Glioblastoma (GBM)
An aggressive brain cancer. One of the first solid tumors where CAR-T is showing real responses. Discussed extensively by Carl June at Session V.
Penn’s Dual-Target CAR-T Trial
- Design: OR-gated bicistronic CAR hitting mutated EGFR (~60% of GBM) or IL-13Rα2 (~75% of adult GBM)
- Led by Donald O’Rourke (neurosurgeon, Penn)
- Delivery: intra-CSF via Ommaya reservoir (not IV)
- 18 patients with multiply recurrent GBM; 5–10M cells starting dose
Results
- 13/18 with MRI responses, ~70% disease control rate
- Multifocal lesions improving on gadolinium imaging within ~2 days
- Best patient: leptomeningeal spread, 34 months out, no recurrence
- Responders: more NK cells in CSF (predicts PFS); Tregs inversely correlated
Resistance Biology
- Tumor cells undergo plasticity toward mesenchymal/hypoxic state with loss of aquaporin-4 and EGFR — a resistant niche to target next
- Tumor-associated myeloid cells elevated in non-responders
Sadelain’s Pre-TCR Design
Sadelain’s pre-TCR signaling architecture demonstrated extreme potency in GBM at very low cell doses, outperforming all comparators (Cell, 2026).
Comments