IL-8 Receptor Modified Patient-Derived Activated CD70 CAR T Cell Therapy for the Treatment of CD70 Positive Pediatric Newly Diagnosed and Recurrent High-Grade Glioma and Newly Diagnosed Diffuse Intrinsic Pontine Glioma, Peds IMPACT Trial

Inclusion Criteria

• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: Age 4 – 18 years
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: Newly diagnosed pediatric HGG (pHGG) based on the absence of a previous history of brain tumor (World Health Organization [WHO] grade III-IV glioma) by histopathology
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: CD70 positive (≥ 5%, 1+) * The tumors from the surgical resection by immunohistochemistry will be confirmed by a validated assay performed at University of Florida (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 level ** 3+ = High level ** The criteria for inclusion will be at least 5% of the cells scoring 1+ staining intensity (> 5%, 1+)
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: Karnofsky performance status (KPS) or Lansky Performance Score (LPS) of ≥ 60% * 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
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: Absolute neutrophil count (ANC) ≥ 1000 cells/mm^3
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: Platelet count ≥ 75,000 cells/mm^3 (unsupported-no transfusion within 4 days)
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: Hemoglobin ≥ 8 g/dl. (The use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 8 g/dl is acceptable)
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: 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 glomerular filtration rate (GFR) (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m^2 are eligible
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) for age
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: Alanine aminotransferase (ALT) ≤ 3 times institutional upper limits of normal for age
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: Aspartate aminotransferase (AST) ≤ 3 times institutional upper limits of normal for age
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: For participants < 18 years, written permission will be obtained from a parent or guardian, and age- and developmentally appropriate assent will be obtained from participants whom the institutional review board (IRB) determines are capable of providing assent. Participants aged 18 years or older will provide written informed consent. For an adult participant who lacks decision-making capacity, consent may be obtained from a legally authorized representative in accordance with applicable law and institutional IRB requirements. Informed consent or parental permission and assent, as applicable, will be obtained at screening before PBMC collection and confirmed before CAR T-cell treatment
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: For females of childbearing potential, a negative serum pregnancy test at enrollment
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: 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
• COHORT 1 NEWLY DIAGNOSED PEDIATRIC HIGH-GRADE GLIOMA: 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
• COHORT 2 RECURRENT PEDIATRIC HGG: Age 4-30 years
• COHORT 2 RECURRENT PEDIATRIC HGG: WHO grade III/IV by histopathology based on optional biopsy/re-resection or archival tissue
• COHORT 2 RECURRENT PEDIATRIC HGG: CD70 positive (≥ 5%, 1+) * The tumors from the surgical resection by immunohistochemistry will be confirmed by validated assay performed at UF Health Pathology, Clinical Laboratory Improvement Amendments (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+)
• COHORT 2 RECURRENT PEDIATRIC HGG: Karnofsky performance status (KPS, for patients > 16 year old [yo]) or Lansky Performance Score (LPS, for patients ≤ 16 yo) of > 60% * 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
• COHORT 2 RECURRENT PEDIATRIC HGG: Prior therapy: * Patients with recurrent or progressive disease must have received prior radiotherapy +/- concurrent therapy * 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
• COHORT 2 RECURRENT PEDIATRIC HGG: 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
• COHORT 2 RECURRENT PEDIATRIC HGG: ≥ 12 weeks (84 days) since autologous stem cell transplant prior to enrollment
• COHORT 2 RECURRENT PEDIATRIC HGG: 42 days since completion of any other type of adoptive cellular therapy prior to enrollment
• COHORT 2 RECURRENT PEDIATRIC HGG: Absolute neutrophil count (ANC) ≥ 1000 cells/mm^3
• COHORT 2 RECURRENT PEDIATRIC HGG: Platelet count ≥ 75,000 cells/mm^3 (Unsupported-no transfusions within 4 days)
• COHORT 2 RECURRENT PEDIATRIC HGG: Hemoglobin ≥ 8 g/dl (The use of transfusion or other intervention to achieve Hgb ≥ 8 g/dl is acceptable)
• COHORT 2 RECURRENT PEDIATRIC HGG: 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
• COHORT 2 RECURRENT PEDIATRIC HGG: Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) for age
• COHORT 2 RECURRENT PEDIATRIC HGG: ALT ≤ 3 times institutional upper limits of normal for age
• COHORT 2 RECURRENT PEDIATRIC HGG: AST ≤ 3 times institutional upper limits of normal for age
• COHORT 2 RECURRENT PEDIATRIC HGG: Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment
• COHORT 2 RECURRENT PEDIATRIC HGG: For participants < 18 years, written permission will be obtained from a parent or guardian, and age- and developmentally appropriate assent will be obtained from participants whom the IRB determines are capable of providing assent. Participants aged 18 years or older will provide written informed consent. For an adult participant who lacks decision-making capacity, consent may be obtained from a legally authorized representative in accordance with applicable law and institutional IRB requirements. Informed consent or parental permission and assent, as applicable, will be obtained at screening before PBMC collection and confirmed before CAR T-cell treatment
• COHORT 2 RECURRENT PEDIATRIC HGG: For females with childbearing potential, a negative serum pregnancy test at enrollment
• COHORT 2 RECURRENT PEDIATRIC HGG: 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
• COHORT 2 RECURRENT PEDIATRIC HGG: 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
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: Age 4-30 years
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: Newly diagnosed DIPG defined as tumors with a pontine epicenter and diffuse involvement of 2/3 or more of the pons
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: CD70 positive (≥ 5%, 1+) * 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 level ** 3+ = High level
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: Karnofsky performance status (KPS) or Lansky Performance Score (LPS) of > 60% * 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
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: Absolute neutrophil count (ANC) ≥ 1000 cells/mm^3
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: Platelet count ≥ 75,000 cells/mm^3 (Unsupported)
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: Hemoglobin ≥ 8 g/dl (The use of transfusion or other intervention to achieve Hgb ≥ 8 g/dl is acceptable)
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: 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
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) for age
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: ALT ≤ 3 times institutional upper limits of normal for age
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: AST ≤ 3 times institutional upper limits of normal for age
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: For participants < 18 years, written permission will be obtained from a parent or guardian, and age- and developmentally appropriate assent will be obtained from participants whom the IRB determines can provide assent. Participants aged 18 years or older will provide written informed consent. For an adult participant who lacks decision-making capacity, consent may be obtained from a legally authorized representative in accordance with applicable law and institutional IRB requirements. Informed consent or parental permission and assent, as applicable, will be obtained at screening before PBMC collection and confirmed before CAR T-cell treatment
• COHORT 3 NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: For females of childbearing potential, a negative serum pregnancy test at enrollment

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 * NOTE: Review by study chairs is recommended
• 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
• 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)
• 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 messenger ribonucleic acid (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 positive serum pregnancy test at enrollment