CARv3-TEAM-E T Cells in Glioblastoma

Inclusion Criteria:

-Safety Run In Arm and ARM 1: Recurrent GBM, EGFRvIII mutant

• Participants must have histologically confirmed recurrent GBM or molecular featuresof GBM with presence of EGFRvIII mutation within 30 days of consent. MGMTmethylated, unmethylated, or unknown is allowed.

• Participants must be at first progression or recurrence and have at least receivedprior radiation. Prior temozolomide is not required if the participant is MGMTunmethylated.

Participants must be 4 weeks from prior alkylating therapy or immunotherapy and ≥ 5 half-lives from another investigational agent. No washout is required from radiation since participants will need histological confirmation of recurrence to participate.

• ARM 2: Newly Diagnosed GBM, EGFRvIII mutant

• Participants must have histologically confirmed newly diagnosed GBM withpresence of EGFRvIII mutation and their tumors must be MGMT unmethylated.

• Treatment planned with involved field radiation alone without concomitant orsequential temozolomide.

• ARM 3: Recurrent GBM, EGFRvIII negative (will only open once safety is confirmed inArms 1 and 2)

• Participants must have histologically confirmed recurrent GBM with absence ofEGFRvIII mutation within 30 days of consent but with EGFR amplification.

• Participants must be at first recurrence and have at least received priorradiation. Prior temozolomide is not required if the participant is MGMTunmethylated. Participants must be 4 weeks from prior alkylating therapy orimmunotherapy and ≥ 5 half-lives from another investigational agent. No washoutis required from radiation since participants will need histologicalconfirmation of recurrence to participate.

• ALL ARMS:

• Participants must have measurable disease, defined as at least one lesion ≥10mm (≥1 cm) with MRI. Patients cannot have posterior fossa or intramedullaryspine-only disease. Leptomeningeal disease is allowed anywhere in theneuroaxis. See Section 11 (Measurement of Effect) for the evaluation ofmeasurable disease.

• Resolution of AEs from any prior systemic anticancer therapy or radiotherapy toGrade 1 or baseline (except Grade 2 alopecia and Grade 2 sensory neuropathy)

• Medically able and willing to undergo placement of an Ommaya reservoir.

• Steroid dose anticipated to be ≤ 4 mg of dexamethasone a day or equivalent attime of first CAR-v3-TEAM-E infusion.

• Age ≥18 years

• Karnofsky ≥60% (see Appendix A).

• Must be able to undergo an MRI with contrast.

• Life expectancy of greater than 3 months.

• Participants must have adequate organ and marrow function as defined below:

• absolute neutrophil count ≥1,000/mcL

• platelets ≥80,000/mcL

• total bilirubin ≤ institutional upper limit of normal (ULN)

• AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN

• creatinine ≤ institutional ULN OR

≥60 mL/min/1.73 m2

For patients with Gilbert's syndrome, total bilirubin can be ≤ 3xULN.

• Participant has no prior history of malignancy, unless the subject has been free ofthe disease for ≥5 years with the exception of the following noninvasivemalignancies:

• Basal cell carcinoma of the skin

• Squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

• Incidental histologic finding of prostate cancer (T1a or T1b) or prostatecancer that is curative

• Left ventricular ejection fraction >50% as determined by TTE.

• The effects of CARv3-TEAM-E on the developing human fetus are unknown. For thisreason, women of child-bearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately. Men treated orenrolled on this protocol must also agree to use adequate contraception prior to thestudy, for the duration of study participation, and 4 months after completion ofCARv3-TEAM-E administration.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Intraparenchymal posterior fossa disease

• Intramedullary spinal disease as the only site of disease.

• Prior EGFRvIII targeted therapies.

• Treatment with an any prior gene-therapy or gene-modified cellular therapy.

• Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine or systemicsteroids above physiologic dosing). Intermittent topical, inhaled, or intranasalcorticosteroids are allowed

• Participants who have not recovered from adverse events due to prior anti-cancertherapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.

• Participants who are receiving any other investigational agents.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to CARv3-TEAM-E (ex. cetuximab).

• Participants with uncontrolled intercurrent illness.

• Human immunodeficiency virus (HIV)-infected participants are not eligible.

• Participants with evidence of chronic hepatitis B virus (HBV) infection or activehepatitis C virus (HCV) infection are not eligible.

• Participants with psychiatric illness/social situations that would limit compliancewith study requirements.

• Pregnant women are excluded from this study because there is an unknown butpotential risk for adverse events in nursing infants secondary to treatment of themother with CARv3-TEAM-E , breastfeeding should be discontinued if the mother istreated with CARv3-TEAM-E.

• For Arm 2, prior to CARv3-TEAM-E Infusion, the following criteria should beconfirmed in addition to the relevant criteria above:

• Participants must have completed 75% of the planned 6 weeks of involved fieldradiation without temozolomide

• Tumor location and size criteria as in 3.1.7 above.

• Prior cancer directed therapy other than radiation is not allowed.