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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
29
Given via catheter
Correlative studies
Undergo leukapheresis
City of Hope Medical Center
Duarte, California, United States
Incidence of grade 3 adverse events
Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and arm.
Time frame: Up to 3 years
Dose limiting toxicities (DLT)
Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval \[CI\]) will be estimated for participants' experiencing DLTs at the recommended phase 2 dose (RP2D) schedule.
Time frame: Up to 3 years
Incidence of adverse events
Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and arm.
Time frame: Up to 3 years
Chimeric antigen receptor (CAR) T cells detected in tumor cyst fluid, peripheral blood, and cerebrospinal fluid (CSF)
Statistical and graphical methods will be used to describe persistence and expansion of the CAR T cells (tumor cyst fluid, peripheral blood and CSF) over the study period. In study participants that undergo a second biopsy resection or following autopsy, T cells numbers, location, and antigen levels will be described.
Time frame: Up to 3 years
Tumor cyst fluid, peripheral blood, and cerebrospinal fluid (CSF) cytokine levels
Statistical and graphical methods will be used to describe persistence and expansion of cytokine levels (tumor cyst fluid, peripheral blood, and CSF) over the study period.
Time frame: Up to 3 years
Progression free survival
Kaplan Meier methods will be used
Time frame: At 6 months
Overall Survival (OS)
Kaplan Meier methods will be used to estimate median OS and graph the results.
Time frame: At 6 months
Disease response
Will be measured by Response Assessment in Neuro-Oncology Criteria (RANO) criteria. Will estimate the rate (90% CI) progression free at 6 months and rate (90% CI) with disease response.
Time frame: Up to 3 years
Chimeric antigen receptor (CAR) T cells detected in tumor tissue
T cells numbers, location, and antigen levels will be described.
Time frame: Up to 3 years
HER2 antigen expression levels in tumor tissue
Time frame: Up to 3 years
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