Inclusion criteria
1. Age >/= 16 years
2. Disease status
a. Relapsed or recurrent Glioblastoma Multiforme (GBM) confirmed by pathology review of surgically resected tissue
b. Tumour tissue is positive for EGFRvIII expression as performed by immunohistochemistry (IHC) (≥15% expression by IHC)
3. ECOG 0-2
4. Research participants must agree to undergo a pregnancy test and use adequate contraception (where applicable)
5. Provision of written informed consent
6. **Some patients with GBM may be incapable of providing their own consent due to the neurological effects of their disease. In these cases, a legal representative may be sought to provide consent**
7. Radiotherapy:
a. ≥6 months since completion of primary radiotherapy.
b. Prior history of standard dose, conventionally fractionated brain radiotherapy (i.e. 54-60Gy in 28-33 fractions).
c. Up to and including three enhancing lesions.
d. Predicted re-irradiation Gross Tumour Volume
6. Maximum diameter of enhancing disease must be ≤6cm
Exclusion criteria
1. Women who are pregnant or breast feeding
2. Organ function:
a. Cardiac: Serious and uncontrolled cardiac arrythmias despite medical management, history of ischemic heart disease within the last 6 months prior to eligibility confirmation and left ventricular ejection fraction (LVEF)
b. Pulmonary: Requirement for supplemental oxygen and/or oxygen saturation ≤90% on air
c. Renal: Glomerular filtration rate
d. Hepatology: Bilirubin >2x upper limit of normal
e. Neurologic: Pre-existing significant neurological disorders unrelated to the CNS malignancy investigated in this study
3. History of active hepatitis B, C or HIV
4. History of active or severe infection
5. History of other active medical or psychiatric condition that is uncontrolled with current treatment or deemed by the investigators to be severe enough to preclude participation in this study
6. Unable to undergo leukapheresis due to contraindications, inability to tolerate procedure and/or issues with adequate venous access for the procedure
7. Known allergy to study product excipients (albumin, DMSO, dextran)
8. Any contraindications to receiving a PD-1 antibody, pembrolizumab.
9. History of auto-immune disease or connective tissue disease requiring systemic immunosuppression/disease modifying agents within the last 24 months or resulting in end organ damage
10. Steroid therapy
11. Evidence of active pneumonitis on chest computed tomography (CT) or PET-CT scan at screening or current interstitial lung disease. Prior radiation pneumonitis (fibrosis) in the radiation field is allowed if >24 weeks before eligibility
Exclusion criteria on the day of infusion
1. Severe intercurrent infection at the time of scheduled CARGO-T infusion
2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CARGO-T infusion
3. Theme 2 only:
a. Presence of grade 3 or 4 ICANS causally related to the ATIMP following infusion of Dose 1
b. Grade 1-2 neurotoxicity (if occurred) following Theme 1 CARGO-T infusion (Dose 1-IV) that has not fully resolved prior to proposed administration Dose 2
c. Grade 3-4 CRS following infusion of Dose 1
d. Persisting Grade 2 CRS following Dose 1 that has not resolved to ≤ grade 1 CRS prior to proposed administration of Dose 2
4. Pregnancy