Optimizing Lymphodepletion to Improve Outcomes in Patients Receiving Cell Therapy With Kymriah (LOKI)

Inclusion Criteria: Age ≥ 18 years at the time of informed consent Life expectancy ≥ 12 weeks Biopsy-proven and histologically confirmed relapse/refractory (R/R) large B cell lymphoma, including Primary mediastinal B-cell lymphoma (PMBCL), R/R DLBCL and transformation from Follicular lymphoma (FL). Radiographically documented measurable disease as per Lugano response criteria (i.e. longest transverse diameter of a lesion (LDi) > 1.5 cm that is [18F] fluorodeoxyglucose (FDG) avid). At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic cancer therapy at the time the subject provides consent Eligible for standard of care CAR T cell therapy, specifically, relapsed or refractory large B cell lymphoma after two or more lines of systemic therapy, and subjects must have received adequate first-line therapy including at a minimum: Patient is sufficiently stable to facilitate planned CAR T-cell therapy (e.g. not rapidly progressing on temporizing therapy, no significant compromise of vital organ functions (intubation, dialysis, requiring Intensive care unit (ICU)/vasopressor support)) and has good performance status Patient does not have active central nervous system (CNS) disease Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at enrollment Patient has not received prior adoptive T-cell immunotherapy Patient is not human immunodeficiency virus (HIV) positive Patient did not receive prior allogeneic stem cell transplant Adequate bone marrow, renal, hepatic, pulmonary and cardiac function Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential) Sexually active males who accept to use a condom during intercourse during treatment and for 12 months after treatment as they should not father a child in this period. A condom is required to be used also by vasectomized men (as well as during intercourse with a male partner) in order to prevent delivery of the drug via seminal fluid Must have an apheresis product of non-mobilized cells accepted for manufacturing. Exclusion Criteria: Persisting disease bulk (defined as ≥10 cm) on restaging imaging following bridging therapy. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) unless disease free for at least 3 years History of Richter's transformation of chronic lymphocytic leukemia (CLL) History of allogeneic stem cell transplant Received < 2 lines of therapy for large B cell lymphoma Prior CD19 targeted therapy Subject has received or undergone the protocol defined treatments/therapies Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing. Active tuberculosis Subjects with detectable cerebrospinal fluid malignant cells or known CNS involvement; a history of prior treated CNS lymphoma which is not active at the time of relapse is permitted History or presence of significant non-malignant CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement Subjects with cardiac atrial or cardiac ventricular lymphoma involvement History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac disease within 12 months of enrollment Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression History of autoimmune disease, requiring systemic immunosuppression and/or systemic disease modifying agents within the last 2 years. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment Any medical condition likely to interfere with assessment of safety or efficacy of study treatment History of severe immediate hypersensitivity reaction to tocilizumab or any of the agents used in this study Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of chemotherapy on the fetus or infant. Subjects of either sex who are not willing to practice birth control from the time of consent and at least 6 months after tisagenlecleucel infusion In the investigators 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.