Targeting Clonal Mutations with Synthetic Microbes

Recently concluded, large-scale cancer genomics studies involving multiregion sequencing of primary tumors and paired metastases appear to indicate that most patients have one or more “clonal" mutations in their tumors. Clonal mutations are those that are present in all of a patient’s cancer cells. Clonally mutated proteins can potentially be targeted by inhibitors or E3 ligase glues, but developing new small molecule drugs for each patient is not feasible currently. One company is using an immunotherapy approach to specifically target clonal mutations. Another is using a different immunotherapy tactic that targets clonal and subclonal mutations. A third is planning to use a self-amplifying mRNA-based vaccination approach to target clonal mutations. To address the potential limitations of immunotherapy, I have devised another approach for exploiting clonal mutations, which I call “Oncolytic Vector Efficient Replication Contingent on Omnipresent Mutation Engagement” (OVERCOME). The ideal version of OVERCOME would employ a bioengineered facultative intracellular bacterium. The bacterium would initially be attenuated, but (transiently) reverse its attenuation upon clonal mutation detection.