Genetically Engineered Cells (E-SYNC CAR T Cells) for the Treatment of Patients with EGFRvIII+ Glioblastoma

Inclusion Criteria

• COHORT 1: Age >= 18 years
• COHORT 1: Karnofsky performance status (KPS) score of >= 70
• COHORT 1: Peripheral absolute neutrophil count >= 1000/mm^3
• COHORT 1: Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• COHORT 1: Absolute lymphocyte count (ALC) >= 300/uL and/or CD3 count of >= 150/uL
• COHORT 1: Creatinine clearance or radioisotope glomerular filtration rate >= 50 mL/min/1.73m^2
• COHORT 1: Total bilirubin =< 1.5 x upper limit of normal (ULN) except for Gilbert's syndrome
• COHORT 1: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
• COHORT 1: Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram or multi-gated acquisition scanning (MUGA)
• COHORT 1: Adequate pulmonary function, defined as no evidence of dyspnea at rest and pulse oximetry > 92% while breathing room air
• COHORT 1: Pathological criteria: EGFRvIII+ GBM from most recent surgery, confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab using a next-generation sequencing panel
• COHORT 1: MGMT promoter must be unmethylated or with a methylation index < 3
• COHORT 1: Must have completed at least SOC external beam radiotherapy (EBRT) as initial therapy
• COHORT 1: Participants must be anticipated to be able to complete E-SYNC T cell infusion within 12 weeks (+ 4 weeks) after completion of EBRT
• COHORT 1: Must be willing to provide voluntary informed consent for apheresis (and tissue screening if needed) and for study treatment
• STEP 1 FOR COHORT 2: Age >= 18 years
• STEP 1 FOR COHORT 2: KPS score >= 70
• STEP 1 FOR COHORT 2: Peripheral absolute neutrophil count >= 1000/mm^3
• STEP 1 FOR COHORT 2: Platelet count >= 100,000/mm^3 (transfusion dependent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• STEP 1 FOR COHORT 2: ALC >= 300/uL and/or CD3 count of >= 150/uL
• STEP 1 FOR COHORT 2: Creatinine clearance or radioisotope glomerular filtration rate >= 50 mL/min/1.73m^2
• STEP 1 FOR COHORT 2: Total bilirubin =< 1.5 x ULN except for Gilbert's syndrome
• STEP 1 FOR COHORT 2: ALT and AST =< 3 x ULN
• STEP 1 FOR COHORT 2: LVEF >= 50% by echocardiogram or multi-gated acquisition scanning (MUGA)
• STEP 1 FOR COHORT 2: Adequate pulmonary function, defined as no evidence of dyspnea at rest and pulse oximetry > 92% while breathing room air
• STEP 1 FOR COHORT 2: Pathological criteria: EGFRvIII+ GBM from most recent surgery, as defined by an EGFRvIII H-score of >= 250 based on central review
• STEP 1 FOR COHORT 2: Must be willing to provide voluntary informed consent for apheresis (and tissue screening if needed)
• STEP 2 FOR COHORT 2: KPS score of >= 70
• STEP 2 FOR COHORT 2: Must have received at least SOC EBRT as initial therapy; any number of prior recurrences is allowed
• STEP 2 FOR COHORT 2: Pathological criteria: EGFRvIII+ GBM from most recent surgery, as defined by an EGFRvIII H-score of >= 250 based on central review
• STEP 2 FOR COHORT 2: Must have radiographic progression consistent with the Response Assessment in Neuro-Oncology (RANO) criteria for progressive disease (PD)
• STEP 2 FOR COHORT 2: Recurrence must be surgically amenable, with expectation for ability to resect at least 500 mg of tumor tissue
• STEP 2 FOR COHORT 2: Participants with reproductive potential agree to use reliable and double barrier method of contraception during the study and for at least 6 months after the last study intervention, including refraining from donating sperm during this period
• STEP 2 FOR COHORT 2: Females of childbearing potential must have a negative serum beta-human chorionic gonadotropin (HCG) pregnancy test prior to receiving study interventions
• STEP 2 FOR COHORT 2: Peripheral absolute neutrophil account >= 1000/mm^3
• STEP 2 FOR COHORT 2: Platelet count >= 100,000/mm^3 (transfusion dependent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• STEP 2 FOR COHORT 2: ALC >= 300/uL and/or CD3 count of >= 150/uL
• STEP 2 FOR COHORT 2: Creatinine clearance or radioisotope glomerular filtration rate >= 50 mL/min/1.73m^2
• STEP 2 FOR COHORT 2: Total bilirubin =< 1.5 x ULN except for Gilbert's syndrome
• STEP 2 FOR COHORT 2: ALT and AST =< 3 x ULN
• STEP 2 FOR COHORT 2: Coagulation tests prothrombin time (PT) and partial thromboplastin time (PTT) have to be within normal limits, unless the participant has been therapeutically anticoagulated for previous venous thrombosis
• STEP 2 FOR COHORT 2: Adequate pulmonary function, defined as no evidence of dyspnea at rest and pulse oximetry > 92% while breathing room air
• STEP 2 FOR COHORT 2: LVEF >= 40% by echocardiogram or multi-gated acquisition scanning (MUGA) (confirmed within the last 12 months)
• STEP 2 FOR COHORT 2: Must be willing to provide voluntary informed consent for study intervention

Exclusion Criteria

• COHORT 1: Participant who has been treated with any investigational agents and chemotherapy targeting GBM =< 4 weeks prior to date of study registration. Exceptions to this include: must be >= 23 days from last dose of temozolomide (TMZ) or radiotherapy, must be >= 6 weeks form last dose of nitrosourea
• COHORT 1: Female participants of reproductive potential who are pregnant or lactating. Female study participants of reproductive potential must have a negative serum pregnancy test as part of eligibility confirmation
• COHORT 1: Known addiction to alcohol or illicit drugs
• COHORT 1: Prior treatment with any EGFR-targeting therapy
• COHORT 1: Participants with leptomeningeal dissemination
• COHORT 1: Participants with serologic status reflecting active HIV, hepatitis B or C infection. Patients that are positive for hepatitis B surface antigen (HBsAg+) will be excluded. Patients that are positive for hepatitis B core antibody or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment, and patients that are positive for hepatitis B core antibody must be taking prophylactic therapy for hepatitis B. PCR positive patients will be excluded
• COHORT 1: Participants with a known disorder that affects their immune system, such as HIV or an autoimmune disorder requiring systemic cytotoxic or immunosuppressive therapy. Participants who are currently using non-systemic steroids (e.g., inhaled, intranasal, ocular, topical) are not excluded from the study
• COHORT 1: Participants who have received prior solid organ or bone marrow transplantation
• COHORT 1: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, second cancer currently receiving active treatment or anticipated to receive treatment within the next year, or psychiatric illness/social situations that would limit compliance with study requirements
• COHORT 1: Participants who are unable to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy
• STEP 1 FOR COHORT 2: Participant who has been treated with any investigational agents or chemotherapy targeting GBM =< 4 weeks prior to date of study registration. Exceptions to this include: must be >= 23 days from last dose of TMZ or radiotherapy, must be >= 6 weeks from last dose of nitrosourea
• STEP 1 FOR COHORT 2: Female participants of reproductive potential who are pregnant or lactating. Female study participants of reproductive potential must have a negative serum pregnancy test as part of step 1 eligibility confirmation
• STEP 1 FOR COHORT 2: Uncontrolled active infection
• STEP 1 FOR COHORT 2: Participants with a known disorder that affects their immune system, such as HIV or an autoimmune disorder requiring systemic cytotoxic or immunosuppressive therapy. Participants who are currently using non-systemic steroids (e.g., inhaled, intranasal, ocular, topical) are not excluded from the study
• STEP 1 FOR COHORT 2: Participants with serologic status reflecting active HIV, hepatitis B or C infection. Patients that are positive for hepatitis B surface antigen (HbsAg+) will be excluded. Patients that are positive for hepatitis B core antibody or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment, and patients that are positive for hepatitis B core antibody must be taking prophylactic therapy for hepatitis B. PCR positive patients will be excluded
• STEP 1 FOR COHORT 2: Known addiction to alcohol or illicit drugs
• STEP 2 FOR COHORT 2: Prior treatment with any EGFR-targeting therapy
• STEP 2 FOR COHORT 2: Participant who has been treated with any investigational agents or chemotherapy targeting GBM =< 4 weeks prior to date of study registration. Exceptions to this include: must be >= 23 days from last dose of TMZ or radiotherapy >= 12 weeks, must be >= 6 weeks from last dose of nitrosourea
• STEP 2 FOR COHORT 2: Participants with imaging or clinical evidence of uncontrolled tumor mass effect; the assessment of mass effect will be made by the investigators
• STEP 2 FOR COHORT 2: Participants with leptomeningeal dissemination
• STEP 2 FOR COHORT 2: Participants with a known disorder that affects their immune system, such as HIV or an autoimmune disorder requiring systemic cytotoxic or immunosuppressive therapy. Participants who are currently using inhaled, intranasal, ocular, topical, or other non-oral or non-IV steroids are not necessarily excluded from the study
• STEP 2 FOR COHORT 2: Participants with serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B surface antigen (HBsAg+) will be excluded. Patients that are positive for hepatitis B core antibody or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment and patient that are positive for hepatitis B core antibody must be taking prophylactic therapy for hepatitis B. PCR positive patients will be excluded
• STEP 2 COHORT 2: Participants who have received prior solid organ or bone marrow transplantation
• STEP 2 FOR COHORT 2: Female participants who are pregnant or breast-feeding
• STEP 2 FOR COHORT 2: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, second cancer currently receiving active treatment or anticipated to receive treatment within the next year, or psychiatric illness/social situations that would limit compliance with study requirements
• STEP 2 FOR COHORT 2: Participants who are unable to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy