The AdAPT-001 “Whichdunit”

Apr 10, 2023

Ok, so everyone likes a good “whodunit”.

This is the genre of classic “pure puzzle” mysteries where the dramatic final “reveal” of the culprit, the person “who did it”, takes place at the end or denouement after a long suspense-filled buildup, with plot twists and red herrings (or fake clues) galore. The typical story presents a cast of characters grouped together at an isolated and familiar location—usually an English country house—after a murder, usually by poison, has taken place and—shock! Gasp! —one of these characters is the murderer/poisoner. But which one? And why? The local police are summoned but make no progress because the solution is hidden behind a proliferation of secret motives, cover-ups, wicked lies, and false alibis. As a result, suspicion falls on many or all the characters, who are driven by lust, greed, hatred, and dishonesty, and the murderer, always at least one step ahead, remains hidden as the body count—and the tension—builds. To the rescue comes an eccentric, preternaturally intelligent detective, or sleuth with a never-ending desire for truth and justice, like Hercule Poirot or Miss Marple or Ellery Queen who doggedly follow the evidence, narrow down the clues, make deductions, and—voila! — in a dramatic final scene ingeniously solves the impenetrable mystery, restoring order and making plausible what previously appeared to be implausible.

In the case of AdAPT-001, the oncolytic adenovirus that carries a TGF-beta trap, and that has been designed to eradicate tumors, the question is not so much “whodunit” but “whichdunit”—which out of several suspect mechanisms are behind the ongoing “cancer killing spree” with AdAPT-001 in the ongoing Phase 1/2 BETA PRIME clinical trial.

Here is the AdAPT-001 list of suspects in no particular order:

  • Immunogenic cell death (ICD)
  • Tumor lysis
  • Abscopal effect
  • TGF-β neutralization
  • Inhibition of DNA repair
  • Altered gene expression
  • Cytokine and chemokine release
  • Anti-angiogenesis
  • Improved T-cell trafficking
  • Decreased fibrosis
  • Innate immune system activation

Use your “little grey cells” like Hercule Poirot, the Belgian detective from the novels of the acknowledged queen of the genre, Agatha Christie, to figure out which out of the above is most responsible.

Hint: For the solution you must expressly “orient” yourself.

Ok so whichdunit? The key is the hint above about having to “expressly orient yourself”. This is a reference to Agatha Christie’s Murder on the Orient Express, which, if you haven’t read it, is a real doozy (the movie from 2017 less so, despite the star-packed lineup) because, spoiler alert, everyone did it. The same goes for multimechanistic AdAPT-001—all the above-listed “suspects” are “in on it” together. Which makes perfect sense. Cancer is far too wily and versatile to be taken down or out by “one and done” unimechanistic agents; only those agents, which run the gamut and make use of several different mechanisms, e.g., tumor lysis, immune activation and TGFβ suppression like AdAPT-001, stand a chance.

As to the motive in Murder on the Orient Express, it was out of revenge for the kidnapping and murder of a small child. The motive to treat with AdAPT-001 is also to avenge the deaths of so many friends and family members that cancer has prematurely taken from all of us—and that “us” certainly includes you as well. Let AdAPT-001 serve as the agent of our revenge.