may compromise compliance with the treatment protocol, or which does not allow for appropriate informed consent (as determined by Principal Investigator and/or his designee).
6. Pregnant or lactating. The effects of the immunosuppressive medications that could be required to treat GHVD are likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to an infant.
7. Serum total bilirubin \> 2.5 mg/dl, serum ALT and AST values greater than or equal to 2.5 times the upper limit of normal based on age-specific normal values. If the abnormal liver function is attributable to liver involvement by malignancy, patients may be eligible with serum total bilirubin up to 5.0 mg/dl, and serum ALT and AST values up to 5.0 times the upper limit of normal, provided the patient has no evidence of impending hepatic failure (encephalopathy or prothrombin time \>2 times the upper limit of normal).
8. Serum creatinine greater than 1.6 mg/dL
9. Absolute neutrophil count of less than 1000 cells/microL unless low neutrophil count is thought to be due to malignancy in the bone marrow and malignancy is documented in the bone marrow.
10. Active cerebrospinal fluid involvement with malignancy or brain metastasis.
11. Platelet count less than 30,000/microL unless low platelet count is thought to be due to malignancy in the bone marrow and malignancy is documented in the bone marrow.
12. Hemoglobin less than 8.0 g/dL.
13. Receiving systemic corticosteroids including prednisone, dexamethasone or any other corticosteroid at doses of higher than 5 mg/day of prednisone within 28 days prior to anti-CD19-CAR-transduced T cell administration. Corticosteroid creams, ointments, and eye drops are allowed.
14. Blood blast percentage higher than 5%.

Exclusion Criteria: Donors

1. History of psychiatric disorder which may compromise compliance with this protocol or which does not allow for appropriate informed consent.
2. History of hypertension that is not controlled by medication, stroke, or severe heart disease (donors with symptomatic angina will be excluded). Donors with a history of coronary artery bypass grafting or angioplasty who are symptom free will receive a cardiology evaluation and be considered on a case-by-case basis.
3. Donors must not be pregnant.
4. Anemia (Hb \< 11 gm/dl) or thrombocytopenia (platelets \< 100,000 per microL). However, potential donors with Hb levels \< 11 gm/dl that is due to iron deficiency will be eligible as long as the donor is initiated on iron replacement therapy. The NIH Clinical Center, Department of Transfusion Medicine/NMDP physicians will determine the appropriateness of individuals as donors.
D: Inclusion Criteria:

* Subjects must meet all of the following criteria to be enrolled in this study:

  1. Age ≥ 18 years at the time of consent
  2. Signed written informed consent obtained prior to any study procedures
  3. Relapsed or refractory B-cell NHL.
  4. PET-positive disease BY Lugano classification
  5. Archived tumor biopsy tissue available from the last relapse and corresponding pathology report available or, if at least one tumor-involved site is deemed accessible at time of screening, willing to undergo pre-treatment biopsy (excisional when possible) for disease confirmation. If a subject has never had a complete response, a sample from the most recent biopsy is acceptable.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  7. Adequate bone marrow, renal, hepatic, pulmonary and cardiac function
  8. Adequate vascular access for leukapheresis procedure
  9. Subjects who have received previous CD19-targeted therapy must have CD19-positive lymphoma confirmed on a biopsy since completing the prior CD19-targeted therapy
  10. Subjects must agree to use appropriate contraception.

Exclusion Criteria:

* Subjects who meet any of the following criteria will be excluded from participation in this study:

  1. Subjects with central nervous system (CNS)-only involvement by malignancy (note: subjects with secondary CNS involvement are allowed on study)
  2. History of another primary malignancy that has not been in remission for at least 2 years.
  3. Treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis
  4. Active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection at the time of screening
  5. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment at the time of leukapheresis or JWCAR029 administration
  6. Presence of acute or chronic graft-versus-host disease (GVHD)
  7. History of cardiovascular disease
  8. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
  9. Pregnant or nursing women.
  10. Prior CAR T-cell or other genetically-modified T-cell therapy, with the exception of prior JWCAR029 treatment in this protocol for subjects receiving retreatment

Answer: A