Immunotherapy for Malignant Pediatric Brain Tumors Employing Adoptive Cellular Therapy (IMPACT)
This is an open-label phase 1 safety and feasibility study that will employ multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T) directed against proteogenomically determined personalized tumor-specific antigens (TSA) derived from a patient's primary brain tumor tissues. Young patients with embryonal central nervous system (CNS) malignancies typically are unable to receive irradiation due to significant adverse effects and are treated with intensive chemotherapy followed by autologous stem cell rescue; however, despite intensive therapy, many of these patients relapse. In this study, individualized TSA-T cells will be generated against proteogenomically determined tumor-specific antigens after standard of care treatment in children less than 5 years of age with embryonal brain tumors. Correlative biological studies will measure clinical anti-tumor, immunological and biomarker effects.
⁃ Diagnosis (select one group):
∙ Group A: New diagnosis of CNS embryonal tumors: medulloblastoma, embryonal tumor with multilayered rosettes, pineoblastoma, atypical teratoid/rhabdoid tumor, and embryonal tumor, not otherwise specified (NOS).
‣ Group B: Radiographic evidence consistent with recurrent ependymoma, with planned or recent re-resection.
⁃ Age:
⁃ o Group A: \<5 years of age at enrollment
⁃ o Group B: \>1 year and \<30 years of age at enrollment
⁃ Tissue:
∙ Group A: Availability of sufficient fresh or frozen tumor tissue (approximately 50 mg).
‣ Group B: Expectation of sufficient fresh or frozen tumor tissue, in the opinion of study PI or sub-I (based upon radiographic evidence of disease).
⁃ Non-pregnant:
∙ Group A: N/A
‣ Group B: For female of childbearing potential, must have negative pregnancy test.
⁃ Common to both groups:
⁃ Karnofsky or Lansky score of ≥60%.
⁃ Adequate organ function, defined below:
⁃ i. ANC ≥750/µL. ii. Absolute lymphocyte count (ALC) \>500/μL. iii. Platelets ≥75K. iv. Bilirubin ≤3xULN. v. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) \<5x upper limit of normal (ULN).
⁃ vi. Serum creatinine ≤1.0 mg/dL or 1.5x ULN for age (whichever is higher). vii. Pulse oximetry \>90% on room air.
⁃ The patient (if ≥18 years old), or the patient's parent(s)/legal guardian(s) (if the patient is a minor), is capable of providing informed consent.
⁃ Patient deemed to be of sufficient size to undergo MNC apheresis for TSA-T generation (Groups A and B) and PBSC rescue (Group A only).
⁃ Patient is a surgical candidate for placement of a Rickham reservoir in the opinion of study PI or medically licensed sub-I.
• 1\. Karnofsky or Lansky score of ≥60%. 2. Adequate organ function, defined below: i. ANC ≥750/µL. ii. Absolute lymphocyte count (ALC) \>500/μL. iii. Platelets ≥75K. iv. Bilirubin ≤3xULN. v. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) \<5x upper limit of normal (ULN).
• vi. Serum creatinine ≤1.0mg/dL or 1.5x ULN for age (whichever is higher). vii. Pulse oximetry \>90% on room air. 3. Non-pregnant:
• Group A: N/A
• Group B: For female of childbearing potential (if applicable; see section 2.3.1.6), must have negative pregnancy test.
⁃ Applicable to TSA-T infusion #1 only: Group B participants must have histopathologic confirmation of recurrent ependymoma.
⁃ Karnofsky or Lansky score of ≥60%.
⁃ Adequate organ function, defined as below:
⁃ i. Bilirubin ≤3x ULN. ii. AST and ALT ≤5x ULN. iii. Serum creatinine ≤1.0mg/dL or 1.5x ULN for age (whichever is higher). iv. Pulse oximetry \>90% on room air.
⁃ Applicable to TSA-T Infusion #1 only: Adequate count recovery, as described below, from prior therapies:
⁃ i. Absolute Neutrophil Count (ANC) \>1000/μL ii. Absolute Lymphocyte Count (ALC) \>500/μL
⁃ Patients must have received their last dose of:
⁃ a. Myelosuppressive chemotherapy (if applicable) ≥14 days prior to TSA-T infusion b. Focal radiation (if applicable) ≥14 days prior to TSA-T infusion c. Craniospinal irradiation (if applicable) ≥28 days prior to TSA-T infusion
⁃ Patients must have recovered from all acute effects of prior surgical intervention/s.
⁃ Group B female of childbearing potential or male capable of fathering a child (if applicable): Agree to use contraceptive measures during TSA-T treatment participation through 6 months following last administration of TSA-Ts
⁃ Group B female of childbearing potential (if applicable; see section 2.3.1.6), must have negative pregnancy test.
⁃ Neurologic status: Patient must have a stable neurologic exam for 2 weeks, on a stable or decreasing dose of steroids, prior to administration of the first dose of TSA-T cells, and stability for 1 week prior to all subsequent infusions. The exams demonstrating stability must be performed by the study team, although these may occur via telemedicine if necessary. Patient must agree to a brief (\<72 hours) course of steroids if the PI or medically-licensed sub-I deems it clinically necessary in the context of clinical deterioration.
‣ Presence of a Rickham reservoir and catheter for intracerebroventricular administration of TSA-T therapy, placed \>7 days prior to TSA-T infusion.
‣ For patients with programmable VP shunts: Able to tolerate the shunt being closed for at least 4 hours, in the opinion of study PI or medically licensed sub-I.