iwCAR-T 2026 | Advancing cellular therapies for solid tumors: CAR T engineering and beyond

Randolph Hecht
My name is Randy Hecht, and I’m a GI oncologist at UCLA. And I apologize for sounding like I have gravel in my throat, but I’m doing my best. But I’m really lucky to have a wonderful panel of researchers, both clinical as well as basic, who are really moving the needle on cell therapies in solid tumors. For a long time, we’ve been looking ambitiously at our colleagues in the hematologic space. And I think really now, some of the data that was presented has some interesting results. And I’d like to have my colleagues introduce themselves, since I’m losing my voice.

Saul Priceman
My name is Saul Priceman. I am a cell therapy researcher and the director of the Cell Therapy Research Center at the University of Southern California at the Keck School of Medicine, Norris Comprehensive Cancer Center.

Elliott Brea
I’m Elliott Brya. I’m a thoracic oncologist at Dana-Farber Cancer Institute, as well as a cell therapy researcher interested in a role for cell therapy in non-small cell lung cancer.

Benjamin Schlechter
My name is Ben Schlechter. I’m a GI medical oncologist, also at Dana-Farber in Boston. I co-direct the Colorectal Cancer Center. My main clinical interest is in immune effector cell therapies and new cellular therapies for solid tumors, in particular GI malignancies.

Jennifer Specht
My name is Jennifer Specht. I’m a breast medical oncologist at the University of Washington and Fred Hutch Cancer Center. And I am the clinical director of our research program and have interest in cellular-based therapies as well for breast cancer.

Randolph Hecht
Would each of you want to give a one or two minute summary of what you discussed today for the audience?

Saul Priceman
Sure. Most of our work has been in solid tumors and developing CAR T-cell therapies, although we’ve dabbled in a number of immunotherapy modalities, some of which we’ve taken to clinical trial for prostate cancer, for breast cancers that have metastasized to the brain, and in ovarian cancer. And then we spend a lot of time engineering those cells because, as we discussed a lot today, we know that single-targeted CAR T cells may not be as effective for solid tumors as for hematologic malignancies. And so we’re engineering them in a multitude of ways and aiming to get good clinical experience now in those settings.

Elliott Brea
Yeah, and I think building on what Saul had mentioned, we’ve seen that while we’re getting early signals that our CAR Ts in solid tumors are working, we’ve had unfortunately dismal results for a number of our trials, and we’re trying to figure out what strategies we can use to optimize it. Some of the work that I’ve participated in that we’ve been pushing forward is looking at using targeted therapy. These are often either pills or antibody-based approaches, which we know target oncogenes that drive the cancer. Many of these are FDA-approved. Patients tolerate them very well. They have high response rates. But these patients will ultimately progress on these targeted therapies.

And we’re looking to see if these can synergize with CAR Ts. And our early preclinical data suggests that they will work more potently together. It allows for the CAR Ts to be more effective and more durable, and hopefully achieve what we see in some of the hematologic malignancies with our CAR T strategies that have led to approvals, with really significant durability being seen.

I think that’s what we all hope for, that we can have more of our patients getting a one-time dose of CAR T. Obviously, it’s a logistically challenging therapy to give and often involves patients getting admitted to the hospital. But we’ve talked to patient advocacy groups, and they’ve expressed interest in a therapy that’s a one-time thing that would have a long-term ongoing benefit to them. Because our hope is that the toxicities are up front and that patients can get these long durable benefits and then not have to be coming in for repeat infusions or taking medications that potentially have side effects that affect their daily life. And so that’s what we’re looking to hopefully continue to push forward.

Randolph Hecht
Ben?

Benjamin Schlechter
Yeah. And in the same vein, it was funny as I was thinking about my talk and then I saw Jennifer’s talk, and we talked about the exact same challenges that we’re facing in immune effector cell therapies for solid tumors, where we need good targets, we need persistence, we need expansion, we need tolerability.

So the data that I presented was one approach that we’re using, and one of many approaches, which was this coupled CAR technology, which Lyell and previously Iovance has, of a CD19 CAR vector — actually three CD19 CAR vectors — and then the immune effector approach against a mucosal target, where you give all the above and you create a mix of different CAR cells. Some of those CAR cells are really anti-cancer cells, and some of the CAR cells are going to be just cytokine support. And some of them are this sort of paracrine microenvironment cytokine support to really overcome limitations that we see so that we can get an effective response, generate a durable response, and a deep response in patients using different technology.

We’re all trying to find different technology to do that because it’s hard. It’s not that B-cell CARs are easy, but there are different barriers in solid tumor CARs. So yeah, we’re all talking about the same problems. We’re all approaching them a little differently, but it is interesting to see that we all showed up to the party saying the same thing.

Randolph Hecht
Jennifer, you want to talk?

Jennifer Specht
Exactly. My role today was primarily as moderator, and I think I had the privilege of seeing some really promising data from the other speakers in our session about actual true successes and really remarkable responses in glioblastoma and then in the GPC CAR realm as well.

As a breast oncologist, again, we look longingly at lymphoma and other diseases where CAR T cells and cellular-based therapies have really made a big impact. We’ve made baby steps, and I’m happy to say that the steps that we took laid the foundation of identifying all the problems and all the challenges. But over the course of time, it’s very heartening to see how, with the more widespread use of armored CARs and with really thoughtful manipulations of the tumor microenvironment, we actually are making steps forward that will ultimately really move the needle and bring this to the clinic.

And finally, I’d make the point that there are so many patients in my world who are really in need of these types of advanced therapies. Even in the setting of having many different targeted therapies for breast cancer, there are still a lot of patients who continue to need additional therapies.

Randolph Hecht
I’ve been fortunate enough to be at IWCART now for a number of years, and I think they’ve been forward-thinking in having this solid tumor day. And one of the nice things is that we are seeing responses, and we used to not see responses at all in solid tumors.

And the next real hurdle — and I think that you all were talking about this — is that we’re not getting the persistence of the cell therapy, and we’re not getting the durable responses that our patients really want. Or if we are, we’re getting them in very small numbers of patients, and we have to figure out who those patients are and how we can optimize it.

Does anyone else have any thoughts about that? Everyone here is actually working on exactly that. And do you think that maybe at a future iwCART we’ll be talking about sequencing things or trying to dial down toxicity? Because we’re not there yet with the efficacy. Any thoughts for the future?

Jennifer Specht
I would just add, I think one of the themes that came up in our session was intriguing thoughts about timing and when to apply the cellular-based therapies. And if we start to see more substantial proof of concept with regard to safety, as well as efficacy signals, trying to implement cellular therapies at the right time is going to be an important step forward. Because we continue to see themes of fewer responses in the setting of very advanced bulky disease, as opposed to maybe more minimal residual disease, such as Dr Brea’s work has suggested.

Elliott Brea
Yeah, and I think that point is well made. The idea is that hopefully we are testing patients with advanced metastatic disease and bulky tumors. We know that heterogeneity and antigen loss is an issue.

I hope that with earlier lines of treatment, and we’re seeing this even with tarlatamab, which is a T-cell engager that’s been FDA approved in extensive-stage small cell lung cancer — now we’ve got trials moving that up into the first-line maintenance setting where patients have been significantly debulked with chemotherapy as well as anti-PD-1 therapy. But we think that might even be a better scenario.

And I think that’s a theme we’ll continue to see: either using T-cell engagers, immune effector cell therapies, hopefully even newer modalities such as NK engagers to show promise and bring in different arms of the immune system to address tumors. So I’m hopeful that as time goes on, we’ll have more of these therapies and a wealth of issues involving how we sequence them and whether we’re involving somebody in an immune effector-based treatment as a second-line option or potentially first line.

Randolph Hecht
In some ways, the more options you have, the harder it is to bring it further forward. In some of our worst diseases, like pancreatic cancer, it becomes easier. But in breast cancer, as you were mentioning Jennifer, or in lung cancer, or in prostate cancer, you have many different options. And it’s harder because of the investment for the patient’s cell therapy.

Probably also similar to vaccines — having worked in the vaccine space — vaccines really have not worked in patients who are heavily pretreated, who are last-line. On the other hand, patients with MRD are probably where we’re seeing our most interesting results.

And so the question goes back to safety as well. You have to have a really safe product if you’re going to give it early on to someone who might live for a while longer or might not even relapse anytime soon.

Benjamin Schlechter
You actually made a lot of choices in LYL273 about who the patients would be that we enrolled. It was actually a pretty restrictive enrollment regarding the most bulky patients. Part of that was when the trial was designed, it wasn’t clear how long it would take to manufacture product, and it wasn’t clear because of the DLT windows — 28 days between patients and things like that — which are required in a phase one trial.

So the early-day designs of that meant that the patients had to have a little more moderate disease. And I think one of the lessons of that experience, where we are seeing real responses — we have patients more than two years off all therapy, which in refractory colorectal cancer is, as you know Randy, essentially unheard of — is that patient selection is important.

That was done to maximize safety, and that’s a reality. But I think it speaks to the lesson that we do need to move these things really early off the first line in colorectal cancer, or as soon as possible in solid tumors. Because by the time we have patients with highly refractory disease, in colorectal cancer response rates are in the single digits.

Randolph Hecht
So that’s going to be patient selection, identifying the right patients, advances in manufacturing, allo, in vivo…

Saul Priceman
I mean, even the most successful therapies we think about that are not T-cell based or immunotherapies — patient selection was such a critical component. And I think we’ve learned this also with other therapies: that lower disease burden and earlier lines of therapy, when patients are not so refractory, especially for CAR T cells, are important.

What we think about today being autologous, we have to take those cells out that are in the body and manufacture them. And it’s the state of the host — of the patient — that’s a critical factor.

Randolph Hecht
I think another question that I have is that I’ve been mostly working with industry, but obviously most of the advances actually come from academia. And these are very expensive trials to run. How do you think academia is going to continue to run these trials, particularly when funding is not what it has been? Or will it just be in collaboration with industry?

Saul Priceman
Yeah, I mean, we’ve seen earlier partnerships with industry in our development, even at the preclinical stages, where we require that not only for design and help and forward-thinking toward commercialization, but also for funding.

And there’s also another theme that I think we could adopt, which is: do we need 12 to 18 patients on a phase one to demonstrate safety early, but also an early and robust clinical signal that gives you confidence to move something to a phase two? At what point do you see the right signal that you can move on? And I would argue we don’t need 12 to 18 patients to identify that these days.

Randolph Hecht
Do you think that’s more for safety? If you have efficacy in the first patient — several of the talks had efficacy in the first patient in a cohort, which always makes you feel good. But if you’re seeing efficacy, then that may attract the funding that you need to go big.

Elliott Brea
I also think there are going to be a lot of changes in the manufacturing. We’ll see more in later sessions about the in vivo CAR, but that’s been certainly very promising. I think the in vivo BCMA CAR that was recently presented, I believe at AACR, has shown a lot of promise.

And so that may change a lot of our clinical paradigm because we’re used to giving off-the-shelf therapies. It’s nice to be able to dose a patient with an antibody-drug conjugate a couple days later. It’s very hard with a patient that’s rapidly progressing.

I think that’s been the difficulty even in the case of small cell. We’ve had a DLL3 CAR-T trial. It’s been very difficult to enroll because we have tarlatamab approved. There’s no wait for manufacturing, and our patients with small cell have rapidly progressive disease.

Randolph Hecht
It was easier in the heme space because the prior products already worked. So now you’re just trying to make it easier and bring it to the masses, as opposed to having to get somewhere near their efficacy and durability.

Benjamin Schlechter
There’s this target pile-on effect, and we certainly see this with HER2, right? Where there’s a good target and everyone’s jumping on it, and there start to be problems with the target, but everyone’s already committed.

And rather than seeing that as a sunk cost and moving on to new targets, I feel like both academia and our industry partners stay committed to the same targets. So it was also nice today to see some novel targets and some novel techniques, whether that’s armoring with IL-12 or whatever it was, to not just jump on the really important targets but actually be pretty creative.

And I think we do need some creativity to take the next step in these therapies because these are hard diseases and hard challenges to overcome.

Randolph Hecht
Thank you very much for your attention. I think we’re really fortunate to have some of the leaders in the field in some of the most difficult-to-treat solid tumors.

I think today’s session really showed that we are seeing responses. And I think that after years of really depressing results with cell therapy, these results are interesting enough that I think they offer hope to patients. And I think it also may open up additional funding that we need to really bring the field forward.

Thank you very much.