CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. Or adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
* At least 1 measurable lesion per Lugano at time of screening.
* At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy however steroids only require a 7-day washout.
* At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc).
* Age 18 or older
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
* Adequate renal, hepatic, pulmonary and cardiac function defined as:

  * ANC ≥1000/uL
  * Platelet count ≥50,000/uL
  * Absolute lymphocyte count ≥100/uL
  * Creatinine clearance (as estimated by Cockcroft Gault or CKD-EPI) ≥ 30 mL/min
  * Serum ALT/AST ≤2.5 per institutional ULN
  * Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert's syndrome.
  * Cardiac ejection fraction ≥ 40%, no clinically significant pericardial effusion, and no clinically significant ECG findings
  * Baseline oxygen saturation \>92% on room air.
* 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).
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years.
* History of Richter's transformation of CLL.
* Autologous stem cell transplant within 6 weeks of planned axicabtagene ciloleucel infusion.
* History of allogeneic stem cell transplantation.
* Presence of uncontrolled fungal, bacterial, viral, or other infection at time of screening.
* Known history of acute or chronic active hepatitis B or C infection. Subjects with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines.

  * Patients should also be negative for latent Tb, CMV (NAT), EBV (NAT) and adenovirus (NAT) by PCR testing.
* No evidence of active CNS disease regardless of prior CNS history.
* History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage within 6 months of enrollment.
* History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment.
* History of symptomatic pulmonary embolism within 3 months of enrollment; ongoing anticoagulation is allowed if beyond 3 months.
* Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
* History of allergic reactions or severe immediate hypersensitivity reaction to any of the agents used in this study or compounds of similar chemical or biologic composition.
* Females who are pregnant or breastfeeding or female or male participants who are not willing to practice birth control from the time of consent through 6 months after the completion of axicabtagene ciloleucel
* 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.
* History of autoimmune disease requiring ongoing systemic immunosuppression. Steroids are allowed up to 5mg predinosine-equivalent for adrenal insufficiency.
* Patients anticipated to require canakinumab, JAK inhibitors, TNF inhibitors, and tocilizumab for non-CAR-T management of baseline autoimmune/inflammatory disease at the time of emapalumab initiation.
* Receipt of a BCG vaccine within 12 weeks prior to Screening.
* Receipt of a live or attenuated live (other than BCG) vaccine within 4 weeks prior to screeing.
* Participants who are receiving any other investigational agents for this condition.

主要终点：Incidence of grade 2+ CRS per ASTCT · Assessed using American Society for Transplantation and Cellular Therapy (ASTCT). All participants will be monitored and assessed for grade 2+ cytokine release syndrome (CRS) for 24 months after post treatment. · Day -1 to 24 months post treatment
次要终点：Rate and severity of ICANS as per ASTCT；Objective response rate (ORR)

• Emapalumab · EXPERIMENTAL · Leukapheresis will happen within approximately 5 days of eligibility confirmation. Emapalumab is given as a single dose on Day -1 by intravenous infusion over about 1 hour. Lymphodepleting Chemotherapy with cyclophosphamide and fludarabine will occur once a day for 3 days (Days -5 through Day -3) by intravenous infusion over about 2-4 hours. Axicabtagene ciloleucel will be given once on Day 0 by intravenous infusion over about 30 minutes.

This research study involves assessing the impact of emapalumab as preventative management of CAR-T related cytokine release syndrome in participants with Non-Hodgkin's lymphoma (NHL). The research study involves the following study interventions: * Fludarabine and cyclophosphamide (Lymphodepleting Chemotherapy) * Axicabtagene Ciloleucel * Emapalumab