Cell Therapies in Sarcomas: Lete-cel in Synovial Sarcoma and MRCLs

In this episode of OncoDaily, Dr. Sandra D’Angelo, a renowned sarcoma expert from Memorial Sloan Kettering Cancer Center, joins Amalya Sargsyan to discuss the IGNYTE-ESO trial. This pioneering study highlights Lete-cel, an adoptive T-cell therapy showing a 42% response rate in synovial sarcoma and myxoid round cell liposarcoma (MRCLS). Dr. D’Angelo delves into key findings, including response durability, safety profiles, and the transformative potential of cell therapies in sarcoma care.

Dr. Amalya Sargsyan is a Medical Oncologist at Yeolyan Center, a Research Physician at the Immune Oncology Research Institute, and Senior Editor at Oncodaily. She holds an MD from Yerevan State Medical University and an MSc in Precision Medicine from the University of Cyprus.

Dr. Sargsyan completed her clinical training at the Bank of Cyprus Oncology Center and has been honored with an ASCO IDEA award. Her research focuses on the potential of novel immune checkpoint inhibitors (ICI) in low- and middle-income countries (LMICs), aiming to bridge disparities and enhance access to innovative cancer care.

Sandra D’Angelo, MD is a Associate Attending Physician at Memorial Sloan Kettering Cancer Center. She is medical oncologist specializing in the care of soft tissue sarcomas and bone sarcomas, as well as Merkel cell carcinoma. She completed her fellowship in Medical Oncology from Memorial Sloan Kettering Cancer Center. She completed her residency in Internal Medicine from New York University.

Dr. D’Angelo is also a member of the Immunotherapeutics Clinic (ITC), which designs and conducts early clinical trials using investigational therapies that use the body’s own immune system to fight multiple types of cancer. Dr. D’Angelo earned her MD in Medicine from SUNY Downstate College of Medicine.

Amalya Sargsyan: Hello everyone and welcome to OncoDaily. I’m Amalya Sargsyan, a medical oncologist and a senior editor at OncoDaily, and today we’re excited to discuss the latest updates on cell therapies in sarcomas. We are honored to have with us Dr. Sandra D’Angelo, an expert sarcoma oncologist and one of the pioneers in cell therapies at Memorial Sloan Kettering Cancer Center. Dr. D’Angelo is also an investigator of the IGNYTE-ESO trial of Lete-cel in synovial and myxoid round cell liposarcomas, and we look forward to hearing her insight on this promising data.

Sandra D’Angelo: Thanks so much for the invitation, and I’m excited to be here and talk more about Lete-cel.

Amalya Sargsyan: So, as we’re going to briefly discuss IGNYTE-ESO trial, can we start by giving a brief overview of the trial, specifically the patient population it targets, the phase of the trial, and where in the treatment landscape of synovial sarcomas and liposarcomas it fits?

Sandra D’Angelo: Of course, sure. So, just starting by way of background, generally for patients with synovial sarcoma and myxoid round cell liposarcomas, the standard therapy is comprised of initial surgical resection, followed by chemotherapy to prevent recurrences for some patients, as well as radiation. Oftentimes, though, patients develop metastatic disease despite this initial treatment plan, which highlights the need to initiate alternative therapies when the cancer comes back and spreads.

And for those patients that develop metastatic disease, while there are some nuances and differences amongst both synovial sarcomas and myxoid round cell sarcomas, the common theme is generally that chemotherapy is often used to treat recurrences. Chemotherapy, though, is not curative, and while response rates can be promising, there is a need for ongoing therapy, and inevitably chemotherapy almost always stops working. And so, there’s been an interest in exploring alternative and novel approaches for patients in the field of sarcomas and beyond, as well.

When we look at the criteria of this particular trial, actually, I’ll just start with a little background. Lete-cel actually has been investigated previously in a number of different clinical trials. So, the first trial was a pilot trial that was published back in 2018.

In that trial, a number of different questions were asked, including the role of lymphodepletion chemotherapy and the doses that need to be integrated. From that effort, we learned that fludarabine forms a pivotal part of the lymphodepletion regimen. We also explored those patients who had low-expressing NY-ESO-1 and found that overall response rates were not as promising in those low-expressors.

Ultimately, that initial effort in synovial sarcoma prompted an interest in myxoid round-cell liposarcoma, where we again investigated two different lymphodepletion regimens and noted that using a higher dose or a standard dose of lymphodepletion regimen seems to be more effective. With that background, the basis of the IGNYTE-ESO study was formed. And in order to qualify for that particular trial, there is a need for the specific HLA-A*02:01, A*02:05, or A*02:06.

Patients must have been older than 10 years old. The tumors must express NY-ESO-1 at least 30% at 2 to 3 plus per immunohistochemistry. Patients must have metastatic or unresectable synovial sarcoma or myxoid round-cell liposarcoma with appropriate performance status.

Further, they must have received standard anthracycline-based chemotherapy and must have had progression on their last line of therapy, as well as measurable disease per RECIST. And so, those are the eligibility criteria. The primary endpoint of the trial is overall response rate per RECIST 1.1, and a number of secondary endpoints are fairly standard for many clinical trials, including evaluation of safety, time-to-response, duration-to-response, disease control rate, progression-free survival, and overall survival.

Amalya Sargsyan: Thank you for sharing the inclusion criteria for the trial and the main population, which were included in the trial. So, you mentioned that these were advanced, pre-treated populations, which indeed have very limited options for other treatment, and this was the chance to give them to survive. So, you have touched upon the response rates and limitations, from what you have already shared during ASCO and recently on CTOS. Can you share with us more on the efficacy data? Were you satisfied with the results? How would you describe it in general terms?

Is it better than what was already available for those patients?

Sandra D’Angelo: It’s a great question. I think that all our therapies offer additional options for our patients and expand upon what we already have available. And I always think about chemotherapy as truly forming the cornerstone of how we approach care for our patients with recurrent metastatic sarcoma.
However, I already highlighted the limitations. So, with Lete-cel, what we found was that the response rate was 42%. It was 41% specifically in synovial sarcoma with three complete responses.

And then in mixoid/round cell liposarcoma, it was 43 percent, again, with three complete responses noted. I think one of the most important aspects of this approach is the duration of the response. In synovial sarcoma, the duration was 18.3 months, and in mixoid/round cell liposarcoma was 12.2 months. And so, when we think a little bit about, you know, we have to take caution in comparing these results with other standard therapies. Obviously, it’s difficult to conclude that our approach with Lete-cel is superior.

We can only make some observations, right? The only way to truly say that something’s better than another is obviously by having a randomized trial, which in the context of these rare malignancies that are selected by specific HLA haplotypes, that’s not appropriate. That being said, the 40 percent response rate obviously is exceedingly promising.

To add some perspective, pazopanib was one of the last drugs approved for synovial sarcoma, and the response rate is approximately 10 to 15 percent in synovial sarcoma. And the progression-free survival for the duration of response, again, is probably in the less than six-month range. And for mixoid/round cell liposarcoma, some of the standard chemotherapies we use, for example, trabectedin, again, offer a fairly high response rate, but the duration of response is lower than what we see.

The other important aspect of cell therapy, adoptive cell therapy, more broadly speaking, is the fact that this is a one-time infusion. You receive treatment once, and with hope and, you know, the durability can be long-lasting, because in theory, the cells would be long-lasting in the patient’s body. So, that’s a big distinction with how we generally treat patients with standard chemotherapy.

It’s an important point and an important distinction. Obviously, you always want to weigh that in the context of adverse events and toxicity.

Amalya Sargsyan: Thank you. So, you have shared with us that it got quite a good response rate, and we were able to achieve durable responses if compared. Of course, it’s a specific population, so we’ll be cautious when discussing this.
And you have touched the safety profile. So, how would you describe it? Is it tolerable?
What were the major side effects? And can you share with us a little bit more about it?

Sandra D’Angelo: Yeah, of course. So, when we looked at the adverse events in the context of the clinical trial, we looked at them in two ways. One, side effects related to the lymphodepletion chemotherapy.
And from that perspective, we saw adverse events in nearly all treated patients, most commonly cytopenias, which is not surprising given the dose of chemotherapy that’s utilized for lymphodeplete patients prior to receiving the T-cells.

Importantly, there was one grade 5 event where a patient had persistent thrombocytopenia and developed a pulmonary alveolar hemorrhage in the setting of this persistent thrombocytopenia. And after that event, actually, the dose of the cyclophosphamide was actually decreased from 3,600 milligrams per meter squared to 2,700 milligrams per meter squared over three days.

Secondly, we also looked at adverse events in the context of the T-cells. And from that perspective, again, we did see adverse events in most patients, most commonly cytokine release syndrome occurred in 92% of patients, but was grade 3 or higher only in 12% of patients. And then skin rash again occurred in many patients, 64% of treated patients, but then grade 3, 35% of the time.

These events were appropriately treated and manageable. And in the context of the T-cells, there was also one grade 5 event. This was a patient who developed neutropenic sepsis, cytokine release syndrome, hypotension, and a port infection and ultimately felt and passed away in the context of cardiac arrest.

And so importantly, yes, these are therapies that can cause adverse events, but recognizing these adverse events and treating them appropriately is feasible. And obviously, for those that are familiar with these approaches are fairly standard and expected with what we would otherwise anticipate.

Amalya Sargsyan: Thank you. So, you say that it’s manageable and somewhat predictable. The adverse events were somewhat what you had anticipated.

And with the efficacy, we can have this tolerability, it’s quite a good compromise. Maybe we should have been touching on this at first, but for our listeners and for a broader audience, can you briefly share with us what is actually cell therapy and especially these T-cells? So how they’re different from our conventional therapies and administration?
Why cell therapy is different?

Sandra D’Angelo: Well, it’s a great question. So the basket of cell therapy actually comprises a number of different approaches. The big umbrella I refer to is adoptive cell therapy.
And in the basket of adoptive cell therapy, some of the earliest work and sort of most developed are what we refer to as CAR T-cells or chimeric antigen receptors. With CAR T-cells, the target is typically a surface protein, and the CAR T is designed to recognize that surface protein. Then the second approach is what I refer to as TIL therapy.

TIL therapy usually involves removing a lymph node, extracting the lymphocytes, expanding them, and then re-infusing them in patients. This approach has actually recently been FDA-approved for those patients with melanoma and really offers an advancement over the standard of care for those patients with melanoma, specifically where standard immunotherapy has stopped working. And then T-cell therapy is what we’re talking about in the context of sarcoma.

T-cell therapy, the promise of the advantage over, let’s say, CAR T is that you’re able to recognize a number of different targets beyond the cell surface protein. CAR T recognizes up to 25% of proteins that are found on the surface, but remember that most of the targets are actually found elsewhere. And so by using an engineered T-cell approach, you can actually reach a number of other different targets, for example, neoantigens and intracellular proteins and public neoantigens and private antigens.

And so you are actually able to expand the targets by over 75%. Though one of the limitations of T-cell therapy is the requirement of the specific HLA types, because if a protein is intranuclear, then it needs to be presented to the surface by the specific MHC2 class. And so there are pros and cons with each of the approaches.

And I think, at least in the context of sarcoma, all our efforts have been focused with engineered T-cells. Targeting cancer testes antigens, which are, again, intranuclear proteins that are expressed in malignancies, but actually not expressed in normal somatic cells, which again offers an important advantage of limiting off-target toxicity.

Amalya Sargsyan: Thank you for giving us a general overview and explaining how cell therapies work and how these two differ from each other in the context of Lete-cel. And of course, you were there with the Afami-cel and now with Lete-cel and pioneering the cell therapy field of sarcomas. As an expert, how will you see the future of cell therapies working in sarcomas?
Do you see more targets coming or what is next in plans?

Sandra D’Angelo: So Afami-cel obviously laid the foundation for our efforts in the field of sarcoma. It’s the first FDA-approved T-cell therapy for solid tumor malignancies, which really has laid the groundwork. Lete-Cel builds on that effort by expanding the applicability to another sarcoma subtype with mixedoid/round cell liposarcoma.

I envision a world where you have an expression of a particular cancer antigen, whether that be MAGE-A4 or NY-ESO-1. So then, studying these approaches and these respective expressing tumors is a rational next step. I think that while the durability is promising and a clear advancement over the current standard of care, there’s obviously always improvement to do more.

And so, thinking about novel approaches, novel constructs of combinational strategies, perhaps can really build upon what’s already been done. And then in the context of T-cells in general, again, one of the limitations is the specific HLA requirement. And I think thinking above and beyond that requirement will be important to really continue to broaden the applicability of these therapies.

Amalya Sargsyan: Thank you for sharing. Hopefully, this will become more and more accessible and more and more patients are going to deliver the benefit of this novel treatment. And we’ll hopefully try to find a way of overcoming the limitations as well.

If we look at the context of the previous years, the changes were dramatic. So now with having approved the cell therapy already, the upcoming years are going to be more promising. Anything else you would like to add to conclude our overview of the latest development on the new T-cell?

Sandra D’Angelo: No, I mean, I think this is a, it’s a remarkable time in the sarcoma field. Oftentimes rare cancers are often neglected and ignored, but here we have, you know, really pivotal advancements in the solid tumor space, all being spearheaded in sarcoma, which is a testament of the commitment to rare cancer drug development by our sarcoma community, as well as our collaborators. So this is just a really remarkable time.

Amalya Sargsyan: Thank you for sharing your insights and for sharing the difficulties of doing trials in rare settings, but getting good results, and hopefully we’ll have an even brighter future. Thank you for accepting our invitation and being with us today. It was a pleasure to have you with us.

Sandra D’Angelo: Thanks so much. Thanks again for the opportunity.