COMMENTARY

Is Cell-Based Immunotherapy Entering the Mainstream?

Stefan Zimmermann, MD; Fiona Thistlethwaite, MB, BChir, PhD; John B. Haanen, MD, PhD

Disclosures

January 30, 2019

Stefan Zimmermann, MD: Welcome to Medscape Oncology Insights, coming to you from the 2018 Congress of the European Society for Medical Oncology (ESMO). Today we'll try to answer this question: Is cell-based immunotherapy becoming mainstream? Joining me in this discussion is Dr Fiona Thistlethwaite, a medical oncology consultant within the experimental cancer medicine's team and cell therapy team leader at the Christie NHS Foundation Trust at the University of Manchester, in England, and Dr John Haanen, chief scientific officer of immunotherapy and staff scientist in the division of immunology at the Netherlands Cancer Institute in Amsterdam. Thank you very much for joining us.

We are at the ESMO 2018 annual meeting, and again, this year the presidential sessions highlight news about immune checkpoint inhibitors in previously uncharted disease settings or in new diseases that were previously considered a bit off the chart for immune checkpoint inhibitors. Their use is now so pervasive that we have been forgetting a bit about cell-based therapy, which has become the poor cousin, so to speak—developed and studied in academic research centers but not applied to the wide pool of patients. Nevertheless, we are seeing news coming out with these cell-based products: more data in melanoma and in solid tumors, for tumor-infiltrating lymphocytes (TIL), genetically modified T-cell receptors (TCRs), and chimeric antigen receptor (CAR) T cells. Do you think we will be treating our patients more broadly with these medicines in the future?

Fiona C. Thistlethwaite, MB, MChir, PhD: Yes, I believe that is entirely true. We've heard exciting data in the hematologic and lymphoma setting, and these drugs are now becoming more widely available and being adopted in clinical practice as a standard of care. In the future, I hope we'll be able to provide more disease settings for these exciting new drugs.

Zimmermann: You were referring primarily to CD90-positive hematologic malignancies for the CAR T cells, and we have regulatory approval for two products now. TILs and TCRs are lagging a bit behind. We do see pharma interest in these two, even if they're not off-the-shelf products yet. But we have Iovance Biotherapeutics on a registration path with their products, and we see companies such as Adaptimmune, which is transitioning its TCR product to a bigger pharma. So we see a real push. Will these therapies be mainstream in the next few years?

John B. Haanen, MD, PhD: I think it's still too early to say whether, for solid cancers, these products will have the same effect as we have seen in the hematologic malignancies. We are still struggling with finding the right antigens, especially for CARs and also for the TCRs in solid tumors. That is still quite complicated. For example, look at the NY-ESO specific TCR, which has already been used in several trials. In multiple myeloma, in synovial sarcoma, and melanoma, you clearly see some activity, and so far the toxicity seems to be quite manageable. That was not something we have seen in the CAR T field when that just started. So there is activity; the durability of the responses is still not completely clear. But yes, clearly the field is moving in this direction. Also for TIL. As you mentioned, Iovance is conducting some interesting trials in that space in melanoma. A lot of work is going on, but still none of these has been approved for one of these indications. I believe the field is now very much interested in what we call neoantigen-specific TCRs or TILs. But this is very early days. Whether these will work as well as we hope they will work is still a question.

Thistlethwaite: For the first time we're seeing big pharma becoming interested in these products, and that will bring a kind of sea change for us as clinicians, being able to develop these in the clinic. Going from small, investigator-led trials that are ever increasingly expensive and difficult to run, the big pharma interest gives us an opportunity to scale up the activity in this field. And it's only through scaling up activity that we'll be able to get the patient numbers through, to decide whether these are actually viable treatments in terms of cost-effectiveness as well as seeing a signal of benefit.

Zimmermann: I totally agree. Do you see a big push in moving away from autologous products to allogeneic products?

Thistlethwaite: This is an interesting concept because it takes away the individualized treatment for one patient, which adds a lot to the expense and complexity. I think it's too early to know whether there is going to be any additional toxicity with these agents and how applicable they are. Although at times they are very attractive, you still need to think about concepts, such as the donor donating the cells and whether there is interdonor variability. So a lot of preclinical work still needs to be done to understand how best to deliver allogeneic cells, as well as understanding the toxicity profile.

Haanen: I agree. The company Allogene is focusing on trying to generate allogeneic T cells for many patients. The concept is very interesting, but how would it work? How long will the cell persist? Will we get differences between donors? What do you have to knock out in the allogeneic cells in order to for them to persist long-term? We are still struggling with these questions.

Zimmermann: For TILs, we do get the feeling that there is kind of a restricted "playground" where, due to the process itself, you actually need tumors to be infiltrated by T cells. And so the indications that are explored now are either HPV-infected tumors, for example, or tumors with high mutational burden, such as melanoma or lung cancer, and squamous head and neck cancer. What are the strategies that will enable us to expand the utility of that kind of approach to other tumors that are not so inflamed?

Haanen: That's a good question and probably also not so easy to answer with the data we have right now. In tumor types where immune checkpoint inhibitors are really active, making use of TIL is probably the best space to start. For the tumor types that are what we call the immune desert [phenotype]—that don't have a lot of T cells that are specific and do not respond to a checkpoint inhibition—maybe the T-cell gene-modified cells are more interesting, because then you can say that there are no T cells in there but we know what the target is, so we'll just go in that direction.

I think you're right. TIL probably will be tested—and I hope on a larger scale than is being done right now—in those disease settings where checkpoint inhibition is working. I think it will be very interesting to use TIL especially in those patients who have failed or progressed after immune checkpoint inhibition. We know that TIL was active still in those patient populations, and for many of these patients we don't have great options right now. So there is still a lot of room for other treatments—such as TIL, but there are also others—to gain momentum.

Thistlethwaite: And also, in the disease groups where we know that checkpoint inhibitors are active, where is the space for TIL? I think [the space for TIL] is in that group of patients who have progressed following checkpoint inhibitors. And then, of course, the question is whether we can increase activity by giving something in addition to checkpoint inhibitors, by combining them, which is a very interesting prospect.

Zimmermann: One of the obvious limitations is that the cells need to be able to traffic to the tumor, to overcome this hostile microenvironment with the immunosuppressive cells and also the metabolic stresses. How is this hampering development of CAR T cells in solid tumor indications?

Thistlethwaite: We know that CAR T cells can traffic to the tumor despite all of those challenges. But as we become more sophisticated with our engineering, we can see opportunities there. With the conditioning regimes, we touched on using checkpoint inhibitors, but there are other drugs that could potentially be combined. Of course, every time you add another drug to affect the tumor microenvironment, you are potentiating toxicities. We need to understand more about the biology of cancer before we can actually give these drugs in combination.

But as the engineering progresses, for example, using armored CAR T cells where we force the cytokine signal through engineering, there are opportunities there, and I think that's what we have to look for.

Zimmermann: In terms of very personalized cell-based therapies, individual neoantigen-directed TCRs, how do you think this will affect the response rates, where we get a kind of plateau at this time, probably because we have no great control over what we give in the infusion bag?

Haanen: For TIL, we do not [have much control over that]. We know that it's probably a mixture of, let's say, shared antigen-specific T cells, completely irrelevant T cells, and neoantigen-specific T cells in that product. We know that's the case. Filtering out those cells that really matter to the patient would be a great addition at the moment. If you were able to do that, really select the cells that matter, perhaps you could give fewer cells, perhaps less extensively cultured cells, and improve the activity of the product.

These are things we think about.

And finding the TCRs that are important—the neoantigens or some other antigen-specific TCRs—and using those for cell therapy is still far-fetched, but I think we are going in that direction slowly and the technologies are allowing us to do that.

Thistlethwaite: One of the keys there is being able to procure the tissues at an early stage of someone's disease so that we can hold their disease down, perhaps with other treatments in the meantime, and then we might manufacture a really active product.

Having said that, as we move toward more focused TCRs, for example, there is something to be said for a polyclonal response. If you are [targeting] a single antigen, there is always a danger that there will be an [antigen-negative] clone that outgrows the antigen-positive cells, because there will be selection for that.

Haanen: We see that in the CAR field.

Thistlethwaite: I think there's a balance to be had, and it involves understanding the biology so that we can determine the right approach. If that's for an individual patient, I'm sure the cost will be eye-watering, but as the technology develops, the financial cost can be brought down.

Zimmermann: If this cracks the glass ceiling, that may be worth it. There must be a sweet spot between very, very focused specificity, or a high percentage of the specific and effective cells, and this polyclonality that you need to overcome the heterogeneity.

Haanen: Yes. And we don't know. An interesting thing that's coming from the TIL field is that if you look at the number of specific TCRs that you can find, that are neoantigen-specific within TIL, there are only a few. So that tells you perhaps that you don't need so many TCRs; you don't need hundreds of different TCRs—maybe only three or four are enough. I think that is really helping us to get there.

Zimmermann: This will actually drive studies where you preferentially expand the few to try to better identify those that are really necessary. [Let's move on to] CAR T cells in solid tumors. We know myeloma will probably be next. And then what are your expectations?

Thistlethwaite: It's hard to say. I think for solid tumors, we're struggling with the toxicity that we see—on-target but off-tumor toxicity. That's a case where we need to find the right antigen, and whether that's actually looking more toward TIL therapy or TCR therapy, in the future, that may be the case. We will wait and see.

Zimmermann: There are other types of cells that we haven't talked about, such as natural killer (NK) cells or dendritic cells; through different mechanisms, these are also very interesting—sometimes because they can be "off-the-shelf" products, I can imagine. Where do you see the field moving?

Thistlethwaite: It's early days in terms of efficacy. It is an exciting time in terms of the level of interest that's been created across multiple cell types. That brings us to the question of how these will actually be delivered in the clinical setting. The necessary scale-up of activities in that setting will be of key importance. If and when an efficacy signal is identified, how do we roll out the therapy, particularly in a solid tumor space? With hematologic tumors, there's already a depth of knowledge and experience with the transplant programs that are in existence. One of the big questions as we move more towards solid tumors, if we can find efficacy signals, is how we will roll out a treatment in a practical and meaningful way.

Zimmermann: We've had a very interesting discussion. I want to thank you both for joining me for this fascinating talk.

This is Stefan Zimmermann, speaking from ESMO 2018 in Munich, Germany.

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