This phase I trial studies the side effects and best dose of memory-enriched T cells in
treating patients with grade II-IV glioma that has come back (recurrent) or does not respond
to treatment (refractory). Memory enriched T cells such as HER2(EQ)BBζ/CD19t+ T cells may
enter and express its genes in immune cells. Immune cells can be engineered to kill glioma
cells in the laboratory by inserting a piece of deoxyribonucleic acid (DNA) into the immune
cells that allows them to recognize glioma cells. A vector called lentivirus is used to carry
the piece of DNA into the immune cell. It is not known whether these immune cells will kill
glioma tumor cells when given to patients.
PRIMARY OBJECTIVES:
I. To assess the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded
autologous memory-enriched T cells that are genetically modified using a self-inactivating
(SIN) lentiviral vector to express a HER2-specific, hinge-optimized, 41BB-costimulatory
chimeric antigen receptor (CAR), as well as a truncated human CD19 (HER2[EQ]BBzeta/CD19t+)
for participants with recurrent/refractory malignant glioma in one of the following ways: Arm
1 (intracavitary/intratumoral HER2(EQ)BBzeta/CD19+ T CM), Arm 2 (dual delivery [both
intracavitary/intratumoral and intraventricular] of HER2(EQ)BBzeta/CD19+ T CM), or Arm 3
(dual delivery [both intracavitary/intratumoral and intraventricular] of HER2(EQ)BBzeta/CD19+
T N/MEM).
II. To determine maximum tolerated dose schedule (MTD) and a recommended Phase II dosing plan
(RP2D) for arm 3 (dual delivery).
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. In research participants who receive the full schedule of 3 CAR T cell doses:
IIIa. To estimate median progression free survival (PFS) rate. IIIb. To estimate disease
response rates. IIIc. To estimate median overall survival (OS).
IV. In research participants who continue to receive infusions after progressing:
IVa. Estimate disease response. IVb. Describe CAR T cell and endogenous immune populations,
as well as cytokine and microenvironment profiles (cerebral spinal fluid [CSF], cyst fluid,
peripheral blood) considering post progression therapy(ies), if applicable.
V. For study participants who undergo an additional biopsy/resection or autopsy:
Va. Evaluate CAR T cell persistence in the tumor micro-environment and the location of the
CAR T cells with respect to the injection.
Vb. Evaluate HER2 antigen expression levels pre and post CAR T cell therapy.
OUTLINE: This is a dose-escalation study of autologous HER2(EQ)BBζ/CD19t+ T cells.
Participants are assigned to 1 of 3 arms.
ARM I: Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via
intratumoral/intracavitary catheter over 5 minutes weekly for 3 weeks. Beginning as early as
1 week later, patients may receive additional T cell infusions as long as patients remain
eligible and there is product available. Patients who progress on intracavitary or
intratumoral administration may move to alternative delivery routes for the optional
infusions.
ARM II: Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via
intratumoral/intracavitary catheter and intraventricular catheter over 5 minutes weekly for 3
weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions
as long as patients continue to remain eligible and there is product available. Based on
clinical response after the first 3 infusions, the study principal investigator may decide to
continue with the optional infusions at either one or both sites (instead of requiring
injections at both sites).
ARM III: Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tn/mem cells via
intratumoral/intracavitary catheter and intraventricular catheter over 5 minutes weekly for 3
weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions
as long as patients continue to remain eligible and there is product available. Based on
clinical response after the first 3 infusions, the study principal investigator may decide to
continue with the optional infusions at either one or both sites (instead of requiring
injections at both sites).
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)
- Karnofsky performance status (KPS) >= 60%
- Life expectancy > 4 weeks
- The effects of HER2(EQBBzeta/CD19t+ T cells on the developing fetus are unknown. For
this reason, 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
- Note: For research participants who do not speak English, a short form consent
may be used with a COH certified interpreter/translator to proceed with screening
and leukapheresis, while the request for a translated full consent is processed;
however, the research participant is allowed to proceed with rickham placement
and CAR T cell infusion only after the translated full consent form is signed
- 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 targeted agents, chemotherapy or radiation; at the principal
investigator's discretion, exception can be made for investigational agents that are
delivered locally into the CSF
- ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT
- Once research participants meet eligibility to proceed with Rickham placement,
they will be deemed accrued on to the study
- Note: if the participant had received prior targeted radiation and new
lesions have appeared outside of that targeted area, then that may be deemed
radiographic evidence of measurable disease even if 12 weeks have not
elapsed
- 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) < 2.5 x 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
- 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 participant 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 2 x 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 CAR 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 CAR
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 must have passed since the completion of Temodar and/or 4 weeks
for any other non-nitrosourea-containing cytotoxic chemotherapy regimen; if a
participant'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 CAR T cell infusion with
the exception of bevacizumab where a wash out period of at least 4 weeks is
required before starting CAR T cell therapy
Exclusion Criteria:
- Research participant requires supplemental oxygen to keep saturation greater than 95%
and the situation is not expected to resolve within 2 weeks
- Research participants with a known history of congestive heart failure (CHF) or
cardiac symptoms consistent with New York Heart Association (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 electrocardiogram (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
