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What is CC-122?
The short answer is that it an experimental oral drug being investigated to treat several different cancers including CLL. It is a direct descendent of thalidomide and lenalidomide, both used with significant successes and real difficulties in clinical trials in CLL. It works in multiple ways, among them by modulating the immune system to better fight the cancer and is thus considered the next step in the development of immunomodulatory drug or IMIDs.
It gets very complicated very quickly, so please don’t be put off by the next paragraph. I promise to unpack it all and share what I believe we need to know.
So take a deep breathe and here goes:
CC-122 is the first-in-class pleiotropic pathway modifiers that may work by binding cereblon and promoting the ubiquitination and the resulting degradation of the transcription factors Aiolos and Ikaros. It has been shown to have potent anti-proliferative, anti-angiogenic and immunomodulatory activities in B cell lymphoma, perhaps though its T and NK-cell activation and B-cell inhibition. It is also almost certainly teratogenic.
Now for the translation.
CC-122 is the pipeline name for the Celgene molecule.
Pleitropic simply means that it affects multiple cellular pathways simultaneously. Cereblon is a small protein that works with an enzyme (ubiquitin) found everywhere (they are ubiquitous) that degrades the activity of certain other proteins (the transcription factors Aiolos and Ikaros) that faithfully copy or transcribe the genetic material encoded in DNA into RNA.
Perhaps because of this, it slows the multiplication of cancer cells (anti-proliferative), stops the blood vessels from growing that support cancers (even blood cancers) and their micro-environments (anti-angiogenic) and modulate our immune system, activating our exhausted T-cells and NK (natural killer) cells to help fight cancer and directly inhibiting our cancerous B-cells (immunomodulatory). Because of the potent combination of all these activities, it can be very damaging to any fast growing tissue, especially a fetus, hence its classification as a potent teratogenic (causing birth defects) agent much like as its grandfather, the notorious 50’s drug, thalidomide. It’s believed that it was primarily the blocking of the growth of the blood vessels necessary for normal development that lead to the profound limb abnormalities and other complications in babies whose mother took the drug for nausea during pregnancy.
Now that explanation wasn’t so bad was it?
CC-122 is part of the ongoing promising immunological research in CLL. CLL has only been cured by harnessing the immune system with an allogeneic transplant. CAR-T therapy is exploring similar territory, so this is a fertile area for researchers.
It makes good sense that CC-122 is being investigated in pre-clinical studies with checkpoint inhibitors that take the brakes off the immune systems and have had such success in treating melanoma and lung cancer.
Take a look at this trial for folks with CLL/SLL:
Clinical research with lenalidomide in CLL is winding down, but fortunately the pre-clinical data suggests that CC-122 is a better molecule for CLL/SLL.
As we have said before, despite the plethora of new great options, a cure is still elusive and we need multiple medications that work synergistically to get us to where we can finally say: “I used to have CLL.”
Brian Koffman, MD 5-2-16