NKTR-255 vs Placebo Following CD19-directed CAR-T Therapy in Patients With Relapsed/Refractory Large B-cell Lymphoma

Key Inclusion Criteria: 1. Male or female ≥ 18 years of age at the time of consent. 2. Received standard of care therapy with axi-cel or liso-cel (Stage 1 and Stage 2), or tisa-cel (Stage 2 only), for the respective FDA (or Summary of Product Characteristics \[SmPC\]) approved indication(s): 1. liso-cel: Patients with LBCL (including diffuse LBCL \[DLBCL\] not otherwise specified \[including DLBCL arising from indolent lymphoma\], high-grade B-cell lymphoma, primary mediastinal LBCL, and follicular lymphoma Grade 3B), who have: 1. refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; 2. refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or, 3. relapsed or refractory disease after two or more lines of systemic therapy. 2. axi-cel: For the treatment of adult patients with LBCL that is: 1. refractory to first-line chemoimmunotherapy; 2. relapses within 12 months of first-line chemoimmunotherapy; or 3. R/R LBCL after 2 lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal LBLC, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. 3. tisa-cel (Stage 2 only): Adult patients with R/R LBLC after two lines of systemic therapy including DLBCL not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. 3. Received lymphodepleting chemotherapy regimen according to the respective FDA (or SmPC) label for CAR-T cell therapy. 4. Fluorodeoxyglucose (FDG)-avid disease on positron emission tomography (PET) imaging within 30 days prior to CAR-T cell infusion. 5. FDG avid lesion(s) on PET/computed tomography (CT) scan following bridging therapy and prior to lymphodepletion, where applicable. 6. Evidence of CD19 expression on any prior or current NHL tumor specimen or a high likelihood of CD19 expression based on disease histology per investigator's assessment. 7. Within 7 days prior to leukapheresis, patient should have an Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 (Appendix 3). 8. Regarding prior systemic anti-tumor therapy: 1. At least 3 months have elapsed since systemic immune checkpoint inhibitory/immune stimulatory therapy (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc). 2. At least 2 weeks have elapsed since other prior systemic antitumor therapy. 3. Bridging therapy (including steroids) is permitted between leukapheresis and lymphodepletion as long as Exclusion Criterion 1 is satisfied. 9. Adequate organ function, defined as: 1. Adequate bone marrow function (prior to lymphodepletion) for lymphodepletion chemotherapy defined as: absolute neutrophil count (ANC) ≥ 1000 cells/mm3, platelets ≥ 50,000 cells/mm3, and hemoglobin ≥ 8 g/dL in the absence of bone marrow involvement by lymphoma. No transfusion within 3 days of bone marrow function assessment; growth factor support is allowed as per institutional practice. 2. Calculated creatinine clearance (Cockcroft/Gault) \> 30 mL/min (Appendix 4). 3. ALT and AST ≤ 3 × upper limit of normal (ULN; or \< 5 × ULN for patients with lymphomatous infiltration of the liver) and total bilirubin ≤ 2 × ULN (or \< 3.0 × ULN for patients with Gilbert's syndrome or lymphomatous infiltration of the liver). 4. Adequate pulmonary function, oxygen saturation on room air (SaO2) ≥ 92%. Patients with a history of interstitial lung disease should undergo pulmonary function testing and must have a forced expiratory volume in 1 second (FEV1) of ≥ 50% of predicted value or diffusing capacity of the lung for carbon monoxide (DLCO; corrected) ≥ 40% of predicted value. 5. Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) within 60 days before randomization. 10. ECG demonstrating Fridericia's corrected QT interval (QTcF) \< 470 ms. Patients with QTcF ≥ 470 ms will require clearance by a local cardiologist. 11. Women of reproductive potential (defined as all women physiologically capable of becoming pregnant) must agree to use suitable methods of contraception from the start of study treatment until 1 month after the last dose of study drug (Appendix 6). 12. Males who have partners of reproductive potential must agree to use an effective barrier contraceptive method from the start of study treatment until 1 month after the last dose of study drug. 13. Ability to understand and provide written informed consent. 14. Able and willing to comply with study visit schedule and procedures, including tumor biopsy where accessible. Additional Eligibility Criteria Following CD19 Targeted CAR-T Cell Infusion Patients who have received commercially released CAR-T cell infusion must satisfy the following criteria on the day of randomization: 15. No fever ≥ 38.0°C/Grade ≥ 1 CRS (American Society for Transplant and Cellular Therapy \[ASTCT\] criteria within 24 hours. 16. No Grade ≥ 3 CRS (ASTCT criteria) within 72 hours. 17. No previous Grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (ICANS) of \> 72 hours duration. 18. No Grade ≥ 2 ICANS (ASTCT criteria). 19. No tocilizumab and/or dexamethasone within 48 hours. 20. No active, serious, and/or uncontrolled infection(s). 21. No other contraindication according to the Investigator's assessment. 22. Patients must satisfy the following laboratory test results: * ANC or absolute granulocyte count (AGC) ≥ 1000/μL * Platelets ≥ 30,000/μL * Hemoglobin ≥ 8 g/dL * Leukocytes ≥ 3000/μL Randomization should occur no more than 1 day before the first study drug infusion. Exclusion Criteria: 1. Use of therapeutic doses of corticosteroids (≥ 5 mg/day prednisone or equivalent) or other systemic immunosuppression within 7 days prior to leukapheresis or within 72 hours prior to CAR-T cell infusion. Topical and/or inhaled steroids are permitted. 2. Prior treatment with any CD19-directed CAR-T cell therapy other than the treatment planned per Inclusion Criterion 2. 3. For allogeneic hematopoietic cell transplant recipients, active graft versus host disease (GVHD) and/or systemic GVHD therapy during screening or up to 30 days prior to leukapheresis. 4. Known active hepatitis B (detectable hepatitis B DNA) or hepatitis C (detectable hepatitis C RNA). 5. Known human immunodeficiency virus (HIV) infection. 6. Pregnant or breastfeeding women. 7. Prior treatment with any IL-2 or IL-15 agonist and/or biosimilar agents. 8. Active autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, ulcerative colitis, Crohn's disease\], celiac disease, or other serious chronic gastrointestinal conditions associated with diarrhea, autoimmune vasculitis, systemic lupus erythematosus, Wegener syndrome \[granulomatosis with polyangiitis\], myasthenia gravis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.) within 1 year prior to randomization. The following are exceptions to this criterion: 1. Vitiligo 2. Alopecia 3. Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement 4. Type 1 diabetes mellitus 5. Psoriasis not requiring systemic treatment 6. Conditions considered to be low risk of serious deterioration by the Investigator and with Medical Monitor approval 9. History of any one of the following cardiovascular conditions within the 6 months prior to randomization: class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, or unstable angina; unless clearance by a cardiologist is obtained. History of other clinically significant cardiac disease that, in the opinion of the Investigator or designee, is a contraindication to study treatment is also excluded. 10. History or presence of clinically relevant central nervous system (CNS) pathology, such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, or psychosis that in the opinion of the Investigator is a contraindication to study treatment. 11. History of CNS lymphoma, primary CNS lymphoma, brain metastases, or detectable malignant cells in the cerebrospinal fluid. 12. History of solid organ transplantation. 13. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the Medical Monitor. 14. Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, indwelling foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted. 15. Active or current participation on any other interventional studies. 16. Use of an investigational agent or an investigational device within 28 days of CAR-T cell therapy. 17. Live, attenuated vaccines are prohibited within 30 days of randomization. 18. Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol or would increase the risk associated with study participation or study drug administration or interfere with the interpretation of results.