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Angst in the IO Combo field – part 2 (lessons from #AACR17)

08:56 EDT 7 Apr 2017 | SugarCone Biotech

I posed this question regarding IO combinations in the last post, leading up to AACR: “Why the perception of angst then? The sentiment has been summed up as “everything will work a little, so what do we research/fund/advance? How do we choose? How will we differentiate”? I was mulling over these questions as I prepared remarks for Jefferies Immuno-oncology conference – the slides below are taken from the deck I presented. Even the comment “everything will work a little” now seems to be an overreach. We could instead say: “most combinations won’t work at all”, meaning they won’t work better than anti-PD-1/PD-L1 monotherapy or anti-CTLA4 monotherapy, or, that they won’t work better than those therapies used in combination with standard of care. Remember two years ago? We were going to take an anti-PD-1 to “release the brake” and add anti-4-1BB or anti-OX40 to “step on the gas”. While it is still early, this seems to be an empty paradigm. Why? Certainly the 4-1BB and OX40 pathways are intensely potent when used to drive T cells directly (e.g. anti-CD3 + anti-4-1BB in vitro or as used in a CAR-T cell). Is it too early to tell? Have the wrong patients been enrolled in trials? Are the antibodies no good? Is it the Fc? IS THE TUMOR COLD? So here we go, onto the next paradigm, summed up in the phrase “make cold tumors hot”. What happened to stepping on the gas? At AACR, Dan Chen (from Genentech, a Roche company) laid out the case for using not 1, not 2, not 3, not 4, not 5 … but up to 11 different therapeutics to successfully treat a given tumor – he exaggerated to make the point that none of the current immune checkpoint inhibitors (ICIs) should be expected to work in synergy with anti-PD-1 therapy, a priori. Why ...

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