Preliminary Safety and Tolerability of CD19x22 CAR T Cells in Adolescent and Adult R/R B-NHL Patients

Inclusion Criteria: 1. Age: ≥ 16 years of age with no upper age limit. (NOTE: the first three subjects on this trial must be ≥ 18 years of age.) COHORT 1: Non-CNS B-NHL 1. Histologically confirmed aggressive B-cell NHL including the following types defined by World Health Organization (WHO) 2008: 1. Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein Barr Virus (EBV)+ DLBCL of the elderly; OR 2. Primary mediastinal (thymic) large B cell lymphoma; OR 3. Transformation to DLBCL; OR 4. High grade B-cell Lymphoma (HGBL). 2. Subjects must not have any signs or symptoms of CNS disease or detectable evidence of CNS disease on magnetic resonance imaging (MRI) at screening; subjects who have been previously treated for CNS disease, but have no evidence of disease at screening are eligible for this cohort. 3. Subjects must have disease progression confirmed by either flow cytometry or immunohistochemistry (IHC), disease stabilization, or disease recurrence after at least two lines of therapy. 1. The two lines of prior therapy must include an anthracycline and anti-CD20 monoclonal antibody treatment. 2. Relapse or refractory after single antigen targeting CAR T cell therapy 4. Must have evaluable or measurable disease according to the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma; lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. COHORT 2: MANTLE CELL LYMPHOMA (MCL) 1. Mantle Cell Lymphoma (MCL). 1. Results of all tests conducted on the tissue at initial diagnosis and/or relapse, including, but not limited to, the MCL subtype (classic and blastoid), Ki-67 proliferation index, and TP53 mutation status should be provided if done. 2. Subjects must have relapsed and/or refractory MCL confirmed by either flow cytometry or immunohistochemistry (ICH), disease stabilization, or disease recurrence after at least two lines of therapy including any combination of the agents below: 1. An anti-CD20-directed therapy 2. A BTK inhibitor 3. Anthracycline or Bendamustine 4. Relapse or refractory after single antigen targeting CAR T cell therapy. 3. Must have evaluable or measurable disease according to the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma; lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. MCL patients without measurable nodal or extranodal disease by IWG criteria are eligible if they have bone marrow involvement of MCL at relapse COHORT 3: PRIMARY CNS LYMPHOMA OR SECONDARY CNS LYMPHOMA 1. Subjects with relapsed and/or refractory primary CNS lymphoma (PCNSL) OR secondary CNS lymphoma (SCNSL), as defined by the following: a. Absence of measurable disease outside the CNS, as determined by radiographic imaging (i.e. PET/CT). b. Detectable CNS disease, as defined as: i. At least 1 site of measurable disease within the brain or spinal cord that is ≥ 1 cm in the longest diameter based on MRI or PET/CT imaging; OR, ii. CSF-positive disease only (confirmed by presence of persistent disease, detected by cytology or flow cytometry) at the time of enrollment iii. Neoplastic B-cells detectable within the vitreous by flow cytometry or cytology 2. Subjects must have disease progression confirmed by either flow cytometry or immunohistochemistry (IHC), disease stabilization, or disease recurrence after at least one line of therapy. ALL COHORTS: 1. Subjects who have undergone autologous stem cell transplantation (SCT) with disease progression or relapse are eligible. 2. Subjects who have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, are: 1. At least 100 days post-transplant, 2. Do not have active graft versus host disease (GVHD) 3. Any standard of care systemic therapy prior to leukapheresis must follow the washout period. 4. Any steroid use (dexamethasone or prednisone) prior to apheresis must follow the washout period. Physiological replacement doses are allowable with no washout period. Topical or inhaled steroids for localized GVHD is allowable. 5. Peripheral blood CD3 count must be \>0.15 x 10 (to the 6th) cells/mL within 14 days prior to proceeding with apheresis. 6. Toxicities from prior therapy must be stable and recovered to ≤ grade 1 (exceptions include non-clinically significant toxicities such as alopecia and the organ function definitions provided in inclusion criteria 12). 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or Karnofsky ≥ 80%. 8. Adequate organ function as defined by: 1. Absolute neutrophil count (ANC) ≥ 500/μL 2. Platelet count ≥ 50,000/ μL. 3. Renal: Creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 60 mL/min. 4. Hepatic: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 upper limit of normal (ULN). 5. Total bilirubin ≤ 2 mg/dl, except in subjects with Gilbert's syndrome where a bilirubin \<4.0 will be acceptable. 6. Cardiac: Ejection fraction ≥ 40%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings within 6 weeks of apheresis. 7. Pulmonary: No clinically significant pleural effusion and; i. Baseline oxygen saturation must be \> 92% on room air 9. Females of childbearing potential must have a negative serum pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 6 months are not considered to be of childbearing potential). 10. Subjects of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for 12 months after receiving the CD19x22 infusion; females of childbearing potential must have a negative pregnancy test. 21\. Must be able to give informed consent; subjects unable to give informed consent will not be eligible for this study. 22\. Be able to consent to long-term follow-up protocol (#20-0188). Exclusion Criteria: 1. Age \< 16 years of age. 2. Patients who are intolerant of contrast-enhanced MRI due to allergic reactions to contrast agents. Only applicable to Cohort 3. 3. Patients with active, poorly controlled hydrocephalus defined as increase/worsening in symptoms (headaches, nausea/vomiting, lethargy, or neurological function with increased hydrocephalus noted on radiologic evaluation and/or need for CSF diversion. Note: If hydrocephalus is controlled after CSF diversion, patient may be eligible for the study. Only applicable to Cohort 3. 4. Patients with brainstem lesions. Only applicable to Cohort 3. 5. History of other malignancies, unless they have been disease free for at least 3 years. Exceptions include non-melanoma skin cancer or carcinoma in situ and localized prostate cancer not on active treatment. 6. Uncontrolled fungal, bacterial, viral, or other infection requiring antimicrobials for management; uncomplicated infections are permitted if responding to active treatment. 7. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (hepatitis B surface antigen \[HBsAg\] positive) or hepatitis C. 8. History of known myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment or have cardiac atrial or cardiac ventricular lymphoma involvement. 9. Venous thrombosis or embolism not managed on a stable regimen of anticoagulation. 10. Any medical condition that in the judgement of the sponsor is likely to interfere with assessment of safety or efficacy of study treatment. 11. History of severe immediate hypersensitivity reaction to any of the agents used in this study. 12. Pregnancy (serum pregnancy test must be obtained at time of enrollment for females of childbearing potential and to be repeated 72 hours prior to lymphodepleting chemotherapy regimen); females who have undergone surgical sterilization or who have been postmenopausal for at least 6 months are not considered to be childbearing potential. 13. Lactating. 14. In the investigator's judgment, the subject is unlikely to complete all protocol required study visits or procedures, including follow up visits, or comply with the study requirements for participation. 15. Unwilling to participate in long-term follow-up protocol that is required if CAR T cell therapy is administered at CU Anschutz. APHERESIS ELIGIBILITY In order to proceed with apheresis, enrolled participants cannot have active, severe infection. For the purpose of this trial, active, severe infection is defined as: * Positive blood culture within 48 hours of the start of the apheresis procedure, OR * Fever \>38.2°C AND clinical signs of infection within 48 hours of start of apheresis procedure Additionally, participants should have the following labs within 14 days of apheresis: * CBC with manual differential * Lymphocyte enumeration (TBNK) panel to measure CD3 count * CD3 count must be \>0.15 x 106 cells/mL LYMPHODEPLETING CHEMOTHERAPY ELIGIILITY: In order to proceed with lymphodepleting chemotherapy, enrolled participants must meet all eligibility criteria below within 72 hours prior to lymphodepletion, unless otherwise specified: * If the participant received bridging therapy after apheresis, confirmation of disease reevaluation is required. It must be within 6 weeks of initiation of LD chemotherapy. * Confirmation that the participant has met the washout period for bridging therapy. * Negative serum pregnancy test (for women of childbearing potential) * Adequate organ function as defined by: * Absolute neutrophil count (ANC) ≥ 500/μL. * Platelet count ≥ 50,000/ μL. * Renal: Creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 60 mL/min. * Hepatic: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 upper limit of normal (ULN). * Total bilirubin ≤ 2 mg/dl, except in subjects with Gilbert's syndrome where a bilirubin \<3.0 will be acceptable. * Pulmonary: No clinically significant pleural effusion and; Baseline oxygen saturation must be \> 92% on room air. * Cardiac: Ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO) (only if subject received bridging anthracycline or developed a significant illness prior to LD-chemo per investigator assessment.) If clinically indicated, ECHO must be performed within 2 weeks prior to LD-chemotherapy. * Cohort 3 patients ONLY: * Patients must not have steroid-dependent CNS lymphoma, defined as requiring more than 1 mg/kg/day or prednisone or equivalent within 14 days prior to the start of LD chemotherapy. * Patients may not have poorly controlled hydrocephalus prior to the initiation of LD chemotherapy. CD19x22 CAR T CELL INFUSION ELIGIBILITY In order to proceed with CD19x22 CAR T Cell Infusion, enrolled participants must meet all eligibility criteria below within 24 hours prior to CD19x22 CAR T Cell infusion, unless otherwise specified: * CD19x22 CAR T cells must have met manufacturing release criteria (unless prospectively approved by IND Sponsor, Gates Institute Medical Lead, and FDA). * Confirmation that the site has Anakinra and Ruxolitinib in stock and available (should IEC-HS treatment be required). * ECOG ≤2 or Karnofsky≥ 50%. * Clinically stable without evidence of vital sign instability, including the lack of supportive vasoactive drugs or intensive care unit support. * Oxygen saturation \> 92% on room air; cannot be on supplemental oxygen. * No evidence of uncontrolled, significant tumor lysis syndrome prior to cell infusion per investigator assessment. * No evidence of rapidly progressive NHL per investigator determination. * Participants' temperature is \<38.0 °C within 48 hours prior to cell infusion. (If the source of fever cannot be identified \[after thorough infectious disease work-up\], and the suspected cause is underlying malignancy, discussion and approval by the Gates Institute Medical Lead may allow continued infusion of CD19x22 cells. This should be appropriately documented in the patient's medical record. * Liver transaminase (ALT and AST) \< 5 x institutional ULN (\< grade 3) based on age- and laboratory- specific normal ranges. * Adequate renal function as defined by creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by the Cockcroft- Gault equation) ≥ 60 mL/min. If these criteria are not met, measures can be taken to resolve the underlying condition(s). If successful, cells may be infused up to (and including) 7 days following the time of the planned infusion with no additional lymphodepletion. If the CD19x22 CAR T Cell infusion is delayed more than 7 days, lymphodepleting chemotherapy MAY be repeated, per the investigator's discretion. Prior to commencing a second round of lymphodepletion, participants must meet lymphodepletion criteria described above.