Genetically Engineered Cells (8R-70CAR T Cells) in Combination with Standard Temozolomide and Radiation Therapy with or without Conditioning Chemotherapy for Treatment of CD70 Positive Adult Glioblastoma and Pediatric High Grade Gliomas, IMPACT Trial

Inclusion Criteria

• ADULT GBM COHORTS: Age ≥ 18 years
• ADULT GBM COHORTS: Newly-diagnosed de novo GBM based on the absence of a previous history of brain tumor (World Health Organization [WHO] grade IV glioma, IDH wild type) by histopathology or molecular studies. (Secondary GBM not eligible)
• ADULT GBM COHORTS: The tumor must have a supratentorial component
• ADULT GBM COHORTS: CD70 positive (≥ 50%, 1+) * The tumors from the surgical resection by immunohistochemistry will be confirmed by validated assay was performed at University of Florida (UF), a Health Pathology, a Clinical Laboratory Improvement Act (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+)
• ADULT GBM COHORTS: Surgical resection of tumors with less than 3cm x 3cm (9 cm^2) residual enhancing tumor as a product of longest perpendicular planes by MRI. (Biopsy only subjects are not eligible for this study)
• ADULT GBM COHORTS: Karnofsky performance status (KPS) of >= 70%
• ADULT GBM COHORTS: Absolute neutrophil count (ANC) ≥ 1500 cells/mm^3
• ADULT GBM COHORTS: Platelet count ≥ 100,000 cells/mm^3
• ADULT GBM COHORTS: Hemoglobin ≥ 10 g/dl. (The use of transfusion or other intervention to achieve Hgb ≥ 10 g/dl is acceptable.)
• ADULT GBM COHORTS: Blood urea nitrogen (BUN) ≤ 25 mg/dl
• ADULT GBM COHORTS: Creatinine ≤ 1.7 mg/dl
• ADULT GBM COHORTS: Bilirubin ≤ 2.0 mg/dl
• ADULT GBM COHORTS: Alanine aminotransferase (ALT) ≤ 5 times institutional upper limits of normal for age
• ADULT GBM COHORTS: Aspartate aminotransferase (AST) ≤ 5 times institutional upper limits of normal for age
• ADULT GBM COHORTS: Signed informed consent. If the patient’s mental status precludes his/her giving informed consent, written informed consent may be given by the legally authorized representative
• ADULT GBM COHORTS: For females of childbearing potential, a negative serum pregnancy test at enrollment
• ADULT GBM COHORTS: 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 study drug
• ADULT GBM COHORTS: 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
• PEDIATRIC HGG COHORT: Age 4-18 years
• PEDIATRIC HGG COHORT: Newly-diagnosed pHGG based on the absence of a previous history of brain tumor (WHO GRADE III-IV glioma) by histopathology
• PEDIATRIC HGG COHORT: CD70 positive (≥ 5%, 1+)
• PEDIATRIC HGG COHORT: The tumors from the surgical resection by immunohistochemistry will be confirmed by a validated assay performed at UF Health Pathology, a 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 ** 3+= High level
• PEDIATRIC HGG COHORT: Karnofsky Performance Status (KPS) or Lansky Performance Score (LPS) of > 70%. 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
• PEDIATRIC HGG COHORT: Absolute neutrophil count (ANC) ≥ 1000 cells/mm^3.
• PEDIATRIC HGG COHORT: Platelet count ≥ 100,000 cells/mm^3
• PEDIATRIC HGG COHORT: Hemoglobin ≥ 10 g/dl. (The use of transfusion or other intervention to achieve Hgb ≥ 10 g/dl is acceptable.)
• PEDIATRIC HGG COHORT: 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 m^2 are eligible
• PEDIATRIC HGG COHORT: Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) for age
• PEDIATRIC HGG COHORT: ALT ≤ 3 times institutional upper limits of normal for age
• PEDIATRIC HGG COHORT: AST ≤ 3 times institutional upper limits of normal for age
• PEDIATRIC HGG COHORT: Signed informed consent, or for patients age < 18, parental permission, and, as appropriate, assent from pediatric patients age ≥ 12. 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
• PEDIATRIC HGG COHORT: For females of childbearing potential, a negative serum pregnancy test at enrollment
• PEDIATRIC HGG COHORT: 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 study drug
• PEDIATRIC HGG COHORT: 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 study drug

Exclusion Criteria

• ADULT GBM COHORTS: Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for ≥ 3 years. (In situ cancer is permissible)
• ADULT GBM COHORTS: Metastases detected below the tentorium or beyond the cranial vault
• ADULT GBM COHORTS: Leptomeningeal disease beyond the cranial vault * (Focal, adjacent leptomeningeal involvement is allowable at the discretion of the principal investigator [PI])
• ADULT GBM COHORTS: Recurrent or multifocal malignant gliomas
• ADULT GBM COHORTS: The patient is not a candidate for cellular therapy
• ADULT GBM COHORTS: Known immunosuppressive disease or human immunodeficiency virus (HIV) infection * Rationale: The need to exclude patients with the immunosuppressive disease or human immunodeficiency virus infection is necessary because the management of potential toxicities from the study drug may involve treatment that is significantly immunosuppressive
• ADULT GBM COHORTS: Severe, active co-morbidity, defined as follows: * Unstable angina and/or congestive heart failure requiring hospitalization * Transmural myocardial infarction within the last 6 months * Acute bacterial or fungal infection requiring intravenous antibiotics at the initiation of radiation therapy (XRT)/temozolomide (TMZ) * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the initiation of XRT/TMZ * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects * Patients with an autoimmune disease requiring medical management with immunosuppressants * Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy * Active connective tissue disorders such as lupus or scleroderma that, in the investigator’s opinion, place the patient at high risk for radiation toxicity
• ADULT GBM COHORTS: Pregnant or lactating women, due to possible adverse effects on the developing fetus or infant
• ADULT GBM COHORTS: Patients treated on any other therapeutic clinical protocols within 30 days prior to enrollment
• PEDIATRIC HGG COHORT: Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for ≥ 3 years. (In situ cancer is permissible)
• PEDIATRIC HGG COHORT: Spinal metastasis and leptomeningeal involvement
• PEDIATRIC HGG COHORT: Patients with Bulky Tumors: * 3 cm in a single dimension (post-surgery) * Tumor causing uncal herniation or mass effect leading to midline shift with or without symptoms or signs of impending herniation or * Obstruction to CSF flow
• PEDIATRIC HGG COHORT: Recurrent or multifocal malignant gliomas
• PEDIATRIC HGG COHORT: The patient is not a candidate for cellular therapy as assessed by the study bone marrow transplant physician
• PEDIATRIC HGG COHORT: 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
• PEDIATRIC HGG COHORT: 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/m^2/day dexamethasone equivalent
• PEDIATRIC HGG COHORT: History of or ongoing pneumonitis or significant interstitial lung disease
• PEDIATRIC HGG COHORT: Ongoing or active uncontrolled infection
• PEDIATRIC HGG COHORT: 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
• PEDIATRIC HGG COHORT: 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)
• PEDIATRIC HGG COHORT: Pregnant or lactating women, due to possible adverse effects on the developing fetus or infant
• PEDIATRIC HGG COHORT: Patients treated on any other therapeutic clinical protocols within 30 days prior to enrollment
• PEDIATRIC HGG COHORT: For females of childbearing potential, a negative serum pregnancy test at enrollment.