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 HER2-specific chimeric antigen receptor (CAR) and EGFRt, delivered by an indwelling catheter in the tumor resection cavity or ventricular system in children and young adults with recurrent or refractory HER2-positive CNS tumors. A child or young adult with a refractory or recurrent CNS tumor will have their tumor tested for HER2 expression by immunohistochemistry (IHC) at their home institution or at Seattle Children's Hospital. If the tumor is HER2 positive and the patient meets all other eligibility criteria, including having a CNS catheter placed into the tumor resection cavity or into their ventricular system, and meets none of the exclusion criteria, then they can be apheresed, meaning T cells will be collected. The T cells will then be bioengineered into a second-generation CAR T cell that targets HER2-expressing tumor cells. The patient's newly engineered T cells will then be administered via the indwelling CNS catheter for two courses. In the first course they 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. Following the two courses, patient's 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 HER2-specific CAR T cells can be manufactured to complete two courses of treatment with three doses given on a weekly schedule followed by one week off in each course. The other hypothesis is that HER-specific CAR T cells safely can be administered through an indwelling CNS catheter to allow the T cells to directly interact with the tumor cells for each patient enrolled on the study safely can be delivered directly into the brain via indwelling catheter. Secondary aims of the study will include to evaluate 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 time points are available, also evaluate the degree of HER2 expression at diagnosis versus at recurrence.

Inclusion Criteria:

1. Age ≥ 1 and ≤ 26 years

2. Histologically diagnosed HER2-positive Central Nervous System (CNS) tumor

3. Evidence of refractory or recurrent CNS disease for which there is no standard therapy

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

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

6. Life expectancy ≥ 8 weeks

7. Lansky or Karnofsky score ≥ 60

8. If patient does not have previously obtained apheresis product, patient must have 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 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 cell 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.

9. Adequate organ function

10. Adequate laboratory values

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

Exclusion Criteria:

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