This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with autologous CD4+ and CD8+ T cells lentivirally transduced to express a B7H3-specific chimeric antigen receptor (CAR) and EGFRt. CAR T cells are delivered via an indwelling catheter into the tumor resection cavity or ventricular system in children and young adults with diffuse intrinsic pontine glioma (DIPG), diffuse midline glioma (DMG), and recurrent or refractory CNS tumors.

A child or young adult meeting all eligibility criteria, including having a CNS catheter placed into the tumor resection cavity or into their ventricular system, and meeting none of the exclusion criteria, will have their T cells collected. The T cells will then be bioengineered into a second-generation CAR T cell that targets B7H3-expressing tumor cells. Patients will be assigned to one of 3 treatment arms based on location or type of their tumor. Patients with supratentorial tumors will be assigned to Arm A, and will receive their treatment into the tumor cavity. Patients with either infratentorial or metastatic/leptomeningeal tumors will be assigned to Arm B, and will have their treatment delivered into the ventricular system. The first 3 patients enrolled onto the study must be at least 15 years of age and assigned to Arm A or Arm B. Patients with DIPG will be assigned to Arm C and have their treatment delivered into the ventricular system. The patient's newly engineered T cells will be administered via the indwelling catheter for two courses. In the first course patients in Arms A and B will receive a weekly dose of CAR T cells for three weeks, followed by a week off, an examination period, and then another course of weekly doses for three weeks. Patients in Arm C will receive a dose of CAR T cells every other week for 3 weeks, followed by a week off, an examination period, and then dosing every other week for 3 weeks. Following the two courses, patients in all Arms will undergo a series of studies including MRI to evaluate the effect of the CAR T cells and may have the opportunity to continue receiving additional courses of CAR T cells if the patient has not had adverse effects and if more of their T cells are available.

The hypothesis is that an adequate amount of B7H3-specific CAR T cells can be manufactured to complete two courses of treatment with 3 or 2 doses given on a weekly schedule followed by one week off in each course. The other hypothesis is that B7H3-specific CAR T cells can safely be administered through an indwelling CNS catheter or delivered directly into the brain via indwelling catheter to allow the T cells to directly interact with the tumor cells for each patient enrolled on the study. Secondary aims of the study will include evaluating CAR T cell distribution with the cerebrospinal fluid (CSF), the extent to which CAR T cells egress or traffic into the peripheral circulation or blood stream, and, if tissues samples from multiple timepoints are available, also evaluate disease response to B7-H3 CAR T cell locoregional therapy.

Inclusion Criteria:

1. Age ≥ 1 and ≤ 26 years

2. Diagnosis of refractory or recurrent CNS disease for which there is no standard therapy, or diagnosis of DIPG or DMG at any time point following completion of standard therapy

3. Able to tolerate apheresis, or has apheresis product available for use in manufacturing

4. CNS reservoir catheter, such as an Ommaya or Rickham catheter

5. Life expectancy ≥ 8 weeks

6. Lansky or Karnofsky score ≥ 60

7. If patient does not have previously obtained apheresis product, patient must have discontinued, and recovered from acute toxic effects of, all prior chemotherapy, immunotherapy, and radiotherapy and discontinue the following prior to enrollment:

   1. ≥ 7 days post last chemotherapy/biologic therapy administration
   2. 3 half lives or 30 days, whichever is shorter post last dose of anti-tumor antibody therapy
   3. Must be at least 30 days from most recent cellular infusion
   4. All systemically administered corticosteroid treatment therapy must be stable or decreasing within 1 week prior to enrollment with maximum dexamethasone dose of 2.5 mg/m2/day. Corticosteroid physiologic replacement therapy is allowed.

8. Adequate organ function

9. Adequate laboratory values

10. Patients of childbearing/fathering potential must agree to use highly effective contraception

Exclusion Criteria:

1. Presence of Grade ≥ 3 cardiac dysfunction or symptomatic arrhythmia requiring intervention
2. Presence of primary immunodeficiency/bone marrow failure syndrome
3. Presence of clinical and/or radiographic evidence of impending herniation
4. Presence of >Grade 3 dysphagia
5. Presence of active malignancy other than the primary CNS tumor under study
6. Presence of active severe infection
7. Receiving any anti-cancer agents or chemotherapy
8. Pregnant or breastfeeding
9. Subject and/or authorized legal representative unwilling or unable to provide consent/assent for participation in the 15 year follow up period
10. Presence of any condition that, in the opinion of the investigator, would prohibit the patient from undergoing treatment under this protocol