Selective Immunomodulating Microtubule Binding Agents (SIMBA): A Novel Approach To Chemotherapy-Induced Neutropenia - Episode 8
The rationale for studying plinabulin, a first-in-class selective immunomodulating microtubule binding agent, for the prevention of chemotherapy-induced neutropenia.
Joyce O’Shaughnessy, MD: Well, we certainly covered the waterfront here, Andy, in terms of a lot of the limitations, as amazingly helpful as they’ve been. It’s night and day from when you and I first started practicing before we had these agents. We had such an inpatient service with febrile neutropenia management. Remember, there was a whole infectious disease specialty that grew up around management, and all the prophylactic antibiotics, and this randomized trial, and that randomized trial. And now we don’t need any of that in most cases.
Andrew D. Seidman, MD: It’s similar to the way that we don’t admit patients for hypercalcemia in the era of bisphosphonate therapy.
Joyce O’Shaughnessy, MD: Exactly.
Andrew D. Seidman, MD: We used to have patients coming in with severe hypercalcemia. And that doesn’t happen anymore. Let’s do that for febrile neutropenia.
Joyce O’Shaughnessy, MD: Exactly, huge progress. Nonetheless, it’s interesting. You don’t really think about the limitations until you say, “Wait a minute. Hey, there might be some other options coming here, for patients. Wow. I guess, do we need another option?” I think the answer, in my mind, is absolutely. I have somebody in the hospital right now who’s ANC [absolute neutrophil count] walking through the door was less than 100 [per μL]. But do you know what? She’s ill, unfortunately. I am living this as we speak as a matter of fact. But let’s talk about this new agent plinabulin. It’s really almost a space-age thing. This is so different, the mechanism of action. Why don’t you give a stab at that, Andy? Let’s have a look at what this agent is.
Andrew D. Seidman, MD: I never met a microtubule agent I didn’t like, going back to the yew tree in the 1990s. Plinabulin is an antimicrotubule agent but has many other effects that probably contribute to its clinical utility. It causes activation of GEF-H1 and RHO, ROCK, and JNK activation signaling pathways that can lead to maturation of dendritic cells and T-cell activation. It appears to shorten that neutrophil vulnerability gap and make it less deep. Unlike a taxane, a vinca alkaloid, which is purely a drug that is designed to treat cancer, this agent seems to have other potential benefits.
Joyce O’Shaughnessy, MD: It’s really interesting, this SIMBA [selective immunomodulating microtubule binding agent]. SIMBA’s a new class; of course, it’s the only member of the class. Maybe there’ll be others coming, but it’s the only member currently and that’s selective immunomodulating….
Andrew D. Seidman, MD: Microtubule binding agent.
Joyce O’Shaughnessy, MD: Microtubule binding agent. Thank you.
Andrew D. Seidman, MD: Not to be confused with the cute lion from the Lion King.
Joyce O’Shaughnessy, MD: That’s how I remember it, of course. It binds microtubules at the colchicine binding sites, [which is] very different than the taxane binding sites. It works very different than eribulin as well, which binds to an unaggregated subunit. But it binds to beta-tubulin, but at the colchicine binding site, and it disrupts polymerization. It’s kind of like a vinca in that regard, but it’s novel. And when it binds to the microtubule and disrupts it, now you’ve got disrupted microtubule, the cell releases this GEF-H1 that you mentioned, which is known to be a dendritic cell activator. You mentioned the pathway there, Andy, the ROCK and the RHO and the JNK. But it’s a dendritic cell. Isn’t that interesting, that connection there between disrupting polymerization of microtubules, and that’s going to be in your immune cells too, right? Your immune cells, your marrow cells, your cancer cells, your endothelial cells. Now you’ve got activated dendritic cells that in turn present antigen.
Andrew D. Seidman, MD: It reminds me of GM-CSF [granulocyte-macrophage colony-stimulating factor] because you have that macrophage dendritic cell activation there. We think of that more like a growth factor.
Joyce O’Shaughnessy, MD: Absolutely. And that whole hypothesis still lives. Some of our old colleagues from industry we’ve known have landed in companies that are still developing the immunomodulatory effects of GM-CSF. Bob Penado was big on that, so you’re right, Andy. This has been around, but of course, that just never got the legs yet, at least in practice. So that’s very interesting.
Transcript edited for clarity.