VIDEO: Potential for bispecific antibodies in follicular lymphoma

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The bispecific antibody story is very long. So blinatumomab was basically invented around the same time as rituximab. And it was initially developed as a lymphoma drug. There was a 30-year developmental history to get blinatumomab to be FDA approved for ALL. And then the California Cancer Consortium also did a 10-year study of blinatumomab bispecific in lymphoma, and they went up to a very high dose, 160 micrograms per day. So those studies ultimately didn't work. People like stopped working on lymphoma with bispecifics until Roche and Genentech brought out CD20 specific CD3 bispecifics. And those drugs are likely to be available in DLBCL soon. And then once they're approved for DLBCL- Coming from follicular lymphoma. So I'm very interested. You know, I think they offer some advantages. So for one thing, they probably work faster than rituximab. So even if you're targeting the same CD20, they're much more potent. And you can tell whether they're working sooner, at a cost of potentially higher toxicities. They're more potent at depleting B cells than rituximab. And unlike rituximab, bispecifics make your T cells proliferate. So it actually increases your lymphocyte count. disease is important when using bispecifics. So the bone marrow is a very accessible space for T cells. The blood is flowing through there, it's highly fenestrated, there's a lot of contact between T cells and normal bone marrow, as well as lymphoma, if it's there. So bispecifics are very good at clearing the bone marrow. The trade-off is that because you have potentially so many lymphoma cells that are available to be attacked, you can also get a lot of toxicities for patients that have bone marrow site of disease. So you can get cytokine release syndrome. I'd say that's the main one. Risk of cytokine release syndrome that you really don't see with regular monoclonal antibodies, because of their higher potency and because they activate T cells. So I don't think it's gonna be a frontline treatment. It's gonna be for people that have maybe progressed on rituximab or maintenance or lenalidomide-rituximab. It is the kind of thing that has to be done in the right setting with the expectation that the first cycle in particular can have significant toxicities. It's CAR T-like toxicities. The bispecific we have for ALL is very short-acting. So you can turn it off. You can walk into the room, the patient has toxicities, you just switch off the continuous infusion and the toxicities are gone, immediately. The blinatumomab has a half-life of seconds. But the newer formulations of bispecifics are half-life extended. They're either given subcutaneously or they're albumin-bound, or they're bound to a modified Fc receptor, so that they can be given weekly or every two weeks. It's not a continuous infusion. The trade-off is that once you've made a drug long-acting, the side effects and toxicity is also long acting. So if somebody has cytokine release syndrome on a long-acting bispecific, you have to use tocilizumab, you have to treat it like it's a CAR T toxicity, because you can't stop the activity of the drug. And so bispecifics that are being tested now either use debulking strategies or they pre-treat with CD20 monoclonal antibody, like rituximab or obinutuzumab to try to reduce the amount of normal B cells that are available to be attacked by T cells under the influence of bispecifics, to reduce the chance of getting cytokine release.