CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

At enrollment:

* Patients with a histologically confirmed diagnosis of:

  * Newly diagnosed high-grade glioma (WHO Grade III or IV)
  * Newly diagnosed DIPG (after first 2 HGG patients are treated)
  * Recurrent or progressive high-grade glioma
* Age 4-18 years old for ndHGG. Age 4-30 for rHGG. Age 4-30 for nd DIPG.
* Patients with M+ disease without gliomatosis cerebri (see definition under exclusion criteria) ARE eligible.
* Patients with primary spinal cord tumors ARE eligible.
* CD70 positive (≥5%, 1+) The tumors from the surgical resection by immunohistochemistry will be confirmed by validated assay performed at UF Health Pathology, CLIA certified Lab.
* CD70 tumor expression performed on paraffin-embedded tumor specimens will be evaluated. Tumor expression will be scored on a scale of 0 to 3 staining intensity:

  0 = Negative
  1. = Low level
  2. = Moderate level
  3. = High level The criteria for inclusion will be at least 5% of the cells scoring 1+ staining intensity (\> 5%, 1+).
* Karnofsky Performance Status (KPS, for patients \>16yo) or Lansky Performance Score (LPS, for patients ≤16yo) of \> 60% (Appendix C)
* Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score provided the neurological deficit is stable.

Organ Function:

* CBC with differential with adequate bone marrow function as defined below:
* Absolute neutrophil count (ANC) ≥ 1000 cells/mm3.
* Platelet count ≥ 75,000 cells/mm3. (Unsupported, no transfusion within 4 days.)
* Hemoglobin ≥ 8 g/dl. (May receive transfusions)
* Adequate renal function as defined below:
* Serum creatinine \< 1.5 x institutional upper limit of normal for age and gender. Patients who do not meet the criteria but have a 24-hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2 are eligible.
* Adequate hepatic function as defined below:
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) for age
* ALT ≤ 3 times institutional upper limits of normal for age
* AST ≤ 3 times institutional upper limits of normal for age
* Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment.
* Signed parental permission and, as appropriate, assent from pediatric patients age ≥14. If the patient's mental status precludes their informed consent, the legally authorized representative may give informed consent. Consent or permission/assent will be obtained at screening (before PBMC collection) and before treatment with CAR T-cells.
* For females with childbearing potential, a negative serum pregnancy test at enrollment.
* Women of childbearing potential (WOCBP) must be willing to use an acceptable contraceptive method to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of the study drug.
* Males with female partners of childbearing potential must agree to practice adequate contraceptive methods throughout the study and should avoid conceiving children for 24 weeks following the last dose of the study drug.
* Prior Therapy for recurrent Cohort only:
* Patients with recurrent or progressive disease must have received prior radiotherapy +/- chemotherapy.
* Patients must have recovered from the acute treatment related toxicities (≤ Grade 1) prior to enrollment.
* Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment. Patients must have received their last dose of non-myelosuppressive chemotherapy at least 7 days prior to enrollment.
* Patients must have received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment. Monoclonal antibody treatment and agents with known prolonged half-lives: Patient must have received their last dose of the agent ≥ 28 days prior to study enrollment.
* Patients with recurrent or progressive HGG must have had their last fraction of:
* Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to spine ≥ 6 weeks (42 days) prior to enrollment.
* Focal irradiation ≥ 14 days prior to enrollment.
* ≥ 12 weeks (84 days) since autologous stem cell transplant prior to enrollment.
* \> 42 days since completion of any other type of adoptive cellular therapy prior to enrollment

Prior to lymphodepletion and therapy:

* Appropriate bridging therapy (radiation/re-irradiation and/or salvage chemotherapy, dependent on cohort) was initiated within 7 weeks of surgery RT or other protocol directed anti-cancer therapy is without significant toxicity that persisted over 4 weeks.
* Early postoperative progression: Patients who progress during radiation treatment that are clinically stable and meet eligibility criteria prior to the start of lymphodepletion may continue on study. If these criteria are not met, these patients will be withdrawn from the study.
* Neurologic Status
* In patients with neurological deficits, deficits should be stable for a minimum of 7 days prior to the start of treatment. A baseline detailed neurological exam should clearly document the neurological status of the patient prior to the start of treatment.
* In patients with seizure disorders, seizures must be well controlled prior to the start of treatment.
* Performance Status Karnofsky Performance Scale (KPS for \> 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) (Appendix C) assessed within one week prior to the start of treatment must be ≥ 60%.
* Organ Function Patients must have adequate organ and bone marrow function as defined in Section 3.1.
* Pregnancy Testing Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the start of treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
* Corticosteroids: A maximum dose of 0.75 mg/kg/day with maximum of 4mg/day.
* No active infection: No fever exceeding 38.5 °C and no acute antibiotics, antiviral, or antifungal PO or IV therapy.

Exclusion Criteria:

* Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease-free for ≥ 3 years. (In situ cancer is permissible)
* Spinal metastasis or gliomatosis cerebri. Gliomatosis cerebri - clear tumor involvement of multiple areas (\>3 lobes), OR presence of clinical and/or radiographic evidence of impending herniation or spinal cord compression.
* The patient is not a candidate for cellular therapy as assessed by the study bone marrow transplant physician.
* Known immunosuppressive disease or human immunodeficiency virus (HIV) infection.

HIV-positive patients are ineligible due to the unknown safety and efficacy of infusing these patients with CAR T cells genetically modified using retroviral vectors. Additionally, the immunosuppression used for treatment in this study will pose an unacceptable risk.

• Concurrent illness: Patients with active autoimmune disease, documented history of autoimmune disease/syndrome, or any other condition that requires ongoing systemic steroids or systemic immunosuppressive agents, except

* Patients with vitiligo or resolved asthma/atopy
* Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome
* Patients requiring physiologic doses of corticosteroids (up to 0.5 mg/m2/day dexamethasone equivalent)
* History of or ongoing pneumonitis or significant interstitial lung disease.
* Ongoing or active uncontrolled infection.
* Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator, would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
* Patients with any of the following cardiac diseases:
* New York Heart Association (NYHA) functional class III or IV
* Clinically significant cardiac arrhythmia including, but not limited to, Torsade de pointes or requiring a pacemaker
* Left ventricular ejection fraction below 50% as determined by echocardiography (ECHO)
* Pregnant or lactating women due to possible adverse effects on the developing fetus or infant.
* Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible.
* Patients who have received the last vaccination of a live vaccine ≤ 30 days prior to enrollment are ineligible.
* Patients who have received an inactivated virus, peptide, or mRNA vaccine within 14 days of the start of protocol therapy are ineligible.
* Inability to participate: Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity of therapy or to adhere to drug administration plan, other study procedures, and study restrictions.
* Patients treated on any other therapeutic clinical protocols within 30 days prior to enrollment.
* For females of childbearing potential, a negative serum pregnancy test at enrollment.

主要终点：Incidence of investigational treatment related severe toxicity (Dose-limiting toxicity event) · Safety is defined as the adverse events (AEs), serious adverse events (SAEs) and dose-limiting toxicities (DLT) observed throughout the trial. · administration of 8R-70CAR T to 28 days post-infusion；Prevalence of enrolled subjects who receive a qualified immunotherapy investigational product. · Feasibility will be measured by the number of patients who receive 8R-70CAR T-cell that met the FDA IND defined quality assurance and quality control release criteria. A minimum of 66.7 % of enrolled subjects must achieve this criterion for the feasibility endpoint. · Enrollment up to 18 weeks；Maximum tolerated dose (MTD) dose-finding endpoint based on Dose-Limiting-Toxicity (DLT) incidence · Determination of the maximum tolerated dose (MTD) of 8R-70CAR T cells based on the incidence of investigational treatment-related severe toxicity (dose-limiting toxicity events) · administration of 8R-70CAR T to 28 days post-infusion

• Newly Diagnosed High Grade Glioma (ndHGG) · EXPERIMENTAL · Participants will receive either 8R-70CAR T 1 x 10\^7 cells/kg or 1 x 10\^8 cells/kg
• Recurrent High Grade Glioma (rHGG) · EXPERIMENTAL · Participants will receive either 8R-70CAR T 1 x 10\^7 cells/kg or 1 x 10\^8 cells/kg
• Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) · EXPERIMENTAL · Participants will receive either 8R-70CAR T 1 x 10\^7 cells/kg or 1 x 10\^8 cells/kg

This is a phase I study to assess the safety and feasibility of IL-8 receptor modified patient-derived activated CD70 CAR T cell therapy in newly diagnosed and recurrent CD70+ Pediatric High-Grade Gliomas (pHGG) and Diffuse Intrinsic Pontine Glioma (ndDIPG)