Photos of Torrey Pines Golf Course; a 2-minute drive from the EpicentRx Torrey Pines headquarters.
As doctors, we were on the back nine last weekend, working on our slice, and it occurred to us that a good name for a golf magazine, should we ever decide to write one, in all our free time, (snort), is “Of course!” No eye rolling please, c’mon, it’s a legit name. Anyhoo…the best shot in golf is, of course, (see, we told you, it works!) a hole-in-one and the PD-1 checkpoint inhibitor, dostarlimab, in mismatch repair (MMR) deficient locally advanced rectal cancer recently hit one with 14/14 complete responses. Let’s unpack that.
Checkpoint inhibitors (CIs) like Opdivo or Keytruda are, of course, (we’re just going to keep saying it) well-known for their game-changing antitumor immune properties. It is hard to read an article in the scientific or popular press about them and not encounter the words “game-changing” or “revolutionary” or “breakthrough”. That is well-deserved. CIs have transformed cancer care with the promise of long-term remissions and, in some cases, even cures. But they are certainly not cure-alls.
The biggest challenge in cancer care today is how to make checkpoint inhibitor-resistant tumors checkpoint inhibitor sensitive so all patients benefit from them. To continue with the golf analogy, checkpoint inhibitors, which rev up the immune system to go after cancer cells, are teed up to work in MMR deficient tumors. The DNA repair machinery in these tumors is defective so many mutations are present, thousands of them, compared to less than 100 in a typical tumor. The more mutations in tumors the better—this makes it easier for the immune system, especially when CIs are on board, to target tumors. Unfortunately, however, only a handful of tumors, including rectal tumors, are MMR deficient, which brings us to our point.
AdAPT-001 is a tumor-specific virus, currently in a Phase 1/2 trial that carries a TGF-beta trap. TGF beta is a protein that is overexpressed in cancer cells because it puts the immune system to sleep. The TGF beta trap, which binds to and neutralizes TGF-beta, wakes up the immune system and puts it back on the trail of the tumor. AdAPT-001 has demonstrated in animal models that it makes CI-resistant cancer cells sensitive to them. Data from the ongoing Phase 1/2 BETA PRIME clinical trial with AdAPT-001 suggests that it also sensitizes patients to checkpoint inhibitors, where previously they were resistant.
Do we really think this can work?
Fingers crossed but, yes, of course.
