This multicenter phase 1 trial with "3 + 3" dose escalation design seeks to examine the feasibility and safety of the administration of autologous T cells that have been modified through the introduction of chimeric antigen receptors targeting the B cell surface antigens CD19/20/22 following administration of a chemotherapy lymphodepletion regimen in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) or Non-Hodgkin's lymphoma (NHL). The overall goals of this study are to estimate maximum tolerated dose (MTD) level, establish the overall safety profile and evaluate initial efficacy of administering duo-CAR-T cell treatment in this patient population.

Dose Escalation Cohort (Phase 1)

This will have 3 enrollment groups:

Group A: Participants with B-ALL (CAR pre-treated or CAR naïve), Group B: Participants with B-NHL (CAR pre-treated), Group C: Participants with B-NHL (CAR naïve)

The trial will begin with a phase I dose escalation evaluation in each of the three enrollment groups. Participants will be treated either at dose level 1 and dose level -1 or at dose level 1 and dose level 2 of CAR T cells. This phase will determine the MTD and /or RP2D for the subsequent Phase 2 study. The trial duration for an individual participant is 15 years from DUOCAR20.19.22-D95-CAR T cell infusion. Following infusion, DLT assessments will continue through end of Day 30 visit during Dose Escalation Phase 1. Efficacy and routine safety monitoring for Phase 1 cohort will occur at established protocol-defined intervals through Year 2 or until the start of a new treatment regimen, whichever occurs sooner. The observational long-term follow-up portion of the study will then become operative.

Inclusion Criteria:

1. Ability of participant to understand this study, and participant willingness to sign a written informed consent

2. Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to the start of preparatory regimen

3. Patients must have histologically confirmed aggressive B-Cell NHL or ALL as stated below:

   A. Patients with relapsed or refractory B-Cell ALL i. Demonstration of one or more antigens of interest (CD19, CD20, CD22) in most recent disease evaluation prior to study entry and within 30 days of study entry.

   ii. Patients with relapsed/refractory disease in blood, marrow, and extramedullary sites including CSF will be eligible when there is immunophenotypic evidence of CD19 and/or CD20 and/or CD22 expression

   iii. Primary refractory disease at study entry defined as: A morphologic complete response has never been achieved prior to study entry.

   iv. Early first relapse at study entry defined as: Disease recurrence by morphologic assessment after duration of first remission at ≤ 18 months

   v. Relapsed Refractory disease (first or later relapse) at study entry defined as: Morphologic complete response was not achieved after initiation of a second-line (or later) systemic therapy

   vi. Second or greater relapse at study entry defined as: Any disease recurrence following a second or later complete response (with treatment history including two or more lines of systemic therapy)

   vii. Additional considerations beyond above criteria:

   • Patients with relapsed or refractory disease after allogeneic stem cell transplantation must be >100 days from HSCT to be eligible for study participation. Furthermore, post-HSCT immunosuppressive medications must be discontinued for at least 4 weeks prior to study entry
   • Prior CAR-T therapy is permissible if ≥ 3 months from therapy completion
   • Morphological disease in the bone marrow Note: Morphologic disease is defined as blasts being at least 5% in the bone marrow.

   B. Histologically confirmed aggressive B cell NHL, including the following types defined by WHO 2008 after 2 or more lines of prior therapy:

   i. 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; Primary cutaneous DLBCL, leg type; OR ii. Primary mediastinal (thymic) large B cell lymphoma iii. Follicular lymphoma 3b and transformation of follicular lymphoma to DLBCL will also be included iv. High-grade B cell lymphoma v. Chemotherapy-refractory disease, defined as one or more of the following:

   • Refractory disease is defined as progressive or stable disease as the best response to the most recent prior therapy or relapse within 12 months of autologous stem cell transplantation. Two prior lines of therapy are required for LBCL eligibility. The second line therapy may be chemotherapy based, autologous stem cell transplantation, or CAR-T.

   • Relapsed or refractory disease after allogeneic transplant provided patient is at least 100 days from stem cell transplant at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment

   • Patients must have received 2 or more lines of adequate prior therapy including at a minimum:

     • anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20- negative and
     • an anthracycline containing chemotherapy regimen
     • for patients with transformed FL must have received prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to DLBCL vi. Prior CAR T therapy permissible if ≥ 3 months from the therapy vii. At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma (Cheson 2007). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy C. Relapsed or refractory indolent non-Hodgkin lymphoma i. Histologically confirmed indolent non-Hodgkin lymphoma, including grade 1-3b follicular lymphoma or nodal or extranodal marginal zone lymphoma (both per WHO 2016 classification criteria) ii. Relapsed or refractory disease (per Lugano criteria) after two or more previous lines of therapy, iii. Previous lines of therapy to include an anti-CD20 monoclonal antibody combined with an alkylating agent iv. Prior CAR T therapy permissible if ≥ 3 months from the therapy v. At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma (Cheson 2007). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy vi. Relapsed or refractory disease after allogeneic transplant provided patient is at least 100 days from stem cell transplant at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment D. Relapsed or Refractory Mantle-Cell Lymphoma i. Histologically confirmed mantle-cell lymphoma with either cyclin D1 overexpression or presence of the translocation (T11:14) ii. Disease that is either relapsed or refractory to at least 2 prior lines of previous regimens for mantle-cell lymphoma iii. Previous therapy must have included anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 monoclonal antibody, and BTK inhibitor therapy

4. Prior CAR T therapy permissible if ≥ 3 months from the therapy

5. At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma (Cheson 2007). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy

6. Relapsed or refractory disease after allogeneic transplant provided patient is ≥ 3 months from stem cell transplant at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment

7. Meet institutional criteria for leukapheresis procedure or have availability of previously- collected and stored leukapheresis product that satisfies minimum requirements

8. Eastern cooperative oncology group (ECOG) performance status of 0 to 2.

9. Adequate hematologic and organ function NOTE: Patients with established diagnosis of benign neutropenia are eligible to participate with ANC between 1000-1500 if in the opinion of treating physician the trial treatment does not pose excessive risk of infection to the patient.

10. Adults ≥ 18 years of age, with no upper limit of age

11. Life expectancy >2 months

12. ≥ 3 months from prior CAR

13. Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing Potential/Pregnancy section from the time of signing informed consent to at least 12 months following DuoCAR20.19.22-D95 infusion and until CAR positive viable T cells are no longer present by quantitative polymerase chain reaction (qPCR) on two consecutive tests. Men must agree not to donate sperm for the same time period.

Exclusion Criteria:

1. Patients with CLL, Richter's transformation, and Burkitt lymphoma

2. Active CNS involvement by malignancy - CNS3 disease, i.e., patients with WBC count in CSF ≥5 and having blasts in the CSF in patients with ALL or detection of NHL on CSF by flow cytometry or active CNS involvement on imaging)

3. Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion

4. Investigational medicinal product within the last 30 days prior to screening Note: Investigational therapies must not be used at any time while on study until the first progression following DuoCAR20.19.22-D95 CAR T infusion.

5. The following medications are excluded:

   1. Steroids: Therapeutic doses of steroids must be stopped > 72 hours prior to leukapheresis and > 72 hours prior to DuoCAR20.19.22-D95 infusion. However, the following physiological replacement doses of steroids are allowed: <12 mg/m2/day hydrocortisone or equivalent
   2. Immunosuppression: Any other immunosuppressive medication must be stopped ≥ 2 weeks prior to leukapheresis and ≥ 2 weeks prior to DuoCAR20.19.22-D95 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators).
   3. Antiproliferative therapies other than lymphodepleting chemotherapy within 2 weeks prior to infusion
   4. Short acting drugs used to treat leukemia or lymphoma (e.g., tyrosine kinase inhibitors, and hydroxyurea) must be stopped > 72 hour prior to leukapheresis and > 72 hours prior to DuoCAR20.19.22-D95 infusion
   5. Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to DuoCAR20.19.22-D95 infusion.
   6. Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respective antibody, whichever is longer. Note: Rituximab is excluded within 4 weeks prior to infusion.
   7. CNS disease prophylaxis or treatment must be stopped > 1 week prior to DuoCAR20.19.22-D95 infusion (e.g., intrathecal methotrexate)

6. Prior radiation therapy within 2 weeks of infusion

7. Active replication of or prior infection with hepatitis B or active hepatitis C (HCV RNA positive)

8. HIV positive patients (excluding false positive HIV test resulting from the viral vector used in prior CAR T)

9. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g., blood culture positive ≤ 72 hours prior to infusion)

10. Unstable angina and/or myocardial infarction within 6 months prior to screening

11. Previous or concurrent malignancy with the following exceptions:

    1. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
    2. In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study
    3. A primary malignancy which has been completely resected and in complete remission for ≥ 5 years

12. Simultaneously enrolled in any therapeutic clinical trial (except for long-term follow up studies)

13. Current or anticipating use of other anti-neoplastic or investigational agents while participating in this study

14. Either diagnosed with a psychiatric illness or under the impact of a social situation that would limit compliance with study requirements in the opinion of the investigator

15. Is pregnant or breastfeeding

16. Intolerance to the excipients of the cell product

17. Cardiac arrhythmia not controlled with medical management

18. Active COVID-19 (follow ASTCT guidelines)

19. Presence of active grade 2 to 4 acute, extensive chronic graft-versus-host disease (GVHD) or that require systemic steroids

20. Patients with active neurological auto immune or inflammatory disorders (e.g., Guillain-Barré Syndrome, Amyotrophic Lateral Sclerosis)