CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Patients must be ≥ 12 months of age at the time of enrollment in the study.
* Diagnosis: Histological confirmation of neuroblastoma or ganglioneuroblastoma at initial diagnosis. (Bone marrow samples with positive catecholamines are acceptable as confirmation of neuroblastoma) OR histological confirmation of osteosarcoma at diagnosis
* Response to prior therapy:

  * High-risk neuroblastoma with refractory, relapsed or progressive disease, defined as:
  * First or greater relapse of neuroblastoma following completion of aggressive multi- drug frontline therapy.
  * First episode of progressive neuroblastoma during aggressive multi-drug frontline therapy.
  * Persistent/refractory neuroblastoma as defined by less than a complete response by the revised International Neuroblastoma Response Criteria (INRC) after at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (such as A3973 or ANBL0532).
  * Note that this excludes patients initially considered low or intermediate-risk neuroblastoma that progressed to high-risk disease but the patient has not progressed after the diagnosis of high-risk neuroblastoma.
  * Relapsed or refractory osteosarcoma that is not responsive to standard treatment
* Disease Status

  * Patients must have measurable or evaluable disease per revised INRC for subjects with neuroblastoma or measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for subjects with Osteosarcoma
  * Performance Level:Patients must have a Lansky (≤16 years) or Karnofsky (\>16 years) score of ≥50
* Prior Therapy

  * Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy before study registration.

    * Prior dinutuximab therapy is allowed regardless of prior response or progression on dinutuximab
    * Prior temozolomide therapy is allowed
    * Prior zoledronate is allowed
    * Prior dinutuximab/temozolomide/irinotecan chemoimmunotherapy is allowed
    * Prior T cell therapy is excluded
* Organ Function Requirements:

  * Hematologic Functions : Absolute Neutrofil count ≥750/uL and platelet count ≥ 75,000/µl, transfusion independent .
  * Renal Function: Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 ULN for age.
  * Liver Function: Total bilirubin ≤ 1.5 x ULN for age and serum glutamic-pyruvic transaminase (SGPT) (ALT) ≤ 135 U/L (≤ 3x ULN).
  * Cardiac Function: Normal ejection fraction (≥ 55%) documented by either echocardiogram or radionuclide multigated acquisition scan (MUGA) evaluation OR Normal fractional shortening (≥ 27%) documented by echocardiogram
  * Pulmonary Function: Normal pulmonary function with no evidence of dyspnea at rest, no exercise intolerance.

Exclusion Criteria:

* Prior T cell therapy
* Pregnancy, breast feeding, or unwillingness to use effective contraception during the study will not be entered on this study.
* Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
* Patients with known active Central Nervous System (CNS) disease (excluding skull disease with intracranial extension). Patients with a history of CNS disease are required to have a brain CT and/ or MRI at study registration.
* Patients with prior allogeneic stem cell transplant
* Patients who are on hemodialysis
* Patients with an active or uncontrolled infection. Patients on prolonged antifungal therapy are still eligible if they are culture negative, afebrile, and meet other organ function criteria
* Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C. Testing is not required in the absence of clinical findings or suspicion.
* Patients with disease of any major organ system that would compromise their ability to withstand therapy.
* Patients who have had to permanently discontinue Dinutuximab due to toxicity
* Patients with serious, uncontrolled cardiac arrhythmias
* Patients with a history of myocarditis
* Patients who have received any live vaccines within 30 days before enrollment

主要终点：Maximum Tolerated Dose/Recommended Phase 2 Dose of gamma delta T cells · The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event (AE) reporting. The MTD/RP2D is defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicity course · 21 Days
次要终点：Describe Non-Hematological Toxicities；Describe Hematological Toxicities；Overall Response

• Dose Escalation Phase I cohort · EXPERIMENTAL · Subjects are assigned a cell therapy dose level at registration. Entry dose is Level 1, with escalation to Level 3 using a 3+3 design. If no progression, up to 4 courses may be given. Each course includes two γδ T cell infusions, one week apart. Toxicity for dose escalation and MTD will be assessed in Course 1. Disease response will be evaluated after Courses 2 and 4. Dinutuximab (17.5 mg/m²), temozolomide (100 mg/m²), irinotecan (50 mg/m²), and zoledronate (0.0125 mg/kg) are consistent across dose levels. Same γδ T cell donor will be used for both infusions per course. Due to stock supply, this may not always be possible. In each cohort, the first two subjects are staggered; the second is enrolled only after the first completes the DLT observation (≥21 days).

The goal of this clinical trial is to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of allogeneic expanded γδ T cells when delivered with Dinutuximab, temozolomide, irinotecan, and zoledronate in children with refractory or recurrent neuroblastoma or refractory/ relapsed osteosarcoma as well as to define the toxicities of allogeneic expanded γδ T cells when delivered with Dinutuximab, temozolomide, irinotecan, and zoledronate