ideasIdea
Turn one tumour into a vaccine to treat all the others
Injecting immune-activating agents into a single tumour, plus a small dose of radiation, can teach the immune system to attack tumours elsewhere in the body.
The in situ vaccine combination of Flt3L to recruit dendritic cells, low-dose radiotherapy to release antigen, and a TLR3 agonist to mature the dendritic cells produced systemic regressions in indolent lymphoma in a phase 1/2 at Mount Sinai. The approach needs no antigen identification and no manufacturing, and has never been properly tested in solid tumours where antigen release by radiotherapy is well characterised.
Hypothesis
Intratumoural Flt3L plus low-dose radiotherapy plus a TLR3 agonist induces abscopal responses in at least 15% of patients with checkpoint-refractory solid tumours, with expansion of shared T-cell clones between injected and non-injected lesions.
Rationale
Antigen supply and dendritic cell availability are the two rate-limiting steps for priming in cold tumours, and this regimen supplies both locally at low systemic cost. Clonal sharing between lesions is a hard mechanistic endpoint that does not depend on tumour shrinkage.
What would test it
A multi-cohort phase 2 in checkpoint-refractory solid tumours with paired injected and distant lesion biopsies and T-cell receptor sequencing as the primary mechanistic endpoint.
Maturity
early clinical
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
6
Bottlenecks it attacks
- Cold tumours and the immunosuppressive microenvironment · Most tumours keep the immune system out or asleep, so immunotherapy helps only a minority.
- No one can predict who responds to immunotherapy · Checkpoint drugs cure some patients and do nothing for most. We still cannot tell the two apart before treating.