Immunotherapy for Malignant Pediatric Brain Tumors Employing Adoptive Cellular Therapy (IMPACT)

Summary

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.

Eligibility

Inclusion Criteria:

RECIPIENT PROCUREMENT (BLOOD COLLECTION FOR TSA-T MANUFACTURING) INCLUSION CRITERIA

* New diagnosis of CNS embryonal tumors: medulloblastoma, embryonal tumor with multilayered rosettes (ETMR), pineoblastoma, atypical teratoid/rhabdoid tumor, and embryonal tumor, not otherwise specified (NOS).
* \<5 years of age at enrollment.
* Lansky score of ≥60% (see appendix B).
* Organ function:

ANC ≥750/µL. Absolute lymphocyte count (ALC) \>500/μL. Platelets ≥75K. Bilirubin ≤3xULN. Aspartate aminotransferase (AST)/ Alanine aminotransferase (ALT) \<5x upper limit of normal (ULN). Serum creatinine ≤1.0mg/dL or 1.5x ULN for age (whichever is higher). Pulse oximetry \>90% on room air.

* Parent(s)/guardian(s) capable of providing informed consent.
* Availability of sufficient pre-trial fresh frozen tumor tissue (approximately 50 mg).
* Patient deemed to be of sufficient size to undergo PBMC pheresis for TSA-T generation and PBSC rescue.
* Patient is a surgical candidate for placement of Rickham reservoir in the opinion of a physician.

RECIPIENT INCLUSION CRITERIA FOR INITIAL TSA-T ADMINISTRATION AND FOR ADDITIONAL INFUSIONS

* Lansky score of ≥60%.
* Organ function:

Bilirubin ≤3x ULN. AST/ALT ≤5x ULN. Serum creatinine ≤1.0mg/dL or 1.5x ULN for age (whichever is higher). Pulse oximetry \>90% on room air.

\- 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

Exclusion Criteria:

PROCUREMENT EXCLUSION CRITERIA

* Patients with uncontrolled infections.
* Patients with known HIV infection.
* Prior immunotherapy with an investigational agent within the last 28 days prior to procurement.
* Patients with medulloblastoma of the SHH subtype.
* Patients who have overly bulky tumors on imaging are ineligible. These include the following:

Tumor with any evidence of herniation or significant midline shift. Tumor with a significant brainstem component. Patients who are deemed to have overly bulky tumor by the principal investigator (PI) of the study.

RECIPIENT EXCLUSION CRITERIA FOR INITIAL AND SUBSEQUENT TSA-T INFUSIONS

* Patients with uncontrolled infections.
* Patients who have overly bulky tumors on imaging are ineligible. These include the following:

Tumor with any evidence of herniation or significant midline shift. Tumor with a significant brainstem component. Patients who are deemed to have overly bulky tumor by the PI of the study.

* Patients who received ATG, Campath or other immunosuppressive T cell monoclonal antibodies within 28 days of TSA-T infusion.
* Patients receiving dexamethasone at a dose of \>0.05mg/kg. All patients who qualify based on the above inclusion and exclusion criteria will be eligible for participation in this study.

Conditions6

Locations1 site

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