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. Patients with recurrent ependymoma have a poor survival and this disease has a dearth of targetable molecular features. 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 (Arm A) and children with recurrent ependymoma (Arm B).
Correlative biological studies will measure clinical anti-tumor, immunological and biomarker effects.
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.
Group A: <5 years of age at enrollment
Group B: >1 year and <30 years of age at enrollment
Patients with progressive disease based on most recent evaluation (for subsequent infusions).
Patients with uncontrolled infections.
Patients who received ATG, Campath or other immunosuppressive T cell monoclonal antibodies within 28 days of TSA-T infusion.
Patients receiving steroids (e.g., dexamethasone) at a dose of >0.05 mg/kg/day.
Single group
Multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T) directed against proteogenomically determined personalized tumor-specific antigens (TSA)
Biological/VaccineParticipants in this study will receive TSA-T after completion of standard-of-care treatment.
Group A Standard-of-Care Backbone Therapy
DrugPatients will undergo surgical resection, then be treated with standard-of-care therapy as required, which may include up to 3 induction chemotherapy cycles (vincristine, cyclophosphamide, cisplatin, etoposide with or without methotrexate) and up to 3 consolidation cycles (carboplatin and thiotepa, each followed by an infusion of autologous peripheral blood stem cells).
Group B Salvage Backbone Therapy
RadiationPatients will undergo surgical re-resection - aiming for gross total resection when feasible - followed by re-irradiation. Re-irradiation may be delivered as a conventional fractionated course, hypofractionated stereotactic radiotherapy, or proton therapy. Bridging chemotherapy may be substituted for re-irradiation or may follow re-irradiation at the treating physician's discretion.
To evaluate the safety of TSA-T in children, adolescents, and young adults with high-risk CNS embryonal and recurrent ependymoma tumors. Safety will be evaluated by the incidence of dose limiting toxicities (DLTs).
The safety endpoint will be assessed by monitoring for incidence of DLTs-defined as any of the below events occurring within 42 days following a participant's first TSA-T infusion (per CTCAE v. 6.0): * Grade ≥3 infusion-related adverse event. * Grade ≥4 non-hematologic adverse event that is not due to the patient's underlying malignancy or chemotherapy related co-morbidities. * Grade ≥3 pneumonitis, uveitis. * Grade ≥3 toxicities that are attributed to TSA-T (possibly, probably or definitely TSA-T related). * Unexpected toxicity of grade ≥3 attributed to the infusion of TSA-T (possibly, probably or definitely TSA-T related).
To estimate the maximum-tolerated dose (MTD) of intracerebroventricularly-administered TSA-T in children, adolescents and young adults with high-risk CNS embryonal tumors and recurrent ependymoma.
The MTD will be estimated adaptively throughout the trial using Bayesian optimal interval (BOIN) design, based on incidence of DLTs. After trial completion, the final maximum tolerated dose regimen (MTDR) will be selected using isotonic regression of pooled safety data from Groups A and B.
Feasibility of TSA identification
The number of TSA identified for each tumor will be measured. The endpoint will be the number of patients with at least 2 TSA peptides identified.
Feasibility of TSA-T cell generation
The time from the acquisition of tissue to the availability of manufactured TSA-T products, measured in comparison to the length of the SOC therapy regimen/s preceding the infusion (\~12-24 weeks).
To record preliminary evidence of objective disease response to TSA-T cells in embryonal tumors and recurrent ependymomas, among patients with residual disease after completion of SOC or salvage treatment per protocol
Objective disease response to TSA-T cells - Patients with residual disease (at primary site or metastatic deposits) after SOC or salvage therapy regimen will be assessed for response to TSA-T according to Response Assessment in Pediatric Neuro-Oncology (RAPNO) Criteria using magnetic resonance imaging (MRI). Patients will be evaluated with appropriate modalities at all prior sites of disease and for any new sites of disease based on symptoms or imaging. Response will be defined as any patient who achieves complete response (CR), partial response (PR), or prolonged stable disease (SD).
To record preliminary evidence of prolonged survival through analysis of progression free survival (PFS) and overall survival (OS).
Progression-free and overall survival - PFS is defined as the interval of time between the date of surgery confirming diagnosis (Group A) or date of surgery confirming recurrence (Group B) and the earliest date of documentation of progressive disease, or secondary malignancy or death (for any reason) for patients who fail; or to date of last contact or initiation of other therapy for patients who remain at risk of failure. OS is defined as the interval of time between the date of surgery confirming diagnosis (Group A) or date of surgery confirming recurrence (Group B) to date of death. PFS and OS will be analyzed by the Kaplan-Meier method and contextualized by outcomes reported in historical studies (when feasible).
To correlate clinical parameters (objective disease response, survival, and adverse events) with in vivo persistence of TSA-T and other measures of immune response in cerebrospinal fluid (CSF).
Correlation of PFS and OS will be descriptively correlated to measures of in vivo TSA-T cell persistence and immune activation (including cytokine/chemokine protein levels in CSF).
To characterize the phenotype of manufactured TSA-T cells prior to infusion and correlate with clinical parameters.
Flow cytometry and single-cell multiomics will be used to characterize TSA-T cells phenotype.
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