CAR-T Therapy
Chimeric Antigen Receptor T-cell therapy — engineered T cells that recognize and kill target cells. A central theme across SDDS 2026, covered extensively in Session V (Rosenberg), Session V (Sadelain), Session V (June), and Session V (Panel).
Current State (2026)
- 7 FDA-approved products: 5 against CD19, 2 against BCMA
-
60,000 patients treated; CRS and ICANS routinely managed
- Major remaining issues: autologous scale-out, access, cost of goods
Three Pioneers
| Pioneer | Key Contribution | Institution |
|---|---|---|
| Steven Rosenberg | Father of cancer immunotherapy; IL-2, TIL, first human gene transfer, first CAR-T cancer regression | NCI |
| Michel Sadelain | Architect of second-generation CAR; coined “CAR” and “living drugs”; first CD19 CAR-T trial | Columbia (formerly MSK) |
| Carl June | Tisagenlecleucel (Kymriah); first FDA-approved gene therapy; Emily Whitehead | Penn |
See also: steven-rosenberg, michel-sadelain, carl-june
Evolution
First Generation (zeta-only)
- Prompt cytolysis → activation-induced cell death or anergy in real T cells
Second Generation (CD28-zeta or 4-1BB-zeta)
- Sadelain’s key insight: co-stimulation must be built into the receptor
- CD28: potent but short-lived; 4-1BB: persistent but slower — it was never about the costim domain, it was activation vs. co-stimulation balance
Next Generation Designs
- 1XX — calibrated ITAM signaling (Sadelain); responses at 10M cells
- HIT — HLA-independent TCRs; 10-50× lower antigen threshold (Sadelain)
- Pre-TCR — thymocyte expansion biology; extreme potency (Sadelain)
- Armored CARs — IL-18 secretion (June)
- OR-gated dual-target — EGFR-vIII + IL-13Rα2 for GBM (June)
- Multiplex CRISPR KOs — Regnase-1 + EGR2 (June)
Four Delivery Modes
- Ex vivo autologous — current standard
- Off-the-shelf allogeneic
- In vivo viral vectors IV — manufacturing CAR-T inside the patient (China-first)
- LNP-mRNA — transient endogenous T-cell reprogramming
Beyond Cancer
- Immune reset in autoimmunity (lupus, scleroderma) — ~300 active trials
- CAR-Tregs for diabetes
- Senolytic CAR-Ts for chronic inflammation
- Neuroinflammation/microglia in Alzheimer’s (very early)
Key Unsolved Problems
- Solid tumors: trafficking, immunosuppressive microenvironment, persistence, target selection
- The 90% problem: solid epithelial cancers cause ~90% of cancer deaths; neoantigen-targeted approaches (Rosenberg) are the leading strategy
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