Sylvia Lee: 
Hi, I’m Sylvia Lee and we’re joining you from the iwCAR-T meeting 2022. And I’m here with Dr Mihaela Druta and Dr John Mullinax, both from Moffitt and we just finished our session discussing melanoma and sarcoma cellular therapy. And I can start with what I covered, so my session was covering melanoma TIL therapy and reviewing the updates and what we talked about was the data from an Iovance Phase II trial that demonstrated that TIL therapy did achieve responses after ICI progression in melanoma patients. And we also discussed the early data from Iovance looking at TIL plus pembro in the PD-1-naive melanoma population which is also showing promising results with a 67% response rate. We discussed some of the practicalities of melanoma TIL and different areas of investigation for the future. And Dr Mullinax brought the perspective of the surgical oncologist. Can you share your thoughts and your perspective about delivering TIL therapy and what we need to do in the future?

John Mullinax: 
Sure. So I think in terms of cellular immunotherapy, obviously TIL is based at the time of the surgical resection. So all of the cell therapy product is generated from that initial resection specimen and so involving the surgeon early in the process of assessing patients for eligibility is really crucial. Obviously site selection relative to patients that have multiple sites of metastatic disease. It’s important to understand where you’re going to target in the operating room for that ultimate resection that’s going to lead to their TIL infusion product. And so I discussed today some best practices that we’ve developed at our institution around eligibility for these TIL therapy trials and that’s allowed us to really streamline the process and decrease the time to enrollment for these patients as they’re screened for these trials. So we talked about intraoperative management of the specimen as well, in terms of ownership of that specimen by the surgeon and preparing it and placing it in whatever media is involved that’s going to go onto the cell therapy facility. I think it’s really important to do that all in the operating room, on the back table, under sterile conditions and not pass it off and not let that leave the operating room from that surgeon. So I think some of those concepts aren’t often talked about certainly in the cell therapy space and we talk a lot about the infusion product and what happens to the patients afterwards but, if you think about the true denominator of what patients might be eligible for these therapies certainly there may be more patients that are eligible with early consultation with a surgical oncologist.

Sylvia Lee: 
And if you know, we look in the future and we sort of imagine what things will be like if TIL becomes commercialized. Do you see anything changing about how things are run at Moffitt?

John Mullinax:
So I think at Moffitt, we’ve developed, as I said, some really solid institutional SOPs around how we not only evaluate those patients up front, but the intraoperative policies and procedures that lead to the cell therapy facility. So that whole sort of soup to nuts process. I think what I envision is being important is involving national societies and generating guidelines that can then be expanded to some of these other sites that may not have familiarity with these processes. As a surgical oncologist, the actual technical aspect of the operation is really pretty straightforward, but it’s all of the portions of the operation around the actual tumor resection that are key, and so I think codifying those and generating even up to privileging criteria for folks that are going to be able to do this in not only in a safe manner, but in a manner that yields an optimal product for patients is going to be crucial and I think we really should look to many of the national societies to craft some of these guidelines and get ahead of this, otherwise we’re going to be in a position where regulatory agencies are sort of telling us what we need to do. And so if we can own this now and think about this now, these conversations can really translate into those policies.

Sylvia Lee: 
I agree. I think that looking at the commercialization of the first CAR-T products and how that was rolled out, it was sort of a very intimidating, daunting process at first and then when you saw more guidelines come out and sort of a way to sort of standardize the care and the management of these patients it became just a lot more feasible and doable for a lot of different places.

John Mullinax: 
Yeah. No, I think that’s key and I think there are certainly centers now that have experience with these early trials, some of which we discussed today, and I think that’s a good core group to begin with in the commercial setting. And then, if everybody trains one other and one other we can really grow this, but it’s going to be that quite honestly, physician to physician training and physician led training that I think is really going to be crucial rather than something that is sort of commanded by a regulatory agency. We’d prefer certainly for that to be more organic and developed by those of us that have pioneered some of these therapies.

Sylvia Lee: 
And then Dr Druta, you shared really interesting work that you’ve been doing in the sarcoma field.

Mihaela Druta: 
Yeah, thank you. And I shared with everyone the excitement for me as a sarcoma medical oncologist that have expertise in the treatment of soft tissue sarcomas they are extremely rare diseases with, heterogeneity, talking about different subtypes of 70, 80 different subtypes. To see these newer therapies and emerging therapies that are FDA approved in other malignancies to be brought to the clinical trials for these patients, it’s extremely exciting. So we covered about the overview of the synovial sarcoma and the myxoid/round cell liposarcoma. These are very rare type of tumors. We are talking about an annual incidence of 800 to a 1000 patients. They tend to occur in young adults so clearly these patients they are younger at the diagnosis with this aggressive sarcomas. Typically, the standard of care for localized patients, they are treated with a heavy chemotherapy with a combination of doxorubicin and ifosfamide. Patients that are undergoing several months of these treatments followed by radiation of their primary disease and followed by the surgery so, they are pretty much on a six month journey of a very aggressive approach. At the end of this, most of the patients will develop a metastatic disease and they will die because of the disease. So it’s clear that we need better therapeutic options than novel therapies. We are still treating these patients with cytotoxic chemotherapies with doxorubicin single agent for 40 plus years so, I think it’s time for us to move the needle in this field and clearly seeing the poor prognosis for these young patients, we need to do better. Therefore, we looked at adoptive T-cell therapy as an emerging strategy for other types of malignancies and how is this applicable for solid tumors in general and for sarcomas in particular. So again, as I emphasized in our talk while these strategies that they were working in heme malignancies in solid tumors they were not necessarily this direct strategies for the cell surface antigens were not really applicable for the solid tumors and mainly because of the lack of this expression for this antigen of the cell surface. Therefore was this strategy with the TCR approach where basically we have the autologous T-cells CD4 and CD8-positive cells, that are genetically modified to have this TCR affinity that is increased for recognizing this tumor-associated antigen, and we look at two specific-tumor associated antigen with MAGEA4 and NY-ESO. MAGEA4 for afami-cel with adaptimmune and with NY-ESO, with lete-cel product that its HLA-bound for a patient from GSK. I presented the data for this Phase II SPEARHEAD, a clinical trial for patients they have HLA-A*02-positivity, and then followed by the expression of the MAGEA4, and then looked at the patients and the outcomes they were treated on these trials. I also emphasized the complexity of these trials, right? So we have to identify the patients. They will go through the screening process and HLA expression followed by the tumor testing for the MAGEA4 and then they will have the apheresis and developing of their product. It typically takes four to six weeks for these cells to expand and to be able to be sent to us for the patients, and these patients are then admitted to the hospital for lymphodepleting regimens with cyclophosphamide and fludarabine, and they have the product infused. They’re typically in our experience in the immunotherapy group, the ISD group, that I am part of that and I am rotating in the inpatient setting, patients that are in the hospital for up to a week, depending on the profile mainly of the CRS, not really observing neurotoxicities with these strategies and they are discharged after that but they need to stay close to the cancer center up to a month. So again, a complex and costly kind of a process for these patients and then they are followed with serial scans up to two years in the ease intervention phase of the trial followed by long-term follow up for up to 15 years. The results so far for the patients with synovial sarcoma and myxoid/round cell liposarcoma they are exciting, we had a overall response rate for these patients that were including stable disease complete response and partial responses up to 40% in these patients and again, we are talking about heavily pretreated patients, they had up to three lines of systemic chemotherapy. So this is clearly for us it’s very exciting to see these responses. Also, we proved that they’re relatively well tolerated or safe toxicity profile. We didn’t see high grades of the CRS. The majority of the patients developed grade 1 and grade 2 CRS with just 2% that developed higher grade CRS. There was no patient on this trial on this cohort, the 50 patients that we analyze at the time of the data cutoff that developed neurotoxicities. So the patients in this trial, we had a cohort one with 45 patients, they were enrolled and that is close to this is the data that hopefully will generate a very productive conversation with the FDA. And then we have ongoing and Moffitt is part of that for the cohort two and hopefully to strengthen the data for this FDA application. I also presented another strategy for the treatment of patients with synovial and myxoid/round cell liposarcoma with NY-ESO, the cancer-testis antigen which is highly immunogenic and also has a high expression in patients with synovial sarcoma and myxoid round cell liposarcomas, depending on the studies with expression of 70, 80% for synovial sarcoma and maybe higher myxoid/round cell liposarcoma. We focus particularly on the cohort two patients, they were treated with a higher dose of the lymphodepletion therapies, that was a thought, that these patients perhaps can achieve a more durable persistence of their cell product. Then these patients that we had overall responses rate of 40% and they were patients, five patients out of ten, they had durable responses. The toxicity profile, as opposed to the MAGEA4 was a little bit different with a more than 20% of the patients developing adverse events. And there were more patients, they developed grade 3 CRS toxicity. However, these were resolved by 7.5, 8 days of onset of their toxicities. The cohort two and the trial that looked at different cohorts with different lymphodepleting regimens they are now close to accrual. We have the patients with myxoid and synovial enrolled in a different protocol with GSK. In summary for us, again, as a sarcoma medical oncologist that I was told by some of my colleagues that is a Twilight zone, it’s very exciting to have the access for the patients, for these strategies, definitely the results of these trials they are proof of concept that they can work and then we notice some durable responses for our patients. Clearly it’s a lot of work to be done to understand better, the mechanism of resistance, the persistence of these products, and clearly it’s a very complex journey for the patients and will require specialized multidisciplinary teams with expertise in delivering these strategies to the patients, and also to know how to manage their side effects. So very exciting for us.

Sylvia Lee: 
Yeah. Well, I know that this work has been sort of a very long arduous road, and so it’s exciting also just as an outsider to see these results to finally come in. And the other nice thing about the cancer-testis antigens is that the work and the success is seen in sarcoma will be able to be taken to other tumors that express the same antigens.

Mihaela Druta: 
Exactly. Yeah, it was the newest data that came from just from adapting that was presented to the annual AACR meeting in New Orleans, they looked at MAGEA4 expression in different subtypes of sarcomas and different other malignancies with 67% of the patients with synovial sarcoma having a MAGEA4 expression with 25 to 30% expression in a variety of other solid tumors. So clearly from the company standpoint and from the sponsors, they want to understand and to make this product working and safe and eventually exactly to be able to deliver in different subtypes of solid tumors that they will have expressions of tumor-associated antigens.

Sylvia Lee: 
Great. Well, thank you Dr Druta, thank you, Dr Mullinax for joining me and thank you for listening to our overview of our updates in melanoma and sarcoma at the iwCAR-T meeting.

Mihaela Druta: 
Thank you.

John Mullinax:
Thank you.