We recently talked to a hedge fund manager, an obsessed scratch golfer, let’s call him Bill, because of how pricey he is, about the EpicentRx anticancer therapy, AdAPT-001. He asked us to explain AdAPT-001 to him in the simplest language possible, and to keep the explanation high level and to stay out of the weeds.
“Sure”, we said.
And, with apologies in advance to any golf haters, here’s how we explained it.
We told Bill to imagine that the tumor is a golfer—and not a very good one. (This got Bill to look up sharply from the imaginary putt he was standing over).
The name of the game in golf is to put the ball in the hole or cup. In this scenario that we asked Bill to imagine the golf ball is a protein or cytokine called transforming growth factor-beta or TGF-β, for short, whose function is to shut down the immune system, and the hole or the cup on the course is its receptor, TGF-βR. Once TGF-β contacts its receptor, then and only then does the receptor transmit an ‘off signal’ to the immune system, which normally keeps tumors in check. This makes TGF-β the centerpiece of the strategy that tumors use to disable or weaken the antitumor immune response.
The only catch is that tumors lack a mechanism to “aim” or “steer” TGF-β in the direction of its receptor, so any interaction between them is down to pure chance rather than intentionality. But no matter, the fix is in—many tumors completely overexpress TGF-β and the TGF-β receptor to guarantee a successful outcome.
“So far, so good?” we asked Bill. He nodded, laughing, and now addressing us instead of his imaginary putter said, “So, unlike me, tumors are shankers. But they completely make up for it by giving themselves the maximum handicap possible, correct?”.
“More or less,”, we replied.
Bill then asked about AdAPT-001.
“Ah”, we said.
A modified common cold virus, AdAPT-001 carries a TGF-β trap, which it expresses in tumors; like a sand trap, this TGF-β trap ‘snares’ TGF-β and in doing so it prevents or reverses immune deactivation.
Immune checkpoint inhibitors like Keytruda or Opdivo that are all the rage in cancer therapy only benefit between 20-40% of patients with certain tumors like melanoma or non-small cell lung cancer. A major reason why the remaining 60-80% of tumors do not respond to these checkpoint inhibitors is because of TGF-β expression.
“So, TGF-β defeats checkpoint inhibitors”, Bill said.
“Exactly”, we replied.
We remade the point that the TGF-β trap takes TGF-β “off of the board” and this raises the degree of difficulty for tumors to protect themselves against the immune system and different immune-activating therapies like checkpoint inhibitors.
Bill pantomimed a series of shanked putts.
In appreciation, we offered Bill our best golf clap like Emilio Estevez and Charlie Sheen below from the movie, “Men at Work”.
