CELL INTELLIGENCE · 肿瘤细胞治疗研究

Procurement Inclusion Criteria:

* 1\) Diagnosis of GPC3-positive recurrent ATRT.
* 2\) Age ≥ 6 months
* 3\) Karnofsky/Lansky score ≥ 60%
* 4\) Informed consent explained to, understood by, and signed by patient/guardian; copy provided
* 5\) GPC3 expression by immunohistochemistry with extent score ≥ Grade 2 (\>25% positive tumor cells) and intensity score ≥ 2 (scale 0-4)

Procurement Exclusion Criteria:

* 1\) No history of organ transplantation
* 2\) No known HIV positivity
* 3\) No active bacterial, fungal, or viral infection (except Hepatitis B or Hepatitis C virus infections)
* 4\) No other risk factors in which administration of the investigational agent is deemed not in the patient's best interest, in the opinion of the investigator

Treatment Inclusion Criteria:

* 1\) Age ≥ 6 months
* 2\) Diagnosis of treatment refractory or unresectable ATRT after standard of care therapy
* 3\) Lansky/Karnofsky score ≥ 60%
* 4\) Stable neurologic exam for 7 days prior to enrollment
* 5\) Stable or decreasing dose of steroids over past 7 days prior to surgery and administration of therapy (max allowable dose is 0.1mg/kg dexamethasone or equivalent per day)
* 6\) Not receiving any concurrent anti-cancer therapy.
* 7\) At least 6 weeks following craniospinal radiation therapy.
* 8\) At least 14 days wash-out needed following small volume radiotherapy (i.e., Stereotactic Radiosurgery (SRS)).
* 9\) At least 21 days or 5 half-lives (whichever is shorter) must have elapsed since any prior systemic therapy
* 10\) Received any other forms of immunotherapy ≤ 42 days before administration of investigational agent
* 11\) At least 28 days following bevacizumab
* 12\) Creatinine clearance as estimated by Cockcroft Gault or Schwartz ≥ 60 ml/min
* 13\) Total bilirubin \< 3 times ULN for age
* 14\) INR ≤ 1.7
* 15\) Absolute neutrophil count \> 500/μl
* 16\) Platelet count \> 100,000/μl (can be transfused but must be achieved prior to enrollment)
* 17\) Hgb ≥ 7.0 g/dl (can be transfused)
* 18\) Pulse oximetry \> 90% on room air
* 19\) Recovered from acute toxic effects of all prior chemotherapy and investigational agents before entering this study
* 20\) Sexually active patients must be willing to utilize one of the more effective birth control methods for 3 months after the T-cell infusion.
* 21\) Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

Treatment Exclusion Criteria:

* 1\) Pregnancy or lactation (for women at child-bearing age, birth control is required)
* 2\) Uncontrolled infection
* 3\) Known HIV positivity
* 4\) Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
* 5\) History of organ transplantation

主要终点：Number of Participants with Dose-Limiting Toxicity · DLT will be defined as any of the following that may be considered possibly, probably, or definitely related to the 21.15.GPC3-CAR T cells: Any Grade 5 event, Non-hematologic dose-limiting toxicity (any Grade 4 non-hematologic toxicity that fails to return to Grade 2 within 72 hours), Grade 4 allergic reaction to CAR T cell administration, Grade 4 reactions due to CRS and neurotoxicity (rarely seen with the use of CAR-based immunotherapy), Grade 3 cytokine release syndrome (CRS) infusion reactions and neurologic toxicity that fail to return to Grade 1 within 72 hours, Grade 4 CRS and neurologic toxicities · 4 weeks after CAR T-cell administration
次要终点：Maximum Tolerated Dose (MTD) of intratumoral and/or ICV injection of 21.15.GPC3-CAR T cells in treating patients with GPC3-positive recurrent or incompletely resected ATRT.；Response Rate

• Treatment with 21.15.GPC3-CAR T Cell Therapy (RADIANT CAR T Cells) · EXPERIMENTAL · Participants will receive autologous 21.15.GPC3-CAR T cells administered intratumorally into the tumor resection cavity and/or intracerebroventricularly via an Ommaya reservoir. CAR T cells are genetically engineered using retroviral vectors encoding a GPC3-specific chimeric antigen receptor and cytokines IL-15 and IL-21. The following dose levels of CAR T cells will be evaluated: * DL0: 1 × 10⁷ CAR T cells * DL1: 3 × 10⁷ CAR T cells * DL2: 5 × 10⁷ CAR T cells * DL3: 1 × 10⁸ CAR T cells If dose de-escalation from DL1 is required, patients will be treated at DL0. Further de-escalation may use half-log reductions if needed. Dose escalation will occur only after safety evaluation of prior cohorts.

This study is being conducted in patients with GPC3-positive brain tumors that have recurred or have not responded to standard therapy. Atypical teratoid rhabdoid tumors (ATRT) are aggressive tumors with poor outcomes and limited treatment options, particularly in young children. There is a need for new therapies that can improve outcomes while minimizing toxicity. This study evaluates a new experimental treatment using genetically engineered T cells (RADIANT-T cells) that target glypican-3 (GPC3), a protein expressed on tumor cells. These T cells are modified to express a chimeric antigen receptor (CAR) targeting GPC3, along with IL-15 and IL-21 to enhance their persistence and activity. The cells also include an inducible safety mechanism (iCasp9) that allows them to be eliminated if necessary. The purpose of this study is to determine the highest safe dose of RADIANT-T cells, evaluate their safety and side effects, assess how long they persist in the body, and determine whether they show anti-tumor activity in patients with GPC3-positive brain tumors.