Symbol of the French revolution, the guillotine, a ruthlessly efficient beheading machine, is in the news of late.
Lead EpicentRx therapy, AdAPT-001, is a molecular guillotine that decapitates the immunosuppressive cytokine, transforming growth factor-beta (TGFβ). The presence of this cytokine predicts resistance to checkpoint inhibitors (ICIs). These are therapies that target molecular checkpoints like PD-1/L1 and CTLA-4, which cancer cells also use to suppress the immune system.
The rationale to combine AdAPT-001 with checkpoint inhibitors is that the decapitation or elimination of TGFβ removes resistance to ICIs. The main takeaway from an ongoing Phase 2 clinical trial called BETA PRIME is that administration of AdAPT-001 sensitizes treatment-resistant tumors to ICIs that they previously received and failed.
If borne out in future clinical trials, this is big, big news because, while ICIs have unquestionably revolutionized the treatment of cancer, most tumors do not respond to them and even ones that do respond initially often later develop resistance. So, the hope and, frankly, the expectation is that AdAPT-001 will make ICIs a viable treatment option for patients that should not, and ordinarily would not, respond to them. This includes patients with poorly T-cell infiltrated “cold” or “non-inflamed” tumors that tend to overexpress TGFβ like glioblastoma (GBM), pancreatic, breast, prostate, sarcoma, and microsatellite-stable colorectal cancers.
To paraphrase the last line from Dickens’ “A Tale of Two Cities,” about the French Revolution and its enduring symbol, the guillotine, that put paid to the monarchy and its supporters, “‘tis a far, far better thing” for AdAPT-001 either to be combined with checkpoint inhibitors or to be used on its own as monotherapy against the “emperor of all maladies.”
Vive la AdAPT-001 révolution!