CIN Treatment Advances: SIMBA Therapy

Hope S. Rugo, MD, FASCO: We will move on to the next area of discussion, which is advances in managing neutropenia. We talked some about the unmet needs. It would be nice to give all the medication on the same day and have good control without worrying about a drug not working or how many doses of short-acting growth factor to give and when.

There is a new area of investigation using something called a selective immunomodulating microtubule binding agent [SIMBA], and a really interesting drug called plinabulin where we have some data. Let’s talk first about how chemotherapy causes myelosuppression and how plinabulin might get around that. What’s the mechanism of action of this drug, and how is it given?

William J. Gradishar, MD: Plinabulin is a drug for which we’re gaining more understanding of its mechanism of action and the complexity of the acronym that was created to encompass what it’s supposed to do. Not only is it capable of potentially preventing the deep neutropenia that we see in some patients, but it also may have an effect on the immune system.

How it works is, it is a microtubule agent, but distinct from the ones that immediately leap to mind. It does bind to microtubules, and it does release a protein, GEF-H1, that in turn activates the signaling pathway. That signaling pathway can cause the maturation of dendritic cells, which in turn are the antigen presenting cells that may have an impact on the body’s immune system to fight cancer. Not only does it affect progenitors that can affect the blood counts, but it may also have an anticancer effect.

Hope S. Rugo, MD, FASCO: That’s fascinating. Can you tell us anything more? What does the microtubule part have to do with it?

William J. Gradishar, MD: I think before we had the acronym SIMBA, we were focusing more on the properties that affected blood counts, specifically the intensity and depth of neutropenia. I think it was something that was observed in one of the clinical trials that suggested there was indeed an antitumor effect, which broadened the acronym to take that into account.

Hope S. Rugo, MD, FASCO: It is fascinating how the tubulins play a role in neutropenia, and by blocking this beta tubulin you might be able to change neutropenia. What is the role of the maturation of cells, and how might planibulin affect the innate and adaptive immune responses? I know there are some data in this area, and it’s fascinating that what you do to prevent neutropenia can also have an impact on the immune response.

Rita Nanda, MD: I find it fascinating as well, but I think we see this often in oncology. We have drugs we know work in one way and are developed for one reason, but then we see other effects.

When you think about the way cancer interfaces with the immune system and all the steps required for cancer cells to be recognized by our immune system and eradicated, it’s complex. There’s antigen presentation, maturation of dendritic cells, which are important in antigen presentation, then these dendritic cells present the antigen to the T cells, which then leads to their activation.

It’s so fascinating that a drug that’s been developed for neutropenia could also have other effects that could potentially impact the efficacy of the agents that we’re using by helping the immune system recognize the tumor cells.

I think there’s potential for 2 benefits in 1 drug. How these drugs may interact with some of the checkpoint inhibitors that we’re developing and are now approved in breast cancer will be interesting to see down the road.

Transcript edited for clarity.