Session I: Emerging CARs and future challenges in solid tumors

Julian Molina:

Hi, I’m Julian Molina, I’m an oncologist at the Mayo Clinic in Rochester, Minnesota. And we’re going to discuss two of the topics that were presented this morning. I’m here in the company of Dr. Matthew Angelos and Dr. Sebastian Kobold. And I’m going to first ask a question to Matthew. And my question has to do with you know, during your presentation you actually talk about the use of macrophages. And one of the issues that always comes to us is, is what is the potential to make this better? You know, what can you add to these macrophages to make them more effective? You mentioned the use of pembrolizumab and some of the immune checkpoint inhibitors, but what other options do we have available to make these therapies more effective?

Matthew Angelos:

Yeah, for sure. So the data that I presented this morning was in regards to our Phase I clinical trial that has utilized monotherapy of CAR macrophages for treating her two overexpressing solid tumors and so far in the data that we’ve reported, these patients have had a best response of stable disease. And the goal obviously is to try to push this a little bit forward so we can recapitulate what we see in the in vivo settings in the mouse models where we have really nice tumor responses and improvement in survival. So one of the thoughts that we could do is utilize some of these new immunotherapeutics and apply them in a combination approach with the cell therapy. And the point of doing this is that we can try to utilize these treatments to really rev up the tumor microenvironment and the goal is to try to activate the endogenous cells that are there like T cells, dendritic cells, NK cells and try to get them to function against the tumor so that they’re more cytotoxic. So one of the things we’re moving forward with in the next sub-study that we’re currently enrolling for is to utilize concurrent pembrolizumab treatment. This is an anti PD-1 therapy that certainly we have data for that suggests that it’s synergistic with the CAR macrophage technology. And I think this really opens the door for other types of immunotherapies to be used. Certainly trying anti-PD-L1 therapies is a certainly reasonable strategy as well and some of these other really exciting new molecules such as BiTE therapy as well I think could be very interesting and trying to combine this with some of our new cell technologies. And so we’ll see. We’ll have to see how it goes with our with our immunotherapy cohort. But I think it’s very exciting with the preliminary data that we’ve generated so far.

Julian Molina:

Very good. And this question is for Dr. Cobbold. You had a really nice presentation on the use of the x-axis to try to modulate this migratory engineering of these cells. Can you summarize your presentation? And the same question that I asked to Matthew is how can we make this better in the clinic? You know, how can we deliver something that is at least brings the promise for better results to our patients?

Sebastian Kobold:

Yeah, so, in a nutshell, so what I’ve tried to highlight some of the work we’ve done using this chemo receptor as a means of engineering of T-cells to make them better. We mainly use the CAR backbone because that’s obviously something that’s hot in the clinic that is broadly recognized and seen in across models that we can really enhance the efficacy of these cars and enable the efficacy in models with otherwise resistant. What we’ve shown as well is that you can utilize both chemokine receptors and in principle the anti-tumor role as a natural function of these receptors in immunity as opposed to those that would be pro-tumor. But we’ve also shown that you can use a pro-tumor or chemokine receptor axis actually recruiting immunosuppressive cells to actually make CARs better as well. So I think in terms of what can we do to make this better, I mean, so of course the first question stands because unlike Matt, we’re not as far yet as in Phase I clinical trial with that concept. So we’re working on that because we also we licensed this concept to carry in a biotech in Adelaide, Australia to move this towards a Phase I clinical trial. It’s a bit easier in Australia than it is in Germany, so that’s the rationale behind that. But we want to do that too. So what we’re doing is also we’re adding additional layers of engineering. That’s what we can do from the engineering side as it taking suppressive factors out of the cells. We have some very promising approaches here or taking something that would stimulate them even more or of course, then the other thing that stands to debate is just as you guys are doing, you know, combine this with approved drugs like checkpoint inhibitors, which certainly would also come with a certain rationale when it comes to combining CARs. Right. I mean, Prasad has already shown that for some of the CARs we’ve been using as well clinically.

Julian Molina:

So you see possible to engineer in addition to a car T cell changes to the T cell receptor to add this as part of the construct?

Sebastian Kobold:

So not part maybe not part of the construct itself, but either within the same genetic cassette or genetic vector or depending on what you do, right? I mean I mean you guys at Penn, I mean you’re doing also CRISPR engineering of T-cells. You had a Phase I trial. So it’s feasible. Right. And it seems to be safe also for the patient from that regard. So that’s certainly something that that we’re very keen on that we exploring and we have some very good because so you can do both. So you could really add something on or you could try to take to take something out and actually that’s from an engineering perspective it’s even better to take to combine something in and something out because it’s simply easier to manufacture just from technically but maybe not regulatory wise. That is not in Germany.

Julian Molina:

And if you want to take something out, what will be that something that you want to take out?

Sebastian Kobold:

I mean, I would say my favorite candidate right now, I can’t disclose it as we speak.

Julian Molina:

but it’s one of the cytokines.

Sebastian Kobold:

No, it isn’t. It’s a receptor which I don’t think is well known to this audience, but we’ll be reporting on that later this year.

Julian Molina:

Probably the last question is we’ve been debating about the differences between what’s going on in the primary tumor and what’s going on at the metastatic site. Do you think that this is going to be important for these macrophage derived based therapies or this is going to work the same no matter if you were talking about the primary tumor or the versus the metastatic site?

Matthew Angelos:

Yeah, that’s a very good question. You know, certainly I think the tumor microenvironments are different between the actual primary tumor itself and some of these other areas of metastatic disease. And partly it’s dependent on what organ these sites are located in. You know, I think we need some more study on those particular areas. You know, all of the patients that we enrolled in our study had metastatic disease. And you know, we look at target lesions. So that may or may not include the primary sites that may or may not include other areas of metastatic spread as well. And so it’s an interesting question moving forward, how do these micro environments really differ and is there a way to basically optimize these cells such that they’re much more effective in all of these different tumor compartments that may arise?

Julian Molina:

Yeah, something good that happens in solid tumor oncology that we usually take good care of the primary tumor and is the metastatic site the one that complicates the life of the patients later on, so I wondered if one should focus more or attention in what’s going on at the metastatic site because the primary tumor is usually removed or cured by radiation or some other therapies. You see the same thing happening, Sebastian?

Sebastian Kobold:

I mean, I totally agree. I mean, I think I mean and that’s a bit of the bias we’ve had at least in IO and especially in cell therapies. And I think it’s different when you use checkpoint inhibitors which were so successful so far because then you have just response everywhere as opposed to highly engineered CAR macrophages, CAR-T’s. But again, all those have been developed with typically, as you showed also today, one stop cute tumor or these things which is not reflecting the patients you want to treat. So in your trial either, right. I mean, these are advanced patients with metastatic disease which would kill them ultimately. And I think that’s something we should focus much more in the future. And I could imagine that if we manage to encompass that more into our strategies, that this perhaps might lead to better therapies or better cell therapies in the future.

Matthew Angelos:

And along that lines too, there’s this this concept of tumor heterogeneity. Right? And even in the case for HER2-targeting cell therapies, I mean HER2 can be a very heterogeneous target on these tumor cells. And so I think a better understanding of how this heterogeneity also plays into overall responses can be very informative moving forward.

Julian Molina:

Very good. Thank you, Matthew. Thank you, Sebastian. Thank you.

 

Session II: Genitourinary cancers

Vivek Narayan:

Great. So we’re here at the iwCART meeting in Scottsdale, Arizona, and my name is Vivek Narayan from the University of Pennsylvania. I’m joined by a colleagues, Saul Priceman from the City of Hope and Nicholas Zorko from the University of Minnesota. And we just had a nice panel discussion about the use of cell therapies in genitourinary malignancies. So we’re going to have a follow up discussion on that now. And maybe I’ll start with Nick if that’s okay. You know, you talked very nicely about the use of NK cell therapies in GU malignancies, including both prostate cancer and urothelial cancer. And you talked a lot about some of the potential advantages of using NK cell therapy. Could you perhaps speak to some of the challenges that we also face with using NK cells as a potential adoptive cell therapy approach, mainly in reference to some of the issues with potential persistence and manufacturing?

Nicholas Zorko:

Okay. Yeah, that’s a great question and I think those are questions that we’re actively investigating as well in the NK cell world. One of the questions is do we get good infiltration in particularly in bone for prostate cancer? We don’t know. We don’t have an answer to that question right now. And so we are while we’re very proud of our NK cells and we’re very interested in the safety sides of it, there’s a lot of unanswered questions. So it makes it a great spot to be in in terms of a researcher. But I think with the unknowns there could be a lot of barriers to that. Persistence is another thing as well with the engineering. You know, there are a lot of off-the-shelf NK products. They have shown that you can use allogeneic NK cell products even if they’re not induced pluripotent derived NKs. But there are differences with the engineering. What is going on with the engineering? Is there any neoantigens that are being introduced as well that may make those NK cells a better target for the immune system after there’s immune reconstitution.

Vivek Narayan:

And you talked about the TriKE product that is being evaluated and which, if I recall correctly, is incorporating expression of IL-15. Can you speak to maybe the biology of that and how IL-15 may also help some of the some of the challenges that we’re facing with NK cells?

Nicholas Zorko:

Yeah. So the TriKE is it’s a single molecule that has a CD16 engager IL-15 and then an antigen engager. We have numerous antigen engagers we’re working on right now. The one in particular that we’re interested for GU malignancies is B7-H3 and the goal of this is to stimulate the NK cell, so binding CD16, which is the strongest stimulator of NK function, but also providing a cytokine signal as well. And by providing that cytokine signal more specifically to the NK cells, we have seen previously that there is increased NK cell number and then also increased NK cell persistence. So that was in a CD33 targeting TriKE that we used for AML and mastocytosis but we believe that that same effect will happen for our solid tumor driven or our solid tumor geared TriKEs.

Vivek Narayan:

So I’ll ask you a question. Now I know you’ve spent many years thinking about T-cell therapy and cancers, including prostate cancer. Tell me what you think. Just maybe more of a general question. What are like if you had to pick the main challenges we face in prostate cancer as a disease with trying to use adoptive T cell therapy?

Saul Priceman:

Yeah, it’s a good question. I mean, it really spans the solid tumor field and not just prostate cancer, of course, but with the predominance of bone metastatic disease. And Nick brought this up but trafficking to bone is very different than trafficking to other sites, which is a major challenge for prostate cancer. But prostate cancer, much like a couple of other cancer types, is immunologically cold. There is really no inflammatory response promoting an antitumor effect in prostate cancer. And so how do we engineer T cells that that actually want to migrate to the tumor to have activity in the presence of this immunologically cold environment. So those challenges we face, we also at the moment are treating advanced stage disease, which we know is heterogeneous by nature, following a number of standard of care therapies that these patients see, including androgen receptor signaling inhibitors, which poses a major challenge of what target antigen to go after that selectively encompasses the prostate cancer enough to generate a therapeutic response.

Vivek Narayan:

And maybe just building on that a little bit, especially related to the immune microenvironment and some of the challenges in prostate cancer. I think one of the questions that always comes up is how do we best utilize things like lymphodepletion chemotherapy and solid tumors and specifically prostate cancer? And so you presented some really nice data about sort of evaluating what lymphodepletion chemotherapy is doing in the context of the immune microenvironment. So could you maybe just briefly summarize what your findings were. And then I guess how can we therapeutically target some of those changes that you observed?

Saul Priceman:

Yeah, so we evaluated the current landscape of lymphodepleting chemotherapy, which is really cyclophosphamide and fludarabine. The field really took what we learned in the hematologic malignancy space in in what would be required for T cells to find space once infused and get the homeostatic cytokines that would enable better activity of those infused products and took it to all of our solid tumors. And so we evaluated cyclophosphamide and what it was doing in addition to the lymphodepleting properties that clearly had a microenvironment effect in prostate tumors and rewired sort of the chemokine milieu and converted some of the myeloid macrophage populations that were suppressive to more pro-inflammatory which was of benefit to the CAR T cells clearly preclinically but I think the jury is out still what lymphodepleting chemotherapy will be required for solid tumors, including prostate cancer. And I think we’ve just sort of scratched the surface. There should really be a systematic attempt to understand what agent lymphodepleting or not would be beneficial in the context of solid tumor CAR T cell therapies. And we haven’t done that really to date.

Vivek Narayan:

And maybe Nick coming back to you, you know, Saul brought up the point of what is the what are the optimal target antigens for cell therapy. Certainly a number have been evaluated in solid tumors, including prostate cancer. You know, some of your work is looking at relatively novel antigens for cell therapy. So B7-H3, could you maybe speak to some of the advantages of B7-H3 and I guess some of the data about what its expression is in prostate cancer, especially across the disease and different phenotypes of the disease?

Nicholas Zorko:

Yeah. So I think it’s we believe it’s a great target here. It’s particularly elevated in prostate cancer itself even compared to normal prostate. And one of the other questions has been about toxicity. If we have a normal marker, you know, the equivalent of PD-1/PD-L1, something along that pathway, what other organs are going to have toxicity with that. It seems to be relatively low expressed at the protein level in most other normal tissues. There’s some elevation I believe in the testes and then in kupffer cells, macrophages in the liver, which I think it was macrogenics that had some liver toxicity that led to the CD3/B7-H3 engager to be closed on that. So there are some toxicity risks for it, but it seems to be relatively restricted to tumor relative to normal tissue. And I think even Eugene Shenderov recently published a paper with polatuzumab and there were there were few toxicities in that overall, so pointing towards B7-H3 being a great target I think.

Vivek Narayan:

Yeah. And if I could just maybe add a little bit on that. I know that there’s been some data that’s been presented about B7-H3 really being highly expressed across the landscape of prostate cancer clinical stages and appears to be associated with sort of AR-driven prostate cancer, which raises again I think some of the limitations we may think about with PSMA and other antigens about some of the more neuroendocrine variants of prostate cancer and what are the optimal targets to go after in that phenotype of the disease. But so certainly I think both of you are highlighting that there’s a lot of promise but still a lot of unanswered questions in cell therapy for GU cancers, including prostate cancer. So look forward to more discussion and more work from both of you. Thank you.

Nicholas Zorko:

Thanks, Vivek.

Saul Priceman:

Thank you.

 

Session III: CAR-T clinical advances in lung cancer

Prasad Adusumilli:

My name is Prasad Adusumilli. I’m a thoracic surgeon at Memorial Sloan-Kettering Cancer Center, New York, and I moderated a session today on lung cancer adaptive cell therapy. And I’m here with my colleagues. William Go from A2 Bio and Adam Schoenfeld, my colleague in thoracic medical oncology at from Memorial Sloan-Kettering Cancer Center. The session focused on adaptive cell therapy, different approaches and challenges and opportunities in solid tumors, most importantly, focused on lung cancer. So on that note, Will, your entire team has done a lot of advances in the set up to cell therapy and congratulations on getting the FDA IND approval. What have we learned from the existing clinical trials and how you design the new trial with your product?

William Go:

Yeah. Thank you, Prasad and thank you for being here. You know what I learned from my previous experience in CD19, we all sort of cheated in the CD19 because you can live without a B cell and can without live without a plasma cell, but you can’t live without linings of your GI tract and lung. And so one of the biggest things we learned is how to do and address tumor heterogeneity and tumor specificity. So therefore, we’re trying to do logic gates to kill the tumor but leave the normal one alone. But that’s what we learned there. And then the other thing we learned we’re talking in this session was patients need a lot of the novel therapies, whether it’s TIL, CAR, TCRs and logic gated CARs. So we need to really work to try to bring it to earlier lines where patients are not that needed and are still incurable, where they have better performance status and lower tumor burden.

Prasad Adusumilli:

Yeah. Thanks Will. I totally agree. I think it will be a hope and dream for us to bring these therapies to an earlier stage. On that note, Adam, it’s very impressive results that you are able to harvest the TILs from the lung cancer patients and the clinical trials are ongoing, moving on to the next phase. You talked about some of the modifications are advances that we can do to make it more practical. Can you briefly highlight those modifications?

Adam Schoenfeld:

Yeah. Thanks. Prasad and this was a great session. I really enjoyed talking with both of you about the different cell therapies in lung cancer that are that are coming to fruition now for TIL it’s a little bit different than CARs and TCRs, you have to extract a tumor lesion and then expand it, so you have a little bit different challenges. And then because you’re using the native TCR, you also need co-stimulation. And so we’ve typically done this exogenously with IL-2, high dose IL-2, and I think strategies in the future that will allow us to move away from high dose IL-2 to or lower the dose of how high dose IL-2 will be particularly important in lung cancer to lower the toxicity. I also think as we discussed moving this into earlier line settings when patients have haven’t received so many different lines of therapy and they’re frail and sick and really have a lot of comorbidities, I think that would be really helpful and advantageous for the field as well.

Prasad Adusumilli:

We also I think all three of us presented in the earlier sessions as well. Two important things is one is co-stimulated domains and the second is combination therapies. I presented on our new co-stimulatory domain that acts through interferon gamma signaling pathway unlike CD28 for giving an advantage of combining. Well, what are your thoughts on the co-stimulatory domains for adaptive cell therapy?

William Go:

Yeah, no, that’s a good point. I mean, I think some of the challenges that we’ve seen in adaptive cell therapy, one is that you get like tonic signaling T-cell exhaustion. How do we prevent that from happening? You get some also how do you then adapt it to then either have an on board cytokines or like some of these other types of TIL therapies as well to the CAR and TCR therapies. And it would be interesting because similar to IL-2 toxicity, there’s a lot of other cytokines coming now that are being given in single agent exogenously that are less. So I’ll be curious to see what you guys think about in addition to just the co-stimulation domain and everything else. I know you had some experience too and some of these other booster type strategies. What do you guys think about all these other cytokines coming and how that can be played into this TIL TCR CAR world?

Prasad Adusumilli:

Yeah, I think it’s going to be the safety window, right? What we are all on one hand we cannot compromise safety achieving the therapeutic efficacy and that’s probably we’ll find out in the clinical trial. But we did learn from the checkpoint blockade and that thanks to that knowledge we are able to quickly combine CAR-T cells and checkpoint blockade. And Adam, on that note, you talked about some of the trial results where patients received anti-PD-1 developed resistance or PD-L1 is low, still able to see some responses with TIL therapy. Can you highlight on that?

Adam Schoenfeld:

Sure. Yeah. So there are two trials that have looked at TIL therapy with PD-1 blockade in in lung cancer So far, there was one in patients who had received prior nivolumab and then at the time point of resistance they received TIL plus nivolumab. And that study showed in the PD-1 resistance setting a 25% response rate, including two complete responses. Additionally, there is a study that was recently just had a press release in the front line setting in patients that had not received prior checkpoint blockade and it was a combination of PD-1 blockade plus TIL and encouragingly again, the side effect profile seemed comparable to what we see with TIL monotherapy or PD-1 monotherapy. What you’d expect from combining the two as well as an increased response rate, a significantly increased response rate. Almost 50% of patients responded and that was irregardless of PD-L1 expression.

William Go:

One thing, if I may, is that for the naysayers because obviously we’re believers in this is that as a checkpoint blockade works in lung about a third and front line it’s now the front line plus chemo is pretty much the standard of care. One challenge, though, is that they’re responding with long tails on the kaplan-meier curve. However, you’re not seeing deep complete remissions or and even though you have long term survival, you’re still not curing a lot of folks. So this is where I think that when you can bring it up earlier lines and then actually try to then make the next generation TILs and CARs and TCRs, I think there’s going to be a lot of opportunity for all types of adeno and they’re going to have different challenges, especially when you start having all these different driver mutations as well. One thing that I wanted to ask you Prasad too is in your experience I’ve seen because when you’re having so much prior therapy of IO or other things, is there anything that you should be concerned about or in your experience at Memorial?

Prasad Adusumilli:

Yeah, definitely. I think the multiple lines of therapy obviously tumor is more immunosuppressive, more accumulation of macrophages and Tregs that not only results in loss of efficacy or lack of efficacy signal, but it can also cause macrophage activation syndrome or more cytokine release syndrome that toxicity need to be carefully interpreted in these patients. So, but having said that, how do we screen for that? I don’t think we are at that stage to be able to screen the patients for combination therapies. I think more and more what we have seen and what we are doing is carefully doing an academic setup with a multidisciplinary team. I think we all benefited a lot working with CD19 leukemia, lymphoma, myeloma oncologists. We learned a lot not to repeat the mistakes. I think the combination therapy same thing goes collaboration between the heme and solid tumor oncologists to learning from each other so that we can interpret better. Any thoughts?

Adam Schoenfeld:

Yeah. No. Well, I think that was a great point too that we don’t want to take away from the fabulous success that checkpoint blockade has had in lung cancer. But there have been these groups of lung cancer patients who have unfortunately been somewhat left behind. There are these biomarkers, PD-L1 expression patients who have negative PD-L1 expression or certain oncogene drivers tend not to respond to the immunotherapy and so I think those are particular patient populations where we have an unmet need where cell therapy can be really effective or where we could really employ it on at an earlier time point. Additionally, I totally agree. As we move into this next generation of cell therapy, we really need to learn from the prior experience from our hematology colleagues and then also from our experience in solid tumors with checkpoint blockade. I think for TIL it will get quite confusing when we start engineering these products because we typically didn’t see CRS or ICANN’s with the unmodified product. But once we start adding co-stimulatory domains, we’re not only going to see potentially toxicity from the IL-2 but also potentially CRS. And I can so I think that’s going to be a whole new spectrum of toxicity that we’re going to have to learn about.

Prasad Adusumilli:

Yeah, we’ll have a lot of experience in the biotech with what’s happening in the Wall Street and economy. Do you think our motto should be survival or excellence?

William Go:

Excellence, Always excellence, Prasad. I think the biggest thing to realize is that the amount of biotech and financing in terms of big pharma, small biotech in academia, I always believe, you know, I came from UC San Diego, My parents were in academia at Mayo and UCLA. The reality is that it takes a village and what is great in academic labs with innovation and biotech that’s really trying to take innovation forward and with our large pharma biotech colleagues who can then actually make it to scale. Because one thing that I’ve learned in my experience is that if you can’t make it reliably, can’t deliver it reliably and can get it to patients and a reasonable time, it gets really challenging to make it real for the real world. I mean, it’s great for the patients at Memorial, but it’s going to be harder if you want to go to like upstate New York and outside and especially in other parts of America where it’s hard to get. So that’s where I think that it’s going to take all modalities to really it’s not going to be one winner. We just all want to try to cure cancer together.

Prasad Adusumilli:

All right. I think we’re going to end on that note.

 

Session IV: Logistics & manufacturing

Sarah Nikiforow:

So I’m Sarah Nikiforow from Dana-Farber Cancer Center in Boston.

David Maloney:

And I’m Dr. David Maloney from the Fred Hutchinson Cancer Center in Seattle.

Sarah Nikiforow:

And we have had the honor to be the co-chairs for today’s solid tumor portion of the iwCAR-T meeting here in Scottsdale. And we just finished the session on logistics and manufacturing and some of the regulatory environment around and it sort of wrapped up the first half of the day after some amazing biology and review of clinical data And myself and Dr. Julian Molina had spoken about some of the challenges involved, not with necessarily the biology but the logistical implementation. So what were your thoughts on what Dr. Molina shared?

David Maloney:

I think that what we’re recognizing is in the solid cancers, there’s a lot more screening and patient identification that is needed than in the heme malignancies. If you’re looking at a patient with lymphoma, then the chances of them having CD19 is like 99% and it’s a standard approved assay. But you’re looking now as we’re trying to nitpick solid cancers like lung cancer, you have to have the right HLA type, you have to have the right antigen expression. And so the logistics of doing this turned out to be quite challenging. And the experience from the Mayo is that by investing some money into screening and to nurses, they could actually increase their failure or decrease their failure rate markedly to where they’re getting real data from these patients. And I think that that was the take home that I got is think about this you know, expand your local usage maybe expand your team to be able to do that.

Sarah Nikiforow:

Yeah. And then I thought Dr. Molina had excellent points that none of us would have thought of a priori. And so I spoke also about our experience, which I think was mirrored by some of the questions from the audience as an experience that other centers have shared, which is that as we get into the solid tumor space, the patients are different, the route of administration is different, these cell product types and toxicities you might expect are different. And so there’s a ton of education and reorientation of both your research on infrastructure and who’s involved that has to be taken into account. And then I spoke briefly about the ripple effects which are that as we expand out into solid tumors, the various groups that we had relied on in heme malignancy cell therapy are having to pivot in terms of accreditation by agencies like Fact, the Foundation for the Accreditation for Cellular Therapy and the National Marrow Donor Program and then other groups like the FDA. Right? In terms of how are we going to be able to do this safely? And I brought up the example of community cancer centers and non-fact accredited centers that may get involved, that bring up other educational and infrastructure needs. And then from my homebase as a cell manufacturing professional, is it only the companies who can manufacture these cells or how do we bring academic and local manufacturing into play? And I think that many people agreed these were a challenge to consider for the future. I’m not sure if we had an answer. What was your sense?

David Maloney:

I didn’t yeah, I don’t think people had the answer. But you really did highlight some of the issues. And I think when all of the programs that we’re doing cellular therapy were transplant based programs, which is where we all started and we have extensive cellular based programs in the setting of a transplant program, how do you now do this in cellular immunotherapy and GI malignancy or lung cancer where we just where the peers and the people with the disease expertise have no concept of all the things we’ve been learning in the last ten years. At our institution, we still think that that’s vital to do that within the cellular immunotherapy group because that’s where the expertise of management of CRS and potentially neurotoxicity and what you would expect from cellular therapy can be done. But you know, it may be that that we can use more focus groups and I think that’s what you were pointing out as well that there might be for people who are just harvesting TIL cells, they don’t have to have the whole factory accreditation for every module. They just they just couldn’t pare down to do the part that they’re really doing. I think that was great. I was very impressed that you guys are doing multicenter manufacturing from an academic institution and we’ve it’s something we’ve looked at and we haven’t quite taken the plunge. I think there’s a lot of issues And you identified some of the issues, the cost reimbursement, how the cellular therapy is tremendously expensive. And even if you even if you don’t have to pay for all of the care the patient. It’s still expensive to make a product. And so I think working on ways to potentially get cost reimbursement. But even then, how do you make that into something a viable treatment option for your patients? It was a great, great session, I thought. And we touched on a lot of different areas and it really capped off the morning’s session and I think we’re really excited.

Sarah Nikiforow:

And one of the things is most of the participants at iwCAR-T are from academic centers, but we also have commercial sponsors here and the FDA. And I think that that last session highlighted how we all need to work together to, for any of us. to succeed. So I’m really excited actually to hear the keynote address from Dr. Doss from the FDA and see how that will impact our thinking going forward.

David Maloney:

A great start to the meeting.

 

Session V: Gastrointestinal cancers

J. Randy Hecht:

My name is Randy Hecht. I lead the GI Oncology program at UCLA and I’m happy to be here at iwCAR-T. And we have two distinguished guests with us, Dr. Xianxin Hua who is from Penn and Dr. Diane Simeone, who is at NYU. And we’ve just finished a really nice session on GI Oncology and CAR-T. And in particular Dr. Wah presented a very interesting actually data set based on a novel CAR-T that he’s been involved with really from identification of the target all the way to developing the car. Would you like to give us some information about this?

Xianxin Hua:

Yeah. So we started to identify some GI cancer specific target, a tumor associated antigen and also antibody special nanobody. So for that reason we just screen the antibody which specifically binds these types of tumor and without knowing what it would bind, then with these antibody isolated, we further identify its target that turned out to be CD17 which is a greater tumor associated antigen.

J. Randy Hecht:

You know one of the things from your talk, if you could just talk for a minute about nanobodies in general because not everyone might be familiar with that. It’s a really kind of a neat concept.

Xianxin Hua:

Sure. So Nanobody, unlike a regular antibody like human body has, it’s only have a single domain called a single domain antibody. And the advantage for these is it can directly redirect a CAR-T cell to a tumor with a single domain without like the regular antibody you have the variable region heavy region and you don’t know which one works better. Some may never work a at all.

J. Randy Hecht:

And the antibody is developed how?

Xianxin Hua:

So an antibody is usually expressed from like a camellia family of animals.

J. Randy Hecht

Like llamas?

Xianxin Hua:

Yeah, exactly.

J. Randy Hecht:

And sowhich is which is neat that we’re able to leverage that. And so do you want to say some more just about some of your preclinical data with particularly what looks interesting with CDH17?

Xianxin Hua:

Yeah. So I think one key thing is that these CDH17 not antibody can direct the cell to GI cancer to eradicate the cancer in multiple model clinical preclinical studies. And a key role is that not only eradicate tumor and also it does not cure the normal cell which may happen to express these protein.

J. Randy Hecht:

I think those are two really important things. So one is that CAR-Ts have really been the reason that we’re here is because they have not really we’re on the cusp, we have not really been developed in GI cancers, even though they’ve been incredibly successful in hematologic cancers. And the other thing that’s really important is finding these targets because really over the last decade or so, attempts to use CAR-T’s and other cellular therapies and GI cancers really have been fraught with severe toxicity on-target off-tumor. And the fact that you haven’t seen that so far is good. And so what would you say are the next steps then the development? I know you have a partner, right?

Xianxin Hua:

Yeah. So you summarized that very well. And so going forward, the this technology has been licensed to American therapeutics and which are already assembled very impressive team to get all the procedures established and moving forward for clinical trial.

J. Randy Hecht:

And where are you for getting into first in human?

Xianxin Hua:

where these are I think in the detail. As I mentioned, it’s a Dr. Jason Deaton is in the meeting. He’ll get to it. But in brief we we’re getting started at the University of Pennsylvania and enroll patients there.

J. Randy Hecht:

Which of course has one of the greatest experience with cellular therapies. The one last thing and then I’m going to ask Dr. Simeone. But and you actually, I assume also work with neuroendocrine tumors. And so not only were these as do I. So not only does this look like an interesting target in the currently the second and third most common cause of cancer death in was it pancreas and colon? I think you had also seen, as well as that as well as upper GI, but also one that’s often forgotten which are endocrine tumors which there have been some improvements in outcomes, but and they tend to do much better than patients like with pancreatic ductal adenocarcinoma that that Dr. Simonoe knows so well. But there’s really not that much especially from a cellular therapy standpoint looking at this ah, I may not be where you want to go first. Are you thinking about looking at new endocrine tumors at any point in the future?

Xianxin Hua:

Yes. So that’s in fact the now the tentative plan is to target both neuroendocrine tumor and also other GI cancer because CDH17 is abrogated in most of GI cancers like gastric cancer and colorectal cancer as well as over 95% of GI neuroendocrine tumor. So basically you can cover.

J. Randy Hecht:

Is there a difference between like grade one and grade two as opposed to grade three neuroendocrine tumors and particularly poorly differentiated grade three neuroendocrine tumors are really almost a different disease. They’re like small cell and they’re really bad. Luckily, they’re pretty rare while grade one and grade two and grade three well differentiated are not common but a lot more common and people tend to do well. Is there a difference by grade?

Xianxin Hua:

Yeah, that’s a very good point. In fact, in the GI NET so grade one, grade two express more of these antigen CDH17 and in high in a very high grade. So as you said, almost like a loss the net phenotype, so usually fewer tumor express CDH17.

J. Randy Hecht:

Have you seen one other one last thing is that have you seen much in the way of, you know, on-target toxicity? Because not only do you think about the usual things which would be the GI tract, but also you do need your neuroendocrine cells in your pancreas, for example, to make insulin. You know, we certainly with immune checkpoint inhibitors, we do get diabetes, autoimmune diabetes. Have you seen any when you’re in your animal models, have you seen any effects on normal neuroendocrine tumors?

Xianxin Hua:

Yeah, that’s a very good point. In fact. So CDH17 is a very good tumor associated antigen for NETs insulin secreting beta cell so it’s not expressed its zero so only gain of the dysregulated during the mutation or tumorigenesis CDH17 is upregulated in the islet tumor islet cell. So it’s actually the ideal target as the data so far show.

J. Randy Hecht:

So let’s go from a relatively uncommon tumor whose ribbon actually has zebra stripes on it to which will soon be the second most common cause of cancer or death in the United States, which is pancreatic ductal adenocarcinoma. Dr. Simeone, you want to talk about really your wonderful program that you’ve set up nationally to try to look at this both at NYU where you are, but also trying to get patients into novel studies.

Diane Simeone:

Sure. So one thing that has struck me over the years working in this field is that there was a there were a lot of studies that were being done at individual centers, single arm phase two studies and maybe the straw that we’ve all been there. Straw that broke the camel’s back was when everyone was excited about anti PD-1 therapy and I think there were 6 or 7 different single arm phase two studies done all at institutions at the same time, all negative, no real communication. And it just got me thinking that I think we can do better as a field if we set up a platform that can allow us to work more effectively together. So with that and in partnership with a large nonprofit called PanCAN, we set up an adaptive Phase II/III platform trial which has a lot of economies of function that make it much more favorable to test new therapeutics. One is all the experimental therapies can use a common control arm for standard of care therapy. So that in and of itself saves a lot of patients from having to get standard of care therapy instead of an exciting therapeutic to the trial has a seamless Phase II/III design. So if you test a new therapeutic in the Phase II setting and it’s effective, you don’t have to pause, you just keep going. And it only it takes another 75 patients. So with a total of 175 patients, you can go from the start of a Phase II to FDA registration ready data set, which really can probably save half of the time and half of the cost of a clinical trial.

J. Randy Hecht:

And certainly our patients need it sooner rather than later. Two other things. You also presented some really wonderful translational data which I know is more from your institution. Is there an interaction between which is not just for like signal transduction inhibitors and other immune therapies but also perhaps one day for cellular therapies? Is that also part of the national trial as well or is that really more site from a different sites?

Diane Simeone:

What I presented today was our own programs analysis at looking at pancreatic tissue samples and with single cell analysis to try to discern the immune landscape of pancreatic cancer as it exists both in the primary and metastatic setting as it exists in response to chemotherapy, but also to be positioned to look how it might change in response to any variety of clinical trial regimens. In fact, we have just completed a Phase IB clinical trial in partnership with NYU and Dana-Farber where it was actually very effective in showing us a readout that match responding patients to a combination immunotherapy based regimen as we go into the CAR-T era with pancreatic cancer. I think it sets us up well to understand the effect of CAR-T, to be able to ideally visualize the CAR-T and pancreatic tissues. It’s always been thought that you can’t penetrate into the shield of pancreatic cancer because of its dense stroma. I don’t know if that’s completely true. We definitely see patients that do have responses to therapy. I would I think that tells us that perhaps that dense stroma is maybe more plastic than we think and can react to therapies.

J. Randy Hecht:

Precision promise is sort off and that’s a huge that really is something that’s wonderful from a national standpoint. But you’re also taking part in CAR-T trials as well. And in fact, you’re getting ready, you know, to sort of embark on this. Do you want to tell us a little bit about the car t trial that you’re involved in?

Diane Simeone:

Sure. So CAR-T therapy always seemed a far distance away for pancreatic cancer. But actually a colleague will go who has a broad experience in the CAR-T field reached out to me with a new approach with a company called A2 Biotherapeutics and here it is based on the concept of using a tumor targeting antigen but also there’s a blocker that’s built to try to augment on target effect and mitigate off target effect. And conceptually the study design looked very promising. So we’ve been screening patients for this trial as is your center.

J. Randy Hecht:

We’ve been screening about the same number, but you’ve been more fortunate.

Diane Simeone:

And so yes, but we have identified now two pancreatic cancer patients that have the correct phenotype in their tumor and have undergone leukopoiesis. And one patient is actually will be ready to go as soon as the cells are ready, which will be in about 3 or 4 weeks. So that’s going to be a very –

J. Randy Hecht:

– we’re all really excited about this. And so a lot of this is actually a fairly large trial not just at UCLA and NYU, but multiple large centers across the country. And you know, one of the questions is that can we kind of crack the hard nut of these difficult cancers, particularly pancreatic cancer, as we used to say, pancreatic cancer is low hanging fruit. It’s just really well attached. And so, you know, we’re hopeful that one of your one of the ways that you’re looking at this will help our patients. I know we’re really excited. And I’ve been looking for our pancreatic cancer patients and colorectal and lung cancer patients as well who are involved in the trial.

Diane Simeone:

Yeah. So I think it’s a well-designed trial. It’s a very collaborative trial and it brings us to this meeting people like you or me that are not CAR-T therapy experts but experts in the diseases we take care of. So I think this is a great platform for interdisciplinary collaboration.

J. Randy Hecht:

Well, we know what doesn’t work and I think you actually brought up some of this in throwing immunotherapy spaghetti against the wall without really understanding the biology. We know, at least in these difficult cancers has not worked. I think some of the things that, for example, that doctor has done, you’re going from the other way looking at the molecule and hopefully this will also be helpful. Don’t worry, there’s a lot of room for a lot of these targets and for CAR-T, whether it’s, for example, the Everest trial, which is starting with CEA and these ethylene or whether it’s CDH17 or actually the really exciting data with claudin 18.2, though I am concerned with that about the short duration of response. And there’s but first you’ve got to get responses and it’s nice that we’re getting responses, so we look forward to your data and obviously also the average trials as well. Yeah. 

 

Session VI: Head/neck and CNS cancers

Kedar Kirtane:

My name is Kedar Kirtane, I’m an assistant professor at Moffitt Cancer Center in the Department of Head and Neck and Endocrine Oncology. I’m also the medical director for solid tumor cell therapy at Moffitt. And I was going to allow my colleagues to introduce themselves.

Jong Chul Park:

My name is Jong Park. I’m a medical oncologist at Massachusetts General Hospital in Boston, I treat head and neck cancer.

Rizwan Romee:

And I’m Rizwan Romee at Dana-Farber Cancer Institute in Boston. I’m primarily a lab based physician scientist. I also see patients with leukemias and undergoing stem cell transplantation but my lab works on developing a novel natural killer cell based CARs, including for solid tumors, which includes head and neck cancer as well.

Kedar Kirtane:

So Dr. Park, you gave a nice talk about the vast array of potential options, both combination therapies and new options for head neck cancers that are on the horizon. Can you maybe pick 2 or 3 of them that you think are most promising?

Jong Chul Park:

Yes. So as I mentioned, since 2016 when we have pembrolizumab and nivolumab, no new therapeutics approved for head and neck cancer. But as I mentioned, a number of novel therapeutics are being tested in head and neck cancer, mostly in combination with pembrolizumab. But so far, the single agent activity or the activity in antiPD -1 refractory populations being quite modest. So there’s a huge unmet need in head and neck cancer where we have more robust therapeutic agents. That’s why this iwCAR-T symposium is so interesting. A lot of cell-based therapies are being tested, including head and neck cancer. So I’m looking forward to more development in cell based therapy in head and neck cancer.

Kedar Kirtane:

And Dr. Romee, you obviously work on N cells very nicely and I asked you outside the room, but why did you choose head neck cancers for your trial?

Rizwan Romee:

It’s a great question. As a matter of fact, if you were to take all solid cancers in humans, actually it turns out head and neck has one of the highest NK cell infiltrative phenotypes, meaning patients with cancer tend to have more NK cells in the tumor setting than other solid tumors. We don’t fully understand why that’s the case, although it’s possible that there are some of the chemokines and some of the other tumor milieu elements which are attracting NK cells in more head and neck cancer than other cancers. So that was one of the reasons. And then also when we started this clinical trial with Dr. Glenn Hannahs, who is one of the oncologists at Dana-Farber with his collaboration, we both felt that we had enough data from ongoing AML trials, which we had published at the time, that there was minimal concern for safety of using this approach. So and then also we had tested long acting IL-15 separately in other clinical trials. So with that information we decided not only will put the NK cells, these memory like NK cells in patients head and cancer, but we’ll on top of that we’ll add the long acting IL-15 as well as one of the checkpoint inhibitors to make them really supercharged, if you will, to fight cancer cells.

Kedar Kirtane:

Why? What are the potential advantages and disadvantages of using CAR-NK cells versus CAR-T cells, which is traditionally what has been used in a lot of these cell therapy studies?

Rizwan Romee:

Yeah, no, that’s not a great question. In the last 10-15 years there’s been a really a revolution of cell based therapies and primarily led by CAR-T cells, which is pretty amazing that have rapidly advanced the field. However, over the last several years now we have learned that there are some major disadvantages of using T-cell based CAR-T cells, including side effects, some of the side effects, for example, cytokine release syndrome and cytokine release syndrome can be pretty severe in some of the patients. And then also there’s more interest in going allogeneic route where we are taking NK cells or other cell based therapies from other donors. And if you are using CAR-T cells with allogenic route, then you are at risk for developing another complication called graft versus host disease which is not mediated by NK-cells so that risk is not there. And then lastly, oftentimes tumor cells that applies to a wide variety of tumors down regulate or lose class one expression that helps them escape from T cells. But NK cells are wired in such a way that when any cell decreases the expression of class one molecule that triggers their response. So at baseline you have that advantage that when the tumor cells are trying to escape the T cells, that same mechanism will make them more responsive to cell. So keeping all of those things in mind, I think NK cells have several advantages. Now I don’t claim that NK cells are going to be the winner or T cells are going to be. I think what needs to happen in future is that we need to develop therapies which actually combine on purpose elements of different key cell types. Now you don’t have to put all cell types together, but you can make T cells create stuff or cytokines or chemokines which attract NK cells and vice versa. And then so this crosstalk needs to happen between different cell types in the body. I think that’s where the immunotherapy is going to shine long term.

Kedar Kirtane:

Dr. Park, leave a comment. Yeah.

Jong Chul Park:

Related to that, I think you did a really nice job over viewing the advantages and disadvantages in NK cells and how to overcome this in cell based therapy disadvantages, which is short life, half-life. And so far as you mentioned, the NK cell based therapy has been somewhat disappointing. So in head and neck cancer patients who are very immune suppressive phenotype, do you I’d like to hear your opinion about potential combination to enhance the NK cell efficacy such as an immune checkpoint, some other cytokines.

Rizwan Romee:

And no, this is an excellent question and very critical to help advance the field. So first of all, I think one of the major reasons why NK cells have not been as successful before is because of the fact, as you mentioned, and NK cells, conventional and regular and NK cell in our in our body have a half-life of 10-12 days. So they are quickly gone. So in order for any cell type immune cell type to have sustained activity, they need to be present for more than a few days. And that’s where the phenotype which I described in my talk, the memory like NK cells because in mouse models we have shown that they can last 90 days and now we have some data in patients they can last up to eight months at least in some, but most of the patients at least 60 to 90 days, which makes it quite makes them quite attractive for immunotherapies. Now the other thing you asked, can you combine or can you develop novel checkpoints to further enhance their function? As a matter of fact, some of the checkpoints which are in clinic primarily target NKG2A or you know, like molecules which are expressed as negative regulators for NK cells. So as you mentioned in your talk actually is showing some clinical activity. And part of the reason it seems to work is because NKG2A is highly expressed on activated and NK cells in the tumor microenvironment And then of course there are subsets of T cells which can also have CD8 T-cells which can have NK2 expression. Similarly you mentioned TIGIT and some other novel checkpoints in the development. Many of those molecules potentially will activate and enhance and NK cell-based therapies because at baseline and in activated state some of them are highly expressed on NK cells.

Kedar Kirtane:

I think the difficulty for any of these cell therapies is going to be overcoming the issues of T-cell trafficking, tumor microenvironment, immunosuppressive microenvironment and then target antigen heterogeneity. So in some respects tumor infiltrating lymphocytes can maybe overcome some of those obstacles, although I know the data has been mixed. How do you feel, Dr. Brock Maybe you can answer. How do you feel these TIL products compare to other cell therapies?

Jong Chul Park:

You show the data, so in the end the data speaks. So I mean, compared to other cell therapy, I think a tale so far has been quite promising. Data again, same problems trafficking, hostile microenvironment. So all your talk not just using TIL but engineered TIL, so another way to overcome that challenges. So maybe that’s one way to address those challenges.

Kedar Kirtane:

We think the future is bright. Obviously it’s still very early for head and neck cancers, but it’s nice to see all of you all working on this sort of work. So I’m hopeful for the next few years.

Rizwan Romee:

Likewise, I think the future is bright and I’m super excited to be in the field at the right time. It’s only going to get bigger and bigger. You know, there’s so much research happening in all the directions. Both in solid tumors and liquid tumors. And my hunch is that in next 5 to 10 years, you will see several types of cellular therapies shine quite brightly in different types of tumors. I certainly hope so.