Let’s put this one under the “This is why you run clinical trials” heading. A number of companies have looked at inhibitors of indoleamine 2,3 dioxygenase (IDO) over the last few years. The enzyme turns tryptophan into kynurenine, a pathway which (among other things) regulates immune function. Evidence has accumulated that many tumors have increased IDO activity as part of their ability to decrease T-cell response and evade immune attack, partly through the decreased tryptophan levels in the cells. (They’re probably also doing this through a related kynurenine-producing enzyme, tryptophan 2,3-dioxygenase (TDO), which was earlier thought to be found in only liver and neuronal tissues).
What with immuno-oncology being as blazing hot a research field as it is, a separate mechanism that could be combined with the current therapies is definitely going to get a lot of attention. In 2015, Genentech and NewLink Genetics reported that a NewLink IDO inhibitor (GDC-0919, navoximod) combined with anti-PD-L1 antibodies gave robust increases in activity in preclinical tumor models:
The combination of IDO1 inhibition with PD-L1 blockade has strong rationale since both checkpoints are co-expressed in many cancers and inhibit immune responses via complementary mechanisms. Using mouse syngeneic tumor models we present further evidence of the therapeutic potential of combining IDO1 inhibition with anti-PD-L1 blockade. We observe improved depth and duration of responses in mice treated with the combination regimen versus anti-PD-L1 blockade alone.
This combination was already in the clinic by the time the paper appeared, with a fair amount of optimism from observers. But we now have a readout on how it’s going, and the answer is “not well”. Genentech is handing back rights to GDC-0919, after data presented at the recent ASCO meeting showed only a 10% response rate across several tumor types. You can see from that link that some analysts were trying to remain optimistic, but Genentech apparently doesn’t share that glass-half-full outlook.
Something’s wrong, but what? Incyte is developing an IDO inhibitor of their own (epacadostat) and combining it with Merck’s Keytruda is providing the results that one would hope for. So the mechanism is likely to be sound. Complicating the picture, though, is that the Roche/Genentech PD-L1 antibody used in this study (Tencentriq, atezolizumab) had a recent unexpected failure in bladder cancer. It will be tempting for NewLink (and their investors) to think that the antibody was the problem, but there’s just not enough evidence to make that case one way or another. NewLink itself is under a lot of pressure after they’ve had disappointing results with their other IDO inhibitor, indiximod, in breast cancer, and it might be tough to round up another partner at this point. There’s a fair chance that we may never find out why GDC-0919 did what it did, but I hope that we eventually get some idea.