Anti-CD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma

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 toat least 1 prior line of multiagent chemoimmunotherapy with prior exposure toboth an anti-CD20 antibody agent and an anthracycline.

• No significant circulating disease, defined as an elevated total lymphocytecount above the upper limit of normal (ULN) due to the presence of malignantcells.

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: TheLugano 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 ananti-CD20 antibody and an alkylating agent.

2. Participants must have measurable disease as defined below: o Participants with Marginal Zone Lymphoma or Lymphoplasmacytic Lymphoma/WaldenströmMacroglobulinemia: must either have PET-positive disease according to "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkinand Non-Hodgkin Lymphoma: The Lugano Classification" or serum monoclonalimmunoglobulin M (IgM) paraprotein > 0.5 g/dL.

3. Participants with indolent lymphoma (Marginal Zone Lymphoma or LymphoplasmacyticLymphoma/Waldenström Macroglobulinemia) must have symptomatic disease necessitatingsystemic treatment.

In addition, all participants must meet the following criteria:

1. CD19-positive by either immunohistochemistry or flow cytometry analysis on anybiopsy. If prior anti-CD19 therapy has been administered, CD19-positivity has to bere-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:

6. Adequate bone marrow function for apheresis and lymphodepleting chemotherapy

7. Hemoglobin >8 gm/dl (transfusions allowed)

8. Platelets >50,000/uL (transfusions allowed)

9. Absolute Neutrophil Count (ANC) > 500/uL

10. alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 xinstitutional upper limit of normal (ULN) and Total bilirubin < 1.5 mg/dl xinstitutional ULN, except with Gilbert's syndrome

11. Serum Creatinine < 2 x the institutional ULN

12. 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'sdiscretion.

13. Adequate vascular access for leukapheresis procedure (either peripheral line orsurgically placed line).

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

15. Males who have partners of childbearing potential must agree to use an effectivebarrier contraceptive method.

16. Ability to understand a written informed consent document, and the willingness tosign 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 arepositive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), orhepatitis C antibody must have a negative polymerase chain reaction (PCR) prior toenrollment. (PCR positive participants will be excluded.)

6. Participants with uncontrolled intercurrent illness including, but not limited toongoing or active infection, symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/socialsituations that would limit compliance with study requirements.

7. Pregnant or breastfeeding women are excluded from this study because CAR-T celltherapy may be associated with the potential for teratogenic or abortifacienteffects. Because there is an unknown, but potential risk for adverse events innursing infants secondary to treatment of the mother with CAR-T cells, breastfeedingshould be discontinued. These potential risks may also apply to other agents used inthis study. NOTE: Women of childbearing potential must have a negative serum orurine pregnancy test.

8. Participants with history of clinically relevant central nervous system (CNS)pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolledcerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.

9. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupuserythematosus) 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 areconsidered not clinically significant by the principal investigator AND are not theresult of a demonstrated active infection or an active central nervous systemcondition.

2. ECOG performance status < 2

3. No evidence of uncontrolled intercurrent illness including, but not limited toongoing or active infection, inflammatory response, symptomatic congestive heartfailure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities orpsychiatric 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 usedfor prevention of emesis during lymphodepletive chemotherapy).