This study will assess safety and feasibility of infusing genetically modified autologous T cells transduced to express a chimeric antigen receptor targeting the B cell surface antigen Cluster of Differentiation 19 (CD19).

This is an open-label, pilot, phase 1 study to determine the safety profile of anti-CD19 CAR-T cell infusion in participants with R/R B-cell NHL.

PRIMARY OBJECTIVES

1. To evaluate the safety of administering chimeric antigen receptor T cells targeting CD-19 to patients with relapsed or refractory CD19+ B-cell non-Hodgkin lymphoma (NHL).
2. To determine the recommended phase 2 dose (RP2D) for this cellular therapy.

SECONDARY OBJECTIVES

1. To assess the safety and toxicity of cell collection and infusion of CAR-T cells targeting CD19 in patients with relapsed or refractory CD19+ B cell NHL.
2. To describe the efficacy of chimeric antigen receptor T cells targeting CD-19 in patients with relapsed or refractory CD19+ B cell NHL.
3. To evaluate the feasibility of CD19 CAR T cell manufacturing for patients with relapsed or refractory CD19+ B cell NHL of local manufacturing and ability to produce adequate quantities of vector positive T-cells.

OUTLINE

Participants will be enrolled to either the dose escalation or dose expansion cohorts.

Dose Escalation: CLOSED TO ENROLLMENT

Dose Expansion: The dose expansion phase of the study will be limited to two disease-specific cohorts:

• Cohort B: Participants with Burkitt lymphoma (B).
• Cohort M/W: Participants with Marginal Zone Lymphoma (MZL) and Waldenström Macroglobulinemia (WM).

Participants will receive an infusion of Anti-CD19 CAR-T cells during the main study and will be followed for 12 months before being transferred into long term follow-up during years 1 to 15.

THE DOSE ESCALATION COHORT IS CLOSED TO FURTHER ENROLLMENT.

Inclusion Criteria:

Dose expansion Cohorts:

Cohort B (Burkitt):

1. Participants must have a diagnosis of relapsed or refractory Burkitt Lymphoma

   • Participants with Burkitt lymphoma must have relapsed or failed to respond to at least 1 prior line of multiagent chemoimmunotherapy with prior exposure to both an anti-CD20 antibody agent and an anthracycline.
   • No significant circulating disease, defined as an elevated total lymphocyte count above the upper limit of normal (ULN) due to the presence of malignant cells.

2. Participants must have measurable disease as defined below:

   • Participants with Burkitt Lymphoma must have Positron Emission Tomography (PET)-positive disease according to "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification"

Cohort M/W (Marginal/Waldenström):

1. Participants must have a diagnosis of relapsed or refractory Marginal Zone Lymphoma (MZL), or Lymphoplasmacytic Lymphoma (LPL)/Waldenström Macroglobulinemia (WM):

   o Participants with indolent lymphomas (nodal or extranodal marginal zone lymphoma, and lymphoplasmacytic lymphoma) must have relapsed after or have been refractory to ≥ 2 prior lines of multi-agent chemoimmunotherapy including prior exposure to an anti-CD20 antibody and an alkylating agent.

2. Participants must have measurable disease as defined below:

   o Participants with Marginal Zone Lymphoma or Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia: must either have PET-positive disease according to "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification" or serum monoclonal immunoglobulin M (IgM) paraprotein > 0.5 g/dL.

3. Participants with indolent lymphoma (Marginal Zone Lymphoma or Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia) must have symptomatic disease or steady progression necessitating systemic treatment per investigator discretion.

In addition, all participants must meet the following criteria:

1. CD19-positive by either immunohistochemistry or flow cytometry analysis on any biopsy. If prior anti-CD19 therapy has been administered, CD19-positivity has to be re-established on the most recent biopsy.

2. Age ≥18 years at the time of consent.

3. Absolute lymphocyte count > 100/UL.

4. Eastern Cooperative Oncology Group (ECOG) performance status < 2.

5. Adequate organ function, defined as:

   1. Adequate bone marrow function for apheresis and lymphodepleting chemotherapy
   2. Hemoglobin >8 gm/dl (transfusions allowed)
   3. Platelets >50,000/uL (transfusions allowed)
   4. Absolute Neutrophil Count (ANC) > 500/uL
   5. alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 x institutional upper limit of normal (ULN) and Total bilirubin < 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome
   6. Serum Creatinine < 2 x the institutional ULN
   7. Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) > 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA) within 3 months of screening. Repeat testing may occur at Investigator's discretion.

6. Adequate vascular access for leukapheresis procedure (either peripheral line or surgically placed line).

7. Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of anti-CD19 CAR-T cells.

8. Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method.

9. Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria:

1. Autologous transplant within 6 weeks of planned CAR-T cell infusion.
2. Recipient of prior CAR-T cell therapy targeting CD19 outside of this protocol.
3. Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast).
4. Human immunodeficiency virus (HIV) seropositivity.
5. Serologic status reflecting active hepatitis B or C infection. Participants that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive participants will be excluded.)
6. Participants with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements.
7. Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test.
8. Participants with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.
9. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months.
10. Body weight <40 kilograms(kg).

Eligibility for Infusion of Investigational Product:

Participants will undergo an evaluation of eligibility on day 1 prior to infusion of anti-CD19 CAR-T cell product. This eligibility criterion will include the inclusion and exclusion criteria required for enrollment with the following exceptions and additions:

1. No significant laboratory abnormalities. Laboratory result abnormalities that are considered not clinically significant by the principal investigator AND are not the result of a demonstrated active infection or an active central nervous system condition.
2. ECOG performance status < 2
3. No evidence of uncontrolled intercurrent illness including, but not limited to ongoing or active infection, inflammatory response, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations.
4. No new neurologic symptoms suggestive of an active central nervous system condition, or uncontrolled CNS involvement by lymphoma.
5. No corticosteroid use within 7 days prior to infusion (with exception of agents used for prevention of emesis during lymphodepletive chemotherapy).