What does the term debulking mean? How is tumor debulking completed? Why consider debulking when using T-cell redirected therapy?

What does the term debulking mean? How is tumor debulking completed? Why consider debulking when using T-cell redirected therapy? Debulking means reducing tumor volume or tumor burden in a patient. So debulking chemotherapy could be any chemotherapy or treatment that reduces the amount of tumor burden in a patient. And oftentimes it is treatments like multi-agent chemotherapy like DCEP or DCEP chemotherapy that could be used. And sometimes it could be VD based. And those are done when you want fast reduction in the tumor burden. Tumor debulking can, it really depends on each patient and it's individualized because we want to know what therapies they've had previously and what therapies are available that they're likely to respond to and what their response rates have been previously. But often if we want really quick debulking before we want to take them to a therapy if there's a lot of disease around, things like DCEP chemotherapy, which is a four drug combination, DCEP or VD based chemotherapy, which is also a combination of chemotherapy agents is often used. But it could also just be something similar, like a triplet drug combination like daratum, and carfilzolib that could technically be used if a patient's never seen it before or we think that they are going to respond to it. Having a lower tumor burden would make it easier for the T cells to be more effective because there is less tumor that these T cells are being redirected towards. So in some ways it is partly to debulk so that you could have more likelihood of response. But the other reason also would be is that if a patient is progressing quite rapidly and you need some time, these T cell therapies may take some time to work. And if you need those few weeks, then first reducing the tumor burden and then doing the T cell directed therapy could help. But it's not needed for all patients and many of them we would just go ahead and do a T cell directed therapy directly. In general, debulking refers to reducing the overall volume of tumor cells that are present in the body, which is the goal of all therapy from a very high level. In particular as it relates to immune therapies, there's two reasons why you would want to debulk because as you know, one of the major risks of current immune therapies such as CAR T cells and T cell engagers is cytokine release syndrome. And cytokine release syndrome is a spectrum of symptoms that occur when the activated T cells start releasing signaling molecules that rev up the immune system. And this can be manifest as fever, low blood pressure, low oxygen saturation, a number of different manifestations. And more around the T cell engagers, it appears that the cytokine release syndrome may at least in part be related to the bulk of tumor present when the treatment starts. So patients can often have recurrent cytokine release syndrome symptoms if there's more tumor cells that takes longer to get rid of them and so forth. The mechanism around that is an entire clear and it's not a perfect one-to-one correlation, but in general that would suggest that maybe you would want to reduce the tumor burden with a targeted agent or chemotherapy before rolling in with the T cell engager. The second reason is then efficacy is also somewhat related to tumor burden. So patients have very high tumor burden or if they have very aggressive, rapidly growing tumors, the T cells, the immune system may not have enough time to rev up and put the brakes on the tumor and reduce them before they get out of control. So if you have another way to reduce the tumor volume before you go in with your T cell engager or what have you, it may be more effective in inducing remission and maybe have longer remission.