Melissa Johnson:
Hello, I’m Dr Melissa Johnson from Sarah Cannon. We’re here at the iwCAR-T cell workshop. We’ve just finished a great session on immune effector cell therapy for lung cancers and other cancers that arise in the chest. Let me introduce you to the panel. Sandip Patel from the University of California, San Diego, Sylvia Lee from the Fred Hutchinson Cancer Center and Prasad Adusumilli from Sloan Kettering. We had a really robust discussion after each of the panelist discussions, but we are going to recap that for you, just with little cliff notes from each of the talks. Sandip, maybe I’ll start with you. Do you want to tell us what you talked about?

Sandip Patel:
Yeah and so thanks for the opportunity to discuss our work. So we wanted to provide a broad-based overview of the needs in solid tumor cellular therapy in particular for non-small cell lung cancer, the most common tumor type in the United States and some of the logistical challenges around delivering therapy, whether looking for a needle in a haystack biomarker and the best approaches to screening a large number of patients, not only for host factors like HLA, but tumor-specific factors in terms of expression of the particular target.

Sandip Patel:
We also focused on challenges in terms of mass production. For example, for autologous-derived cellular therapy products for very rare diseases there may be opportunities for bespoke therapies in that setting. However, common tumor types, such as non-small cell lung cancer, breast cancer, prostate cancer, the need for scalable solutions so that if there is an effective product that can be delivered to a wide swath of patients who could benefit is key. And then really focusing on the biomarker story, because many of these cellular therapeutics have a high toxicity in addition to high therapeutic rate that can be durable, but the idea of matching the best therapy for the patient and how we think about biomarkers to best understand which patients can most benefit.

Melissa Johnson:
Great. How about you, Sylvia? What did you talk about?

Sylvia Lee:
I reviewed lung TIL therapy. So basically TIL therapy is a type of cellular therapy that involves removing a portion of the patient’s tumor, bringing it to the lab and growing out the T cells from that tumor that is able to recognize the tumor and expanding that to high numbers and infusing it back into the patient. We have known for a long time that, that therapy is effective for melanoma and the question is, can that therapy be effective for other solid cancers? And just recently, really just over the past year and a half, we have started to have our first data come out from now two different lung TIL therapy trials. One at Moffitt and another that was a multi-institutional trial. It’s really showing that we, the answer is yes, that we are seeing that TIL therapy can achieve responses in lung cancer patients who have actually already progressed on standard immunotherapy like pembrolizumab and nivolumab. So, that’s pretty exciting. It’s pretty huge and sort of a great solid first step for I think, a promising direction.

Melissa Johnson:
And Prasad, why don’t you tell us about your talk? You are one of the surgeons in the room today from a little bit of a unique perspective, talking about anti-mesothelin CAR in mesothelioma.

Prasad Adusumilli:
So my talk focused on developing CAR-T therapy, chimeric antigen receptor T-cell therapy for thoracic cancers, mostly primary malignant mesothelioma, metastatic lung and breast cancer as well. We talked about how we developed it, why we chose mesothelin and what’s the role of mesothelin in this cancers. And with different types of constructs that we are developing. And most importantly, crossing the bridge of, as you just alluded to with Sylvia, crossing the bridge of initial safety and initial sense of efficacy, how can we keep them going? Functional persistence, which to me is the key for the solid tumors. So that is what my talk focused on.

Melissa Johnson:
Absolutely. I, lastly, I presented another challenge in the development of these immune effector cell therapies for solid tumors, and in particular lung cancer has been to identify realistic patient targets, tumor antigens that are expressed in high amounts in the tumor, but not in other wild-type cells of the body. And, and I took a different approach that maybe the way to develop these therapies for lung cancer patients will be more broadly not screening so much, but rather giving an off-the-shelf therapy. So I reviewed a red blood cell-based therapy, I reviewed a natural killer-based therapy and an iNKT-based therapy, all looking at to help get the immune system to the tumor and to expand anti-tumor immune cells there over and above what T-cells are able to do with checkpoint inhibitors. You know, I do think that one of the key questions of the meeting, it was raised in the GU session preliminarily, and then in our session too is the importance of the tumor antigen. And we spent some time on the panel discussing whether, for example, mesothelin, do you need a high or a low amount of it in order to, is that a good way to select patients? And Prasad, you’ve had some really interesting comments. I wonder if you’d share them again.

Prasad Adusumilli:
Yeah. I think it’s a great conversation that we had based on multiple experiences from different clinical trials. Antigen expression is the key. That’s the target that we are targeting the T-cells. So antigen expression should be there and must be there. But beyond that, is that the sole criteria? What other criteria come into the picture and what are the kind of considerations that need to be taken? Because in solid tumors, as we all discussed, there is no CD19 that is homogeneously and uniformly expressed at a high intensity on all the cancer cells. Knowing that’s our battlefield, it’s a heterogeneous antigen expression. How can we now select the patients and streamline the patients through multiple therapies? Most importantly, while we are advancing with cell therapies, checkpoint blockade therapy, multiple other different checkpoint blockades, targeted therapies, they’re already in the play. Once we cross the bridge of safety and initial sense of efficacy, it’s going to be multi-modality therapy. How do we combine, even in tumors that has a relatively low antigen expression, and change the tumor microenvironment and make the other therapies work. That’s what I was alluding to in the talk.

Melissa Johnson:
I thought you made a really good point in your talk. You showed some data that’s emerging. And, and I took note of those slides. I’ll be interested to read those manuscripts about how checkpoint inhibitor therapy and checkpoint plus chemotherapy for preliminarily, for lung cancer and mesothelioma changes the tumor microenvironment in real ways that will impact the success of subsequent therapies like this. And I do think that is an area where we have, we’ve been ignoring that in much of the work that’s been done today.

Prasad Adusumilli:
I think the initial studies were focused in the chemotherapy radiation therapy, targeted therapy on cancer cell lysis, and we, as you alluded to, we had a blind eye to the antigens that are being released following cancer lysis. So there for the tumor eradication, the chemotherapy, targeted therapy, radiation therapy, we look for how much of the cancer is lysed and the changes in imaging. But now that we can alter the tumor immune microenvironment, do we really need high doses to cancer cell lysis? Can we get some cell lysis and neoantigen responses and alter the tumor microenvironment, get rid of the macrophages or promote T-cell infiltration. Now with the combination of this, can we eradicate the metastatic tumors? I think that’s one of the concepts we discussed.

Melissa Johnson:
That’s really exciting. I’ll, I’ll follow that with interest. Sylvia maybe we’ll switch gears and talk a little bit. I, the question I wanted to ask you is as you sit across from a patient, melanoma or lung in the clinic, how do you, how, how do you select patients for TIL? is there something about their case, their molecular profile that makes you think, ah, this would be a great patient, or are there other factor clinical factors that you use?

Sylvia Lee:
Yeah, so usually, you know what, the way we view TIL and the patients who are most likely to benefit are sort of the same patients who tend to benefit from the immune checkpoints, that patients who have really, you know, mutation rich tumors, the lung cancer patients who have a heavy smoking history and, you know, melanoma arises, you know, from all these mutations, from UV light. And, and then also sort of separate from that when we look at TIL, and like other cancers that have a specific, like an HPV oncogene, like something that can be easily recognized by the immune system. So we look at patients that way, but the main, you know, limitation of TIL is you have to surgically resect a portion of their tumor to grow the cells. You can’t just do a leukapheresis. And so you have to have someone who has a portion of their tumor, that you can easily resect with a surgery. That’s not going to be too aggressive where they can sort of come in and out. We can pull out a portion of their tumor and grow their TIL from that. And so they have to be pretty, you know, fit to go through surgery. They have to be pretty fit to go through, like TIL is given with a pretty hefty lymphodepleting regimen with high dose cyclophosphamide and fludarabine, and then also several doses of high-dose IL-2. So it’s not for the faint of heart. They have to be in pretty good shape to be a candidate for TIL therapy.

Melissa Johnson:
Maybe a question for all three of you, to what extent is lymphodepleting chemotherapy, a requisite. And to what extent is IL-2 to follow, not just for TIL, but cytokines, maybe to be a little bit more general. Do you guys have thoughts about that? Maybe Sylvia?

Sylvia Lee:
Yeah, I think, you know, just to back up a little bit, when you were talking about the impact of chemotherapy with immune checkpoint and how, you know, that sort of surprised us in lung cancer, that was such an effective combination, thinking about what chemotherapy does to the tumor microenvironment. One thing that happened like, so TIL predated the immune checkpoint inhibitors and when ipilimumab and nivolumab came out, one of the questions was, is this going to just replace TIL therapy? Is that just doing the same thing that TIL therapy does except in a much easier off-the-shelf way? And what we found in several trials now, you know, in melanoma and lung cancer, is that the answers is no, that TIL therapy can work in people who aren’t responding to the immune checkpoints. And the question is, why is TIL any different because you’re relying on the same endogenous T-cells? And I think one of the components is the lymphodepletion that makes it very different. You’re actually doing something that will help improve the tumor microenvironment in a way that you don’t do when you give someone nivolumab or pembrolizumab. And so I do think that’s a really important component and is, you know, one of the explanations for why TIL can work when the immune checkpoints don’t.

Melissa Johnson:
Yeah. Sandip?

Sandip Patel:
And I think on, on the back end, you know, once those cells enter that hostile tumor microenvironment, that you hopefully made less hostile with lymphodepleting chemotherapy. And I think debates around the dose of FluCy, for example, you know, it is not well established. There are also effects on the microbiome that happened with FluCy that may or may not potentiate a favorable immune microenvironment. And so host factors, I think we have to focus on, but I think on the back end, what to do for those cells, once they’re in that hostile tumor microenvironment, if they become exhausted, is it actually an immune checkpoint that we need? Is IL-2 the right cytokine right, because at high doses we actually stimulate regulatory T-cells as well. And so we’re kind of working against ourselves a bit. Could it be IL-15, IL-12 or, or some modification therein to kind of try to have our cake and eat it, to maximize a pro immune response, an anti-tumorigenic response from these cells we spent a lot of time and a lot of work creating to ensure that they don’t just enter the tumor microenvironment and become as anergic as endogenous T-cells. And so I think this is an area we need to understand a lot more about, because it’s not enough to find a cell therapy that hits the target. It has to be safe as we discussed earlier, but these have to persist. That’s the main reason we’re doing immune checkpoint blockade, as well as long-term cellular therapy approaches for those durable remissions we see in the hematologic malignancies.

Melissa Johnson:
Any other thoughts?

Prasad Adusumilli:
Yeah, no, I agree on what is said. I think as of today, what we know – lymphodepletion is important and how do we achieve it with the less toxicity is that’s something we are all focusing on the practice and beyond lymphodepletion, do we believe that one therapy or one dose is going to get rid of metastatic solid tumors? If it requires multiple doses, then what are we going to do with the lymphodepletion? Because every single lymphodepletion, not in addition to the addition of toxicity, we may be getting rid of some of the good functional memory cells. I think the next thing something we are already working on the lab is how can we avoid multiple times lymphodepletion? Just to keep them going with one lymphodepletion. And if we have to do, how can we make at least these cells resistant? I think that’s going to be more important as we think about the community practice and the, these metastatic tumor patients that were a single dose at this stage is not going to be sufficient.

Melissa Johnson:
Yeah, those are all really good points. Maybe as we wrap up, there’s been a few war analogies over our discussions, both in the, in the workshop and now. Sandip, you mentioned trench warfare with as a, as an analogy to some of these therapies, but I thought to myself, as you said that, but they use trench warfare in World War I. I’m like, you know, what’s the nuclear option here? So fast forward, based on what you’ve heard today and tell us what you think, what will we be doing for our lung cancer patients in five to ten years?

Sandip Patel:
Well, we don’t want the nuclear option for our cancer patients because that’s probably great like grade eight cytokine release syndrome. No, I think, you know, it really is about maximizing the opportunities for the patients. And so I think this is done in a couple ways. One is the safety of the underlying product. Two is the ability to find the right patient for that particular product. Do they have the target expressed on their tumor type? Are they the right HLA type? If it’s an HLA-restricted product. And then three is really, is it a single dose all at once, right? Is it multiple smaller doses? What’s the best back end support? What’s the best amount of chemotherapy? These are the aspects we really have to understand. And I think, you know, taking a step back, we’re talking about non-small cell lung cancer. We even for standard of care, pill-based therapies probably are missing about a third of patients with actionable mutations cause we’re not testing. And this can be done in two tubes of blood. And, so now as we’re moving to the next generation of more bespoke cellular immunotherapies, we not only have to look at those factors related to the tumor, but we may have to look at transcriptome, we may have to look at protein, which you actually can’t do in liquid. And you actually look at the host factors, are they the right HLA type for example. And so I think building in, as we get approved products in cellular therapeutics, building into our existing biomarker platforms, what we already have to do for EGFR and ALK and PD-L1 will be key because trying to find that needle in the haystack, by trying to guess which patient will never work out, we have to test everybody equally, appropriately as part of these platforms. And I think that’s how we identify the patients who can benefit from these very promising, but very toxic therapies. But the goal is the toxicity is worth the price in terms of that durable response, long term.

Melissa Johnson:
Great.

Prasad Adusumilli:
What we discussed in the room, the complexity of how are we going to analyze all these marker and select the right patient and personalize the treatment. I was about to say in an optimistic, philosophical approach, I think 60, 70 years ago, if a human being walked into this room and said, I’m going to take all four of your blood, I’m going to see which blood group you are. And I’m going to do the cross matching, see which blood group matches in the entire world every hospital, I’m going to put a fridge refrigerator, I’m going to put a blood bank and we are going to separate the cells, red cells, platelets and different types of cells, and we are going to decrease the mortality. I don’t know how many of us would’ve believed in it, but we are now in 2022. Can we do all this molecular markers, immune markers, tumor, immune microenvironment, develop an algorithm using all the computer advanced knowledge. And can we do this in a very short time in the period? I think we going to be there in five years.

Melissa Johnson:
I love that. I love that idea. Thank you for joining us. Talking about cellular therapies for the treatment of lung cancers and other tumors of the chest at the iwCAR T-cell workshop 2022.