Research With Cellular Therapy Ramps Up in Mesothelioma

Marjorie G. Zauderer, MD

Mesothelin-directed CAR T-cell therapies, NF2 inhibitors, and EZH2 inhibitors are just 3 of a growing list of novel approaches under study in mesothelioma, renewing optimism in a field which has historically been colored with nihilism, said Marjorie G. Zauderer, MD.

“Even just from when I started 10 to 12 years ago until now, the progress we have made has been slow, with only 1 approval, but it’s really snowballing now in terms of [our understanding of] biology and the discoveries and the models that we have to study and ask the right questions. We should all be optimistic about the things that we can do. Outcomes still have a long way to go, but they’re so much better than they used to be,” said Zauderer.

In an interview with OncLive® ahead of the 16th Annual New York Lung Cancers Symposium®, Zauderer, co-director of the MSK Mesothelioma Program at Memorial Sloan Kettering Cancer Center (MSK), previewed her presentation on some of the new approaches in mesothelioma.

OncLive®: What work is being done to broaden the utility of cellular therapy in mesothelioma? What other approaches are under study?

Zauderer: I was tasked with talking about some new approaches for mesothelioma, and it’s an interesting time for that disease. Last fall, we had our first FDA approval since 2003 or 2004, which was when pemetrexed was approved for use in mesothelioma. Last year, we had the approval of ipilimumab [Yervoy] and nivolumab [Opdivo], which is exciting. Although that regimen really makes a difference for a lot of people, there are still a lot of people where that isn’t the right “magic sauce.” We are always trying to push that envelope.

I’ll be talking about a couple of different research endeavors and clinical trials that are ongoing to help figure out who responds to immunotherapy, who should still get chemotherapy and who should get chemoimmunotherapy—which is a lot like how we treat lung cancer today. Then, of course, we are looking at different ways of triggering the immune system. Lots of different clinical trials are looking to exploit the expression of different proteins on the surface of mesothelioma. One area we at MSK have been really involved in is the development of T-cell CARs targeting mesothelin. [In my PER® presentation,] I’ll be talking about that a little bit and some of the T-cell studies going on elsewhere.

Then of course, we always think about targeted therapies, and that’s certainly been incredibly successful in lung cancer, but we haven’t had the same degree of success in mesothelioma. In part, that is because the genes are different; they’re tumor suppressor genes instead of oncogenic activating genes. In my presentation, I will briefly cover different ways of exploiting NF2 alterations. There have also been studies looking at BAP1, PIK3CA mutations and sort of how we are starting to put together this very complicated interconnected network with rationally designed experiments based on good preclinical science that we’re trying to translate into the clinic.

Could you elaborate on the ongoing research with T-cell and targeted therapies?

Right now, there are a couple different mesothelin-directed T-cell programs. One that we have at MSK is the interpleural injection of our homegrown construct that was developed and created by Prasad S. Adusumilli, MD, FACS, of MSK, who is a physician-scientist that I work with. There is another construct from a company called TCR2 Therapeutics known as TC-210.

There are programs elsewhere across the country, and in the Northeast, where there are a couple of different constructs [being developed]. Each T cell is a little bit different in terms of the signature in terms of how the cells are manipulated, so that they target mesothelin. People are playing around with whether they are given intravenously or into the pleura or into the abdomen, as well as what chemotherapy to give before to prepare people for the treatment. How many times do you give it? How close together? There are a lot of different manipulations around that. Nobody really knows the right answer yet.

Another pathway that we’ve been thinking a lot about and how to target it is looking at NF2 alterations in mesothelioma because it’s a common mutation. There have been a lot of studies with PI3K and mTOR inhibitors, but to date, it hasn’t really been as effective in mesothelioma as we would like.

There are some studies now looking at other functions of NF2 and inhibiting that with inhibitors of a molecule that puts together these cullin-RINGs. By blocking the formation of that cullin-RING, you stop this prooncogenic cascade. Combining that [agent] with some of the PI3K and mTOR inhibitors has been productive in animal models. We’re starting to look at that [approach] in humans and translate that [to practice].

The other study is evaluating the EZH2 inhibitor tazemetostat [Tazverik], which was approved in the past couple of years for INI-deficient sarcomas. There was a phase 2 trial in mesothelioma that was a positive study. It’s one of these constructs that didn’t show a ton of shrinkage. There were a few patients who had real responses, but there was a tremendous amount of stable disease [SD]. The kinetics of the patients who had SD was that over a long period of time, they trended towards tumor shrinkage, which is different than a lot of the other ways that we think about these drugs as working. We often classically have thought about having a response up front, and then maintaining it. However, the idea that there might be an evolution to response over time is a really different way of thinking about the kinetics of response.

[We are looking at ways] to target P16 loss, which is common in mesothelioma and is usually associated with more aggressive disease. By interfering with the MTAP pathway where adenine is made, you can hopefully disrupt that signaling pathway. There is a construct that’s in development, and there are some other ones that are coming to the clinic too.

What does the future of mesothelioma look like, and how can the field continue to make progress?

It’s an exciting time for research because we are starting to extrapolate from other cancers, how they approach their diseases and break mesothelioma down into different subtypes based on biology. One of the biggest barriers is when we look at the SEER [Surveillance, Epidemiology, and End Results] database of how and where patients are treated; so many patients don’t get much treatment, if any, for their disease.

Being seen by a center that has experience doesn’t mean that you’re always going to get treatment––sometimes that’s the right decision for a particular patient. Seeing someone who doesn’t see 1 or 2 cases a decade, but who [treats patients with this disease] day in and out, brings a lot of expertise to [an individual patient’s] case. There are good data that surgical outcomes are better in high-volume centers. One of the barriers is getting the patients to the best regional center to manage their disease.