CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

Recipient Inclusion Criteria for Procurement:

* Diagnosis of relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma, or Wilms tumor
* Refractory disease, residual detectable disease or relapsed disease following available standard of care therapies with known clinical benefit for their specific tumor type, or unable to receive such therapies due to unacceptable toxicity or contraindication
* Measurable or evaluable disease by imaging, as determined following most recent therapy
* Age ≥ 1 year and \< 24 years
* Weight ≥ 10 kg
* No systemic steroid exposure within 1 week of procurement
* Karnofsky/Lansky score of ≥ 60 (See Appendix 3)
* Participants of childbearing potential or capable of fathering a child must agree to use effective contraceptive measure/s (as described in Appendix 5) during study protocol participation through 6 months following the administration of the CAR-TA T cells
* ANC \> 500/µL
* ALC \> 1000/µL
* Platelet count \> 50,000/uL (level can be achieved with transfusion)
* Bilirubin ≤ 2.5 mg/dL
* Aspartate aminotransferase (AST)/Alanine transaminase (ALT) ≤ 5x the upper limit of normal for age
* Serum creatinine Maximum serum creatinine (mg/dL) Age Male Female

  1. to \< 2 years 0.6 0.6
  2. to \< 6 years 0.8 0.8

  6 to \< 10 years 1 1 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.2

  ≥ 16 years 1.7 1.4 OR Creatinine clearance or glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m for patients with levels above
* For FOCBP: Negative pregnancy test
* Pulse oximetry of \> 90% on room air
* Adequate cardiac function defined as:

  * Shortening fraction of ≥ 27% by echocardiogram, or
  * Ejection fraction of \> 50% by echocardiogram or radionuclide angiogram (i.e., MUGA).
* No acute neurological toxicity \> grade 1 (with the exception of peripheral sensory neuropathy or controlled seizure disorder on anti-epileptics).
* The following time frames must have elapsed between prior therapy completion and apheresis cell collection:

  * Myelosuppressive chemotherapy/immunomodulatory medications: At least 3 weeks, or 6 weeks if prior nitrosourea.
  * Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor. At least 14 days after receiving pegfilgrastim.
  * Biological agent, tyrosine kinase inhibitor, targeted agent, metronomic chemotherapy: At least 7 days since the completion of therapy with a biologic agent, tyrosine kinase inhibitor, targeted agent, or metronomic non-myelosuppressive regimen.
  * Monoclonal antibodies and checkpoint inhibitors: At least 3 weeks or 5 half-lives (whichever is shorter) since the last dose of a monoclonal antibody or checkpoint inhibitor.
  * Radiotherapy (XRT): At least 3 weeks since XRT, and at least 6 weeks if radiation involved the CNS or lung fields. Exception: There is no time restriction for palliative radiation with minimal bone marrow involvement and the patient has measurable/evaluable disease outside the radiation port or the site of radiation has documented progression.
  * Autologous stem cell transplant/infusion: At least 6 weeks from their infusion after an autologous stem cell infusion following myeloablative therapy. Patients who received an autologous stem cell infusion following non-myeloablative therapy do not have a wash-out period; they are eligible once they meet all other eligibility requirements, including recovery from acute side effects.
  * Investigational agent: at least 28 days since receiving an investigational agent.
* Adult participant or the legally authorized representative (LAR) of a minor (defined as \<18 years of age) must be capable of providing informed consent. When appropriate, pediatric participants ≥7 years of age will participate in an age-appropriate discussion and provide assent, unless an IRB-approved waiver of assent applies and documentation of the participant's eligibility for the waiver is maintained.

Recipient Inclusion Criteria for CAR-TA T cell product Infusion:

* No systemic steroid exposure within 1 week prior to protocol therapy initiation
* Karnofsky/Lansky score of ≥ 60
* ANC \> 750/uL
* Platelet count \> 75,000/uL
* Bilirubin ≤ 2.5 mg/dL
* AST/ALT ≤ 5x the upper limit of normal for age
* Serum creatinine Maximum serum creatinine (mg/dL) Age Male Female

  1 to \< 2 years 0.6 0.6 2 to \< 6 years 0.8 0.8 6 to \< 10 years 1 1 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.2

  ≥ 16 years 1.7 1.4 OR Creatinine clearance or glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m for patients with levels above
* For FOCBP: Negative pregnancy test
* Participants of childbearing potential or capable of fathering a child must agree to use effective contraceptive measure/s through 6 months following the administration of the CAR-TA T cells
* Adequate respiratory function defined as oxygen saturation 90% or higher on room air
* For participants who underwent prior mediastinum-directed therapies (e.g., post radiation to chest): resolution of any respiratory symptoms
* Adequate respiratory rate, defined as \<30 breaths per minute for patients aged \<18 years, and \<25 breaths per minute for patients aged ≥18 years (respiratory rate may be repeated if initial value is thought to be temporarily abnormal; if repeated, 2 consecutive readings obtained ≥30 minutes apart must be adequate to be eligible)
* No acute neurological toxicity \> grade 1 (with the exception of peripheral sensory neuropathy or controlled seizure disorder on anti-epileptics).
* Adequate cardiac function defined as:

  * Shortening fraction of ≥ 27% by echocardiogram, or
  * Ejection fraction of \> 50% by echocardiogram or radionuclide angiogram
* The following time frames must have elapsed between completion of prior therapy and the initiation of SABRE protocol therapy:

  * Myelosuppressive chemotherapy: At least 2 weeks from last dose of chemotherapy.
  * Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor. At least 14 days after receiving pegfilgrastim.
  * Biological agent, tyrosine kinase inhibitor, targeted agent, metronomic chemotherapy: At least 7 days since the completion of therapy with a biologic agent, tyrosine kinase inhibitor, targeted agent, or metronomic non-myelosuppressive regimen.
  * Monoclonal antibodies and checkpoint inhibitors: At least 3 weeks or 5 half-lives (whichever is shorter) since the last dose of a monoclonal antibody or checkpoint inhibitor.
  * Radiotherapy (XRT): At least 3 weeks since XRT, and at least 6 weeks if radiation involved CNS or lung fields. Exception: There is no time restriction for palliative radiation with minimal bone marrow involvement and the patient has measurable/evaluable disease outside the radiation port or the site of radiation has documented progression.
  * Investigational agent: At least 28 days since receiving an investigational agent.
* Adult participant or the legally authorized representative (LAR) of a minor (defined as \<18 years of age) must be capable of providing informed consent. When appropriate, pediatric participants ≥7 years of age will participate in an age-appropriate discussion and provide assent, unless an IRB-approved waiver of assent applies and documentation of the participant's eligibility for the waiver is maintained.

Exclusion Criteria:

Recipient Procurement Exclusion Criteria:

* Patients with known CNS disease.
* Patients with uncontrolled infection/s or known HIV infection
* Pregnant or lactating females.
* Patients who have undergone previous allogeneic stem cell transplant.
* Inability to tolerate leukapheresis (including any contraindication to the use of Anticoagulant Citrate Dextrose solution).

Recipient Exclusion Criteria for CAR-TA T cell product Infusions:

* Patients with uncontrolled infections or known HIV infection.
* Pregnant or lactating females
* Whole lung/mediastinal radiation within 12 weeks
* Clinically significant systemic illness or medical condition likely to interfere with assessment of safety or efficacy
* Patients who have received any live vaccine in the six weeks prior to planned initiation of lymphodepletion
* Any contraindication to lymphodepletion or to the use of Cyclophosphamide or Fludarabine, as per the clinical judgment of the PI or treating Sub-I
* History of allergy or hypersensitivity to study product excipients (e.g., DMSO)

主要终点：To determine the safety of autologous CAR-TA T cells following LD chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor. · The safety endpoint will be assessed by monitoring for dose limiting toxicities (DLT) for 28 days following CAR-TA T cell investigational product administration. · Within 28 days from the CAR-TA T cell infusion；To determine the manufacturing feasibility of autologous CAR-TA T cells following LD chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor. · Manufacturing feasibility will be determined by the number of CAR-TA T cell products produced in sufficient quantities to meet the participant's assigned dose level for at least one infusion, with all product release testing criteria met. · Within 28 days from the CAR-TA T cell infusion；To determine the clinical feasibility of autologous CAR-TA T cells following LD chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor. · Clinical feasibility will be determined by the number of participants with a released product who are eligible and receive at least 1 infusion. · Within 28 days from the CAR-TA T cell infusion
次要终点：Determine number of patients who respond to CAR-TA T cell therapy for treatment of diseases under study；Overall Survival；To characterize the in vivo immune milieu pre- and post-infusion of CAR-TA T cell product.；To characterize transgene transduction efficiency (B7-H3 CAR and dTBRII) of the CAR-TA T cell product generated prior to infusion.；To characterize reconstitution of anti-tumor immunity following infusion.；To determine in vivo persistence of infused DNR-TA T cells and B7-H3 CAR T cells at 1-,3-, 6-, and 12-months following infusion of CAR-TA T cell product and evaluate the association with clinical response；To characterize the in vivo immune milieu pre- and post-infusion of CAR-TA T cell product.；To characterize the in vivo immune milieu pre- and post-infusion of CAR-TA T cell product.

• This is single arm study. · EXPERIMENTAL · Lymphodepleting chemotherapy regimen with cyclophosphamide and fludarabine will be administered prior to CAR-TA T cell product infusion. The DNR-TA T cells and B7-H3 CAR T cells will be generated and combined into a final product comprised of the two T cell components combined at a 1:1 ratio.

This is a phase I dose-escalation study to determine the safety and feasibility of autologous CAR-TA T cells (B7-H3 CAR+ T cells administered with DNR-PRAME Tumor Antigen-specific T cells) following lymphodepleting chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor. Patients will be enrolled to one of three planned dose levels with B7-H3 CAR T cell dose determined based on the percentage of B7-H3 transduced cells (B7-H3+ population of cells), and dTBRII-transduced PRAME TA-specific T cell dose based on the total cell population. Both doses will be based on the recipient's body weight and combined in a 1:1 ratio. The safety of the CAR-TA T cell product will be evaluated and the maximum tolerated dose (MTD) will be determined. The safety endpoint will be assessed by monitoring for dose limiting toxicities for 28 days following CAR-TA T cell administration.