Memory-Enriched T Cells in Treating Patients With Recurrent or Refractory Grade III-IV Glioma

PRIMARY OBJECTIVES:

I. To assess the feasibility and safety of intracavitary/intratumoral (arm 1),
intraventricular (arm 2), or dual delivery (arm 3: both intracavitary /intratumoral and
intraventricular) cellular immunotherapy utilizing ex-vivo expanded autologous
HER2(EQ)BBζ/CD19t+-expressing cells for adult research participants with recurrent/refractory
malignant glioma.

II. To determine maximum tolerated dose schedule (MTD) and a recommended Phase II dosing plan
(RP2D) for treatment arm 3 (dual delivery). An MTD for arm 2 will only be sought if arm 3 is
found to be too toxic.

SECONDARY OBJECTIVES:

I. To describe persistence and expansion of CAR T cells in tumor cyst fluid, peripheral blood
and cerebral spinal fluid (CSF).

II. To describe cytokine levels (tumor cyst fluid, peripheral blood, and CSF) over the study
period.

III. To estimate median progression free survival (PFS) rate in research participants who
receive the full schedule of 3 CAR T cell doses.

IV. To estimate disease response rates in research participants who receive the full schedule
of 3 CAR T cell doses.

V. To estimate median overall survival (OS) in research participants who receive the full
schedule of 3 CAR T cell doses.

VI. To evaluate CAR T cell persistence in the tumor micro-environment and the location of the
CAR T cells with respect to the injection in research participants who undergo an additional
biopsy/resection or autopsy.

VII. To evaluate HER2 antigen expression levels pre and post CAR T cell therapy in research
participants who undergo an additional biopsy/resection or autopsy.

OUTLINE: This is a dose-escalation study of autologous HER2(EQBBζ/CD19t+-expressing Tcm.

Patients undergo leukapheresis over 2-4 hours. Beginning approximately 21 days later,
patients receive HER2(EQ)BBζ/CD19t+-expressing Tcm via catheter over 5 minutes on days 0, 7,
and 14. Patients may receive additional doses of HER2(EQ)BBζ/CD19t+-expressing Tcm up to the
highest cell dose that is deemed safe.

After completion of study treatment, patients are followed up at 4 weeks, 3, 6, 8, 10 and 12
months, then annually for at least 15 years.

Inclusion Criteria:

- Participant has a prior histologically-confirmed diagnosis of a grade III or IV
glioma, or has a prior histologically-confirmed diagnosis of a grade II glioma and now
has radiographic progression consistent with a grade III or IV malignant glioma (MG)

- Radiographic evidence of progression/recurrence of the measurable disease more than 12
weeks after the end of initial radiation therapy

- Karnofsky performance status (KPS) >= 60%

- Life expectancy > 4 weeks

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control or abstinence) prior to study entry and
for six months following duration of study participation; should a woman become
pregnant or suspect that she is pregnant while participating on the trial, she should
inform her treating physician immediately

- City of Hope (COH) Clinical Pathology confirms HER2+ tumor expression by
immunohistochemistry (>= 20%, 1+)

- All research participants must have the ability to understand and the willingness to
sign a written informed consent

ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION

- Research participant must not require more than 2 mg three times daily (TID) of
dexamethasone on the day of PBMC collection

- Research participant must have appropriate venous access

- At least 2 weeks must have elapsed since the research participant received his/her
last dose of prior chemotherapy or radiation

ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT

- Creatinine < 1.6 mg/dL

- White blood cell (WBC) > 2,000/dl (or absolute neutrophil count [ANC] > 1,000)

- Platelets >= 100,000/dl

- International normalized ratio (INR) < 1.3

- Bilirubin < 1.5 mg/dL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2X upper limits
of normal

ELIGIBILITY TO PROCEED WITH CAR T CELL INFUSION

- Research participant has a released cryopreserved CAR T cell product

- Research participant does not require supplemental oxygen to keep saturation greater
than 95% and/or does not have presence of any radiographic abnormalities on chest
x-ray that are progressive

- Cardiac:

- Research participants does NOT have any known history of congestive heart failure
(CHF) or cardiac symptoms consistent with NYHA classification III-IV within 6
months prior to Day 1 of protocol treatment, cardiomyopathy, myocarditis,
myocardial infarction (MI), exposure to cardiotoxic medications or with clinical
history suggestive of the above must have an EKG and Echocardiogram (ECHO)
performed within 42 days prior to registration and as clinical indicated while on
treatment.

- If the research participants has new symptoms of CHF, cardiomyopathy,
myocarditis, MI, or exposure to cardiotoxic medications they already had a
cardiac consultation, creatinine phosphokinase (CPK), and troponin testing at pre
study deeming them fit for study participation.

- Research participant does not have a fever exceeding 38.5 degrees Celsius (C); there
is an absence of positive blood cultures for bacteria, fungus, or virus within
48-hours prior to T cell infusion and/or there aren't any indications of meningitis

- Research participant serum total bilirubin or transaminases does not exceed 2X normal
limit

- Research participant serum creatinine =<1.8 mg/dL

- Research participant does not have uncontrolled seizure activity following surgery
prior to starting the first T cell dose

- Research participant platelet count must be >= 100,000; however, if platelet level is
between 75,000-99,000, then T-cell infusion may proceed after platelet transfusion is
given and the post transfusion platelet count is >= 100,000

- Research participants must not require more than 2 mg TID of dexamethasone during T
cell therapy

- Wash-out requirements (standard or investigational):

- At least 6 weeks since the completion of a nitrosourea-containing chemotherapy
regimen; and

- At least 23 days since the completion of temodar and/or 4 weeks for any other
non-nitrosourea-containing cytotoxic chemotherapy regimen; if a patient's most
recent treatment was with a targeted agent only, and s/he has recovered from any
toxicity of this targeted agent, then a waiting period of only 2 weeks is needed
from the last dose and the start of study treatment, with the exception of
bevacizumab where a wash out period of at least 4 weeks is required before
starting study treatment

Exclusion Criteria:

- Research participant requires supplemental oxygen to keep saturation greater than 95%
and the situation is not expected to resolve within 2 weeks

- Cardiac:

- Research participants with a known history of congestive heart failure (CHF) or
cardiac symptoms consistent with NYHA classification III-IV within 6 months prior
to Day 1 of protocol treatment, cardiomyopathy, myocarditis, myocardial
infarction (MI), exposure to cardiotoxic medications or with clinical history
suggestive of the above must have an EKG and Echocardiogram (ECHO) performed
within 42 days prior to registration and as clinically indicated while on
treatment.

- Research participants with new symptoms of CHF, cardiomyopathy, myocarditis, MI,
or exposure to cardiotoxic medications must have a cardiac consultation,
creatinine phosphokinase (CPK), and troponin testing at pre-study and as
clinically indicated.

- Research participant requires dialysis

- Research participant has uncontrolled seizure activity and/or clinically evident
progressive encephalopathy

- Failure of research participant to understand the basic elements of the protocol
and/or the risks/benefits of participating in this phase I study; a legal guardian may
substitute for the research participant

- Research participants with any non-malignant intercurrent illness which is either
poorly controlled with currently available treatment, or which is of such severity
that the investigators deem it unwise to enter the research participant on protocol
shall be ineligible

- Research participants with any other active malignancies

- Research participants being treated for severe infection or who are recovering from
major surgery are ineligible until recovery is deemed complete by the investigator

- Research participants with any uncontrolled illness including ongoing or active
infection; research participants with known active hepatitis B or C infection;
research participants with any signs or symptoms of active infection, positive blood
cultures or radiological evidence of infections

- Research participants who have confirmed human immunodeficiency virus (HIV) positivity
within 4 weeks of enrollment