Hi, my name is Gareth Morgan. I'm here at the IMS meeting in Athens and there's been lots of interesting things happening. One of the most interesting things I think is that we sort of stand at the crossroads of us making huge differences in terms of treatment with multiple myeloma. So the development of T cell engaging therapy has been a huge advance and as we get them to more and more patients, more and more people are going to benefit from these drugs. But one of the issues is that the people are still relapsing and trying to understand what drives those relapses is really important and so we hear a lot about the immune micro environment and how that can impact response to these immune therapies. But really it always comes back down to adaptation and survival of the fittest. So the targets we direct therapy against are GPRC5D and BCMA. So if you put a strong pressure in terms of treatment against targets, because there are so many cells in the cancer, merely by chance you wind up selecting for the cells that either lack the target, have mutated the target, have deleted part of the target, are quiescent and not responsive to the drug. So what happens is that you select for a resistant clone that comes to dominate the cancer in the body at relapse. And the important thing that you can learn from this is if you're treated with anti-BCMA, because you select for resistance to BCMA, if you switch to GPRC5D you're going to respond because your immune system is capable of it and vice versa. If you start with GPRC5D you switch to BCMA. And so the really clever thing is that if you make dual binding T cell engagers that engage both BCMA and GPRC5D, that's going to lead to even better therapies where resistance can't happen so easily. So the future is going to be around engineering these molecules so they're even better. There are fewer relapses and patients do better still. So we can see a good way forward for the next few years where things are going to improve dramatically. The important thing about these resistance mechanisms are that there are arguably now five BCMA-directed monoclonal antibodies, four of which are engaged T cells. There are CAR-Ts also that do it. But if you're resistant to one, pretty much you're going to be resistant to the other because it all comes down to the amount of selective pressure that you put on any specific target. So the clever thing will be to either alternate between anti-BCMA, anti-GPRC5D or the dual binding warheads as you might think on the molecules.
HealthTree • October 3, 2023