Boom-Boom Radiation as Bridging Therapy Prior to CAR-T for DLBCL | Christopher D'Angelo, MD | #ASH24

Hi, my name is Christy Angel and I'm a lymphoma and multiple myeloma specialist at the University of Nebraska Medical Center in Omaha, Nebraska. Our group was excited to present a couple of different abstracts at this year's ASH. One of them was a prospective investigator initiated study of what we call boom boom radiation prior to CAR T cell therapy with lysis cell in aggressive B cell lymphomas. What we're reporting at this ASH is the results of the first 20 patients that we've enrolled. We are nearing complete enrollment as of this day, for example, and what we're excited about is when we think about bridging therapy, we know that our patients will need, many of our patients will need it and ideally the optimal bridging strategy would not only control the disease, it also needs to ensure that the patients don't get sick from the toxicities of those therapy that render them weaker or potentially even ineligible for CAR T cell therapy. And ideally in a best case scenario, it would also help the whole CAR T cell therapy work better. We need these strategies ultimately to make CAR T better for everybody, more efficacious and safer. And so the rationale for using boom boom radiation, which is basically a really low dose of radiation, too gray in two doses over two days basically, so just two days of radiation, has almost no toxicity and might actually help immune stimulate the patient where the CAR T cell therapy might actually work better. This is based on some preclinical data that suggested when mice were given this low dose of radiation, not too high of a dose or not too far away from the CAR T cell infusion, that it actually make the whole therapy work better through not only just CAR T cell related mechanisms but potentially just enhancing the immune microenvironment as well. And so we are seeing some potential glimmers that that could be happening in our patients as well. In the first 20 patients that we saw, the majority of patients went into a complete remission afterwards, that's north of 80% or so. And there were no of any of the responses that we had, not everybody responded unfortunately, but in all the responses that we saw, all were in complete remission, which is very different from what's reported for CAR T cells in general. And this is important because complete response and depth of response matters in translating to long term outcomes. Anyone who achieves anything less than a CR is most likely going to relapse and probably in short fashion, but CRs appear to be durable and that's what we're going to be hoping to read out as the study continues is to look at that durability a little more. We are excited about the fact that not only is it demonstrating some efficacy, despite recruiting a pretty high risk population, most patients had elevated LDHs, extra nodal presentations and advanced stage at time of study and enrollment. So this wasn't just a handpicked early limited stage offering for patients to just receive radiation. It was truly those that needed optimal bridging strategies. And so this is not only efficacious, but also very, very safe and very easy to give. We need to make sure that we are offering access to CAR T cell therapy for our patients that live in rural centers that live hours away from our CAR T center. So being able to demonstrate that we can do this in a very short fashion, that it proves efficacious and that we can enroll patients that don't just live in our Omaha area, but across the state of Nebraska and our surrounding neighborhoods as well, our surrounding communities from rural populations, I think is also an exciting part of this abstract for us. The really nice part about the radiation that we are offering in this study is the low dose. So, you know, just like anything in medicine, the dose matters and the dose determines the toxicity in some ways. So low dose radiation here offers virtually no toxicity. You could radiate almost any part of the body with very, very low toxicities. And it's also very easy to give. So you know, you would be seen by a trusted radiation oncologist with expertise in this disease whose staff will kind of line up and sort of use your scan to help determine the optimal way of delivering the radiation. It's very short visits. You come in, you get positioned in the right area and stuff, and then you receive your radiation and you can go on for the rest of your day. With this low dose, you're basically not going to have virtually any toxicity. I don't want to say no toxicity. That wouldn't be entirely fair. But we're excited about the fact that this low dose proves so effective and patients shouldn't be too nervous about the toxicities that could come from radiation. So simple to deliver and fairly low toxicity. I think from the preclinical data, what's happening, I think, is that the lymphoma cells themselves are becoming or expressing different ligands that render them more sensitive to just the regular T cell, innate T cell populations in the patient themselves. So not only will the CAR T cell work a little bit better, but it renders it more sensitive to the rest of the immune system too. And there's some data to suggest that sometimes the CAR T cell is really just the tip of the spear. into that micro environment. But if this radiation sensitizes and awakens and produces some antigens that are recognized by the rest of your T cell and immune environment, that might be how this makes everything work a little bit better. And it's always important to remember that CAR T cell therapy is sort of a whole and living immune therapy, continues to evolve as soon as it goes into your body. And it not only just functions based on the CAR T cells themselves, but also recruiting the rest of your immune system to bring forward in treating the lymphoma. It's important to say right now these are feasibility studies and they're not quite ready for prime time, but we certainly are excited about how we might continue to develop this in the future. And there are a few groups that are trying to explore the right sweet spot when it comes to radiation, not just how close it should be given towards CAR T, how many times you might be able to give it. There's lots of really exciting questions. And really what's most important is we're trying to think about not only ways of making more effective therapies for CAR T cell, but also making them safer for our patients as well.