Session V — Lifetime Achievement: Carl June

Beyond CD19 — Engineering the Next Decade of Cell Therapy

Carl June (Penn) fast-forwards through what his group is building on top of CD19 CAR-T: armored cells, dual-targeted CARs for glioblastoma, multiplex CRISPR screens, and immune reset for autoimmunity.

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Where Cell Therapy Stands in 2026

• 6 FDA-approved CAR-T products; >60,000 patients treated
• CRS and ICANS routinely managed
• Unsolved: autologous scale-out, access, cost of goods

Armored CARs — CD19 + IL-18

• CD19 CAR that also secretes IL-18 (NLRP3-inflammasome cytokine)
• First patient: dosed at 1/100 of FDA-approved dose — achieved durable complete metabolic response
• CAR cells as vehicles for secreting biologic weapons into the microenvironment

Dual-Target CAR for Glioblastoma

• OR-gated bicistronic CAR: mutated EGFR + IL-13Rα2
• 18 patients, intra-CSF via Ommaya; 13/18 with MRI responses, ~70% disease control
• Best patient: 34 months out, no recurrence (leptomeningeal spread)
• Responders show more NK cells in CSF; Tregs inversely correlated with PFS

Multiplex CRISPR Screens

• Cas12a enables true multiplex KOs per cell — ~7,000 paired-KO combinations screened
• Best single-gene KO: CBLB
• Best dual KO: Regnase-1 + EGR2 — wins in essentially every combination
• TET2 did not score in solid tumors (helps in blood cancers but not these models)
• Pool-KO CAR cells cure most NSG mice; CAR alone cannot

Immune Reset — Beyond Cancer

• CD19 4-1BBζ CAR producing dramatic, drug-free remissions in lupus, scleroderma
• ~300 trials active; longest remission: >3 years, drug-free
• Mechanism: deep B-cell depletion → naive repopulation (not classical immunosuppression)

Four Delivery Modes

1. Ex vivo autologous (current standard)
2. Off-the-shelf allogeneic
3. In vivo viral vectors IV (China-first)
4. LNP-mRNA (transient reprogramming)