Session V — Lifetime Achievement: Steven Rosenberg
Forty Years of Teaching the Immune System to Kill Cancer
Steven Rosenberg (Chief of Surgery Branch, NCI since 1974) traces the arc from IL-2 to TIL to the first human gene transfer to neoantigen-targeted cell therapy for solid epithelial cancers.
Key Milestones
IL-2 Era (1980s–1990s)
- 1984: first durable immune-mediated regression of metastatic cancer — patient disease-free 40 years later
- IL-2 became the first FDA-approved cancer immunotherapy (renal cancer 1992, melanoma 1998)
- ~17% objective response, 8% complete — but complete responders almost never recurred
TIL Therapy in Melanoma
- 192 patients: 56% objective response, 25% durable complete responses
- 46 of 48 complete responses lasted >10 years
- Lifileucel (commercial TIL) FDA-approved 2024
First Human Gene Transfer (May 22, 1989)
- First foreign gene ever placed in a human — a tracking marker in T cells
- Contested RAC vote, lawsuits, regulatory battles
- Established safety of retroviral gene transfer into human T cells
CAR-T Origins
- First patient to undergo cancer regression after CAR-T — 48-year-old NHL patient, CR ongoing past 14 years
- Technology licensed to Kite Pharma → acquired by Gilead for $11.9B (2017)
Neoantigen-Targeted Cell Therapy
The current frontier — targeting mutations in solid epithelial cancers (90% of cancer deaths):
Three Approaches
- Selected TIL — isolate only neoantigen-reactive subset
- TCR transduction — clone reactive TCR into patient’s normal lymphocytes
- Shared-mutation TCRs — libraries against KRAS and p53 hotspot mutations (present in ~30% and ~50% of all cancers)
Recent Results
- Selected TIL in chemo-refractory pancreatic/colorectal/cholangiocarcinoma: ~24% RECIST response rate
- KRAS G12V–targeted TCR: pancreatic cancer regression
- p53 R175H–targeted TCR: colorectal liver/lung mets shrinking
- 2014 cholangiocarcinoma patient: disease-free 12 years out
“Any intracellular protein can become a cancer antigen if it is mutated. The good news: virtually all cancers have mutations. The bad news: it is highly individualized.”
Comments