ideasIdea
Vaccinate against the resistance mutation before it takes over
Resistance often arrives as the same few mutations. Teaching the immune system to recognise them in advance could remove the escaping cells while they are still rare.
Recurrent resistance alleles such as EGFR T790M, ESR1 hotspot mutations and KRAS secondary mutations create novel peptides that may be presented on MHC. An off-the-shelf vaccine or T-cell product against a small set of public resistance neoantigens, given at the start of or during targeted therapy, would apply immune pressure precisely to the cells that are expanding under drug pressure.
Hypothesis
Vaccination against a recurrent resistance neoantigen generates detectable specific T cells and reduces the emergence of that allele in plasma during targeted therapy.
Rationale
Public resistance mutations are shared across many patients, which makes an off-the-shelf product feasible; targeting a clone while it is rare is when immune clearance is most plausible.
What would test it
Immunogenicity and pharmacodynamic study in patients on osimertinib or an oral SERD, comparing allele emergence rates in plasma between vaccinated and control groups.
Maturity
speculative
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
7
Bottlenecks it attacks
- Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.
- 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.