ASH 2022 | Advances in immunotherapy for MDS: anti-TIM-3 & anti-CD47 antibodies and small molecule inhibitors

It’s been a real challenge for us to get great immunotherapies in the MDS landscape, but we had learned already from the high success with transplantation that manipulation of the immune environment is absolutely critical. So for a long time we had been trying to take a look at the role of checkpoint inhibitors, and though there were some early encouraging data and safety, we just hadn’t seen a lot of efficacy and changes in outcome.

In the meantime, we’ve gone on to take a look at other types of immune therapies, including drugs that target other alternative negative regulators, like TIM3. So there was a recent sabatolimab combination study with azacitidine, and the initial studies looked very encouraging and interesting in terms of safety, early response rates, including among intermediate and higher-risk patients. At this year’s ASH, they were able to give an update on the STIMULUS-1 trial with the Phase II data where they showed patients that were randomized to azacitidine with or without sabatolimab, and it looked like the response rate and the progression-free survival rate did not meet the primary endpoint, but there was some interesting data when you took a look at some disease subsets where there looked to be some divergence of the curves for certain subsets of patients, maybe those with lower disease burden.

What we ultimately need is an overall survival readout, and that’s been our biggest challenge in MDS is finding drugs and combinations that can lead to that, especially when we’re comparing it historically to a drug like azacitidine. And so there are Phase III studies ongoing, including with sabatolimab, where we’re hoping to see what the overall survival differences are.

Besides sabatolimab, we have a lot of interest in CD47 inhibitors. That’s another checkpoint through the macrophage, don’t eat me signal, and there has been encouraging data when it’s combined with azacitidine, and even in AML with azacitidine-venetoclax, but there is an ongoing trial with azacitidine plus or minus magrolimab, and we’re all looking forward to seeing how that reads out. Besides that, there are indirect, innate immune system therapies, like small molecule inhibitors from IRAK-4 and two other drugs that are now available and being assessed in the lower-risk setting such as canakinumab or CXCR1/2 inhibitors, where in today’s early MDS session, we were able to hear some really encouraging safety data and early responses.