Treating Sarcomas With Cutting-Edge Immune Checkpoint Blockade

In part 3 of an interview with Ravin Ratan, MD, MEd, associate professor, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, he discusses recent study findings published in in Nature Cancer, for which he was a coauthor.¹ The investigation evaluated neoadjuvant immune checkpoint blockade in 2 types of soft tissue sarcoma: dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.¹

Liposarcomas originate in fat cells and are the second most common type of STS diagnosed.² However, dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma are both considered rare diseases,^3,4 for which there are limited treatment options.

Transcript

How does neoadjuvant immune checkpoint blockade work to improve the outcomes of patients with dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma?

For me, the first thing to sort of say is, one of the really cool things about working in a place like MD Anderson is that you get to sort of participate in really cutting-edge science. The publication you referenced was led by a couple of my colleagues: Dr. Christina Rowland [Christina L. Roland, MD, MS, FACS]; Dr. Neeta Somaiah [Neeta Somaiah, MD]; with very significant input from Dr. Emily Keough [Emily Z. Keung, MD, AM, FACS, FSSO], one of our surgeons; and then Dr. Elise Nassif [Elise F. Nassif Haddad, MD, PhD], who is one of our most recent hires in the medical oncology side. I have the good fortune of being able to care for some of these patients and sort of participate in the interpretation of some of what they see, but I also want to make sure that credit is given where it's due.

I think that, in general, immune checkpoint blockade is one of these sort of treatment modalities that has totally revolutionized the treatment of specific cancers. I think the best example is metastatic melanoma, where nearly everyone with that disease died and now we functionally cure a significant number of those patients by using immune treatments, in modulating the body's immune system to try to get it to attack the cancer. I think melanoma is an outlier in sort of how well that process has worked. There are other cancers, many other cancers—and they're continually growing the list of cancers—where immune checkpoint blockade has definitely advanced the field and sort of adds something to chemotherapy, but isn't quite the game-changer that it was in melanoma. That's things like lung cancer, kidney cancer, bladder cancer. And like I said, that list continues to grow, and I think that's been one of the really great stories of the last 10 years.

Sarcomas are challenging in that they're all rare diseases. We are learning that you can't just sort of say immunotherapy works or doesn't work in sarcoma. You really have to look at specific sarcoma subtypes where there seems to be a signal. We've also sort of seen that some of the biomarkers, some of the characteristics of tumors that we use in other cancers to predict whether a tumor will respond to immunotherapy—something like PD-L1 expression, which is commonly used to sort of determine whether a tumor is likely to respond to immune checkpoint blockade—those markers may or may not be as relevant in different sarcoma subtypes.

I think what the study that you're referencing was really trying to get at was to describe what happens to these 2 tumor types for which there has been some sort of earlier clinical experiences that demonstrate they may be responsive to immunotherapy, what happens to them when you treat them with immunotherapy? Doing this in the neoadjuvant setting allows us to get tissue before we start treatment, on treatment, and then certainly when the surgical specimen comes out after radiation. We're able to see how the population of different immune cells in the tumor changes from before we start immunotherapy to when the patient is on immunotherapy to after radiation when the surgery comes out. I think the paper starts to describe some of the immune changes that take place in a tumor that might predict the likelihood of responding to the immune therapy and radiation, and also ultimately sort of the likelihood that that tumor may metastasize in the future.

I think that the science is really exciting. I think we're still just at the beginning of understanding who should get immunotherapy for sarcoma, even after surgery, before surgery, in the metastatic setting. I think those are all things that are still being worked out. I think that the value of the study that you examined, it's not necessarily that it's opened up neoadjuvant immune checkpoint blockade to every patient with these diseases so much as that it's sort of said that, okay, well, now we can start to understand what's happening to sarcomas when we treat with these drugs in a way that may allow us to predict in the future who may benefit from treatment.

I guess I'd emphasize that doing neoadjuvant immune checkpoint blockade is not something that I would, even on the basis of this study, say is now the standard of care. I think that there's still potentially a discussion around chemotherapy, which has a stronger evidence base in some cancers, especially in the neoadjuvant setting. And so you don't necessarily want to just jump to immunotherapy because of a small experience that we've had, although in selected patients, especially in those who aren't candidates for chemotherapy who have specific tumor types, it's something someone to talk about, but I’d stop short of saying it's something that should be done routinely.

What are the advantages of concurrent radiotherapy in this setting?

Again, I think that it's premature to be able to say. There's always been this theoretical thought that if you do something destructive to a tumor, while you're also ramping up the immune system, that you may induce a better tumor response, right? So if you're breaking up cells with radiation or something like that and releasing all of these abnormal antigens into the bloodstream, maybe you sort of enhance the body's ability to recognize that tumor and mount an immune response to it.

I think there's a lot of good theory there. I don't know that we've demonstrated that that actually happens reliably, certainly in sarcomas. But that idea, right. So doing, for example, in the metastatic setting, where you have a patient who is getting a single tumor radiated, hoping that the destruction of that tumor will then somehow get the immune system to recognize other sites of cancer in that patient's body. It's called the abscopal effect, and it’s something that we talk a lot about, but real examples of that actually happening are uncommon.

References

1. Roland CL, Haddad EFN, Keung EZ, et al. A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma. Nat Cancer. 2024;5(4):625-641. doi:10.1038/s43018-024-00726-z

2. Liposarcoma. Sarcoma Oncology Center. Accessed June 17, 2024. https://sarcomaoncology.com/liposarcoma-cancer/#:~:text=Characteristics%20of%20Liposarcoma%20Cancer,(age%2040%20and%20above)

3. Dedifferentiated liposarcoma. Orphanet. Updated May 28, 2024. Accessed June 18, 2024. https://www.orpha.net/en/disease/detail/99970#:~:text=The%205%2Dyear%20disease%2Dspecific,rate%20of%20greater%20than%2090%25

4. Undifferentiated pleomorphic sarcoma. Mayo Clinic. Updated December 30, 2023. Accessed June 18, 2024. https://www.mayoclinic.org/diseases-conditions/undifferentiated-pleomorphic-sarcoma/symptoms-causes/syc-20389554