Autologous CD22 Chimeric Antigen Receptor (CAR) T Cells for the Treatment of Recurrent or Refractory B Cell Lymphomas

Inclusion Criteria

• Must have histologically confirmed disease as defined by World Health Organization (WHO) 2016 of one of the following:
• Follicular lymphoma, grade 1-3a * Relapsed or refractory disease after at least 2 lines of systemic therapy. Prior therapy must have included an anti-CD20 monoclonal antibody combined with systemic therapy (single-agent anti-CD20 antibody does not count as line of therapy for eligibility nor does local radiation). Anti-CD20 antibody is not required for participants with CD20 negative disease. A systemic therapy includes, but is not limited to: Bendamustine, cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), cyclophosphamide, vincristine and prednisone (CVP), CAR T therapy, lenalidomide, or platinum-based chemotherapy. * Relapsed or progressive disease within 24 months of initiation of the initial course of chemotherapy (also known as progression of disease within 24 months POD24). Initial treatment must have included an anti-CD20 monoclonal antibody (unless CD20 negative) plus either CHOP or CVP (R-chemo). Must have completed 3 or more cycles of R-chemo. Progression is measured from the initial day of treatment of the first cycle of R-chemo. In the case of those who received anti-CD20 monoclonal antibody monotherapy previously and then received R-chemo are also eligible if they are progression of disease ≤24 months (POD24), and progression is measured from the initial day of treatment of the first cycle of R-chemo and not from the initial day of anti-CD20 monoclonal antibody monotherapy.
• Mantle cell lymphoma * Relapsed or refractory disease after at least 2 lines of systemic therapy. Prior therapy must have included an anti-CD20 monoclonal antibody combined with systemic therapy. Anti-CD20 antibody is not required for participants with CD20 negative disease. * Participants who have received an anti-CD20 monoclonal antibody in combination with chemotherapy AND a bruton’s tyrosine kinase inhibitor as a single line of therapy are also eligible.
• Hairy cell leukemia (HCL) * Diagnosis of HCL and require treatment as defined by having HCL-related anemia (hemoglobin < 11 g/dL), thrombocytopenia (platelets < 100 x 10^9 /L), or neutropenia (absolute neutrophil count below 1.5 x 10^9/L); symptomatic splenomegaly or adenopathy; or other constitutional symptoms directly related to HCL. * Must have progressed or been refractory to 2 lines of therapy including a purine nucleoside analog.
• Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia [WM]) – participants must meet all eligibility criteria listed * Must have confirmed diagnosis of WM based on Second International Workshop on WM. * Relapsed or refractory disease after 2 or more lines of therapy. ** Prior therapies must include a *** Bruton tyrosine kinase inhibitor (BTKi) *** Either chemotherapy and/or proteasome inhibitor * Requires treatment based on the recommendations from the Second International Workshop on WM. * Requires the presence of serum IgM that is at least 2 times the upper limit of normal. * Patients cannot require plasmapheresis for symptomatic hyperviscosity. * Patients cannot have symptomatic central nervous system involvement (Bing-Neel syndrome) that would prevent the assessment of neurotoxicity. * Patients cannot have transformed to large B cell lymphoma.
• Burkitt lymphoma (BL) * Relapsed or refractory to front line chemoimmunotherapy; Participants with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements will be excluded.
• Marginal zone lymphoma (MZL) * Must have received 2 prior lines of therapy including rituximab in combination with chemotherapy or a BTKi.
• Participants with follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma and marginal zone lymphoma must have 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.
• Participants with Hairy cell lymphoma must have presence of leukemic cells in the bone marrow or blood stream.
• Participants with lymphoplasmacytic lymphoma must have the presence of serum IgM that is at least 2 times.
• CD22 expression: Participants must have archival tissue available for analysis of CD22 expression or must be willing to undergo biopsy of easily accessible disease.
• Participants who have progressed or relapsed after prior autologous OR allogeneic stem cell transplantation (SCT) must be at least 100 days post-transplant, have no evidence of graft-versus-host disease (GVHD), and have been without immunosuppressive drugs at least 30 days.
• Meet required prior therapy washout windows prior to leukapheresis.
• Participants with prior CAR therapy must be at least 30 days post CAR infusion and have < 5% CD3+ cells express the previous CAR prior to apheresis, if a validated assay is available.
• Toxicities from prior therapy stable or resolved (except for clinically non-significant toxicity and cytopenias).
• Age ≥ 18 years of age.
• Adequate performance status (Eastern Cooperative Oncology Group [ECOG] 0, 1, or 2; or Karnofsky > 60%).
• Absolute neutrophil count (ANC) ≥ 750/uL. *A participant will not be excluded because of pancytopenia ≥ grade 3 if it is felt by the investigator to be due to underlying disease.
• Platelet count ≥ 50,000/uL. * A participant will not be excluded because of pancytopenia ≥ grade 3 if it is felt by the investigator to be due to underlying disease.
• Absolute lymphocyte counts (ALC) ≥ 150/uL.
• Creatinine < 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 45 mL/min.
• Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 10 x upper limit of normal (ULN) (except in participants with liver involvement by lymphoma).
• Total bilirubin ≤ 1.5 mg/dl, except in participants with Gilbert’s syndrome.
• Cardiac left ventricular ejection fraction ≥ 45%, no evidence of clinically significant pericardial effusion as determined by an echocardiogram.
• No clinically significant pleural effusion or ascites.
• Baseline oxygen saturation > 92% on room air.
• Participants with central nervous system (CNS) involvement or a history of CNS involvement are eligible only in the absence of neurologic symptoms that may mask or interfere with neurological assessment of toxicity.
• Females of childbearing potential must have negative pregnancy test.
• Females of child-bearing potential and males of child-fathering potential must be willing to practice birth control from time of enrollment and for 4 months post preparative lymphodepletion regimen or as long as CAR cells are detectable.
• Must be able to provide informed consent (legally authorized representative [LAR] is permitted if participant able to provide verbal assent).
• ELIGIBILITY CRITERIA TO UNDERGO LEUKAPHERESIS
• Participants must have no evidence of a clinically significant uncontrolled infection (defined as active infection from fungal, bacterial, viral or other infectious source requiring intravenous anti-microbials) prior to leukapheresis.
• Absolute lymphocyte count ≥ 150/uL within last 7 days (unless lower count attributed to disease status).
• No new signs or symptoms of kidney or liver dysfunction outside eligibility criteria within last 7 days.
• Females of child-bearing potential must not be pregnant.
• Must meet the following washout periods prior to leukapheresis: * Systemic corticosteroid therapy at dose ≥ 5 mg/day of prednisone (or equivalent doses of other corticosteroids) and other short-acting cytotoxic/antiproliferative drugs must be avoided for 3 days prior to leukapheresis. * At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecular therapy. * At least 1 week or 5 half-lives, whichever is shorter, must have elapsed since systemic therapy including chemotherapy.
• CRITERIA FOR INITIATING CONDITIONING LYMPHODEPLETION CHEMOTHERAPY REGIMEN
• There must be 14 days or more than five half-lives from the last dose of standard chemotherapy (7 days from ALL maintenance therapy), with the exclusion of steroids, which may be continued until starting conditioning lymphodepletion regimen. (within 7 days prior to starting chemotherapy)
• No evidence of uncontrolled infection, (defined as [grade 3] active infection from fungal, bacterial, viral, or other infectious source requiring intravenous anti-microbials). (Within 7 days prior to starting chemotherapy)
• No clinically significant cardiac dysfunction (defined as any grade 3 cardiac disorders [requiring urgent medical intervention]). (Within 7 days prior to starting chemotherapy)
• Serum creatinine must be < 2 x ULN. (Within 7 days prior to starting chemotherapy)
• No acute neurological toxicity > grade 1 (with the exception of peripheral sensory neuropathy). (Within 7 days prior to starting chemotherapy)
• Negative pregnancy test in child-bearing females within 7 days of starting chemotherapy. (Within 7 days prior to starting chemotherapy)
• Repeat disease evaluation, at the discretion of the investigator, if the participant received any bridging therapy after enrollment, if greater than 28 days has elapsed between date of enrollment and start of conditioning lymphodepletion chemotherapy regimen, or if investigator believes disease may have significantly advanced since enrollment. (Within 7 days prior to starting chemotherapy)
• ELIGIBILITY CRITERIA FOR SUBSEQUENT CELL INFUSIONS
• Cell infusion of CD22CART has been deemed safe. Dose escalation cohort for participants within that cohort has been completed without 2 participants in the cohort experiencing dose limiting toxicities (DLTs).
• Response to previous infusion. Participants who had a response with clinical benefit may elect to receive another infusion of cells. Participants that initially had a CR may only receive a second dose if evaluable disease recurs. Clinical benefit is indicated by an improvement in the participant’s health status.
• At least 60 days have passed since the previous cell infusion.
• Any toxicity (regardless of causality) after the previous CD22 CAR T cell infusion must resolve such that participants meet all the initial eligibility criteria for major organ function and therapy washout.
• An adequate number of cryopreserved CD22CART and quality (QA) retention vials or an adequate number of apheresis product sufficient to generate an additional dose of CD22CART must be available.

Exclusion Criteria

• Presence rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy.
• History or current other malignancies, apart from non-melanoma skin cancer, low-grade untreated prostate cancer under observation, or carcinoma in situ, unless disease free for at least 3 years, or in remission 1-2 years and principal investigator assesses other malignancy as unlikely to return within 1 year or interfere with CAR T cell safety.
• Presence of active fungal, bacterial, viral or other infection requiring intravenous antimicrobials. Simple urinary tract infection (UTI) or uncomplicated bacterial pharyngitis is permitted if responding to active treatment.
• Ongoing HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. History of HBV or HCV is permitted if viral load is undetectable by quantitative polymerase chain reaction (qPCR) and/or nucleic acid testing.
• Active cerebrovascular ischemic/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement that in investigator’s judgement impair ability to evaluate neurotoxicity.
• History of myocardial infarction (MI), cardiac angioplasty or stenting, unstable angina or other clinically significant cardiac disease within 12 months of enrollment.
• Severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study.
• Is pregnant or breastfeeding.
• Active primary immunodeficiency or history of autoimmune disease (e.g. Crohn’s disease, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
• May NOT, in investigator’s judgment, have any medical condition likely to interfere with assessment of safety or efficacy, or be likely to complete all protocol-required visits and procedures.