iwCAR-T 2025 | Translational insights into T-cell engagers and CAR T-cell therapy: targets, the microbiome, & more

Saar Gill

Hello, I’m Saar Gill from the University of Pennsylvania and I had the pleasure of co-moderating this really fascinating session today at iwCAR-T about translational aspects of bispecifics and CAR T-cell therapies. And we have a star-studded cast of international investigators who I’ll ask to introduce themselves. Ladies first. 

Ciara Freeman

Thank you. So my name is Ciara Freeman. I work at the Moffitt Cancer Center with a primary interest in treating patients with myeloma with complex immune therapies. 

Maik Luu

Hey, my name is Maik Luu. I’m an assistant professor at the University Hospital in Würzburg and my main research is focusing on microbiota or CAR T-cell interaction. 

Francesco Maura

Hi, I’m Francesco Maura. I’m a doctor from Memorial Sloan Kettering and in addition to my clinical activity, I run a lab focused on genomics and mechanisms of resistance in multiple myeloma and lymphoma.

Saar Gill

So I think what was particularly interesting about this session, which was largely focused on myeloma, but not only, was that we covered three different aspects of the fascinating milieu that comprises cellular immunotherapies, specifically T-cell fitness, as well as underlying aspects of the disease under treatment, for example, myeloma. And then let’s think of it as sort of soluble mediators of immunity and response or failure of immunotherapy, which is the microbiome and metabolome. So maybe I can ask Dr Freeman, firstly, to summarize some of the results that might be of interest for people to hear about. 

Ciara Freeman

Yeah, so we looked at patients who had multiple myeloma treated longitudinally at our center. And those patients had all undergone previous transplantation at our center. And then later, when CAR T-cell therapy was approved after four or more treatment lines, they went on to have collection to be made into their CAR T-cell product. And so what we did was we were able, in a paired patient population, to go back into the freezers and pull out some of the original T-cells that they had in the freezer from when they collected for their transplant and then also compare them to their T-cells that ultimately went to make their commercial product. In this case, it was ide-cel or otherwise known as abecma. And we basically did a paired comparison and looking at the behaviour of the T-cells phenotypically, so how they looked, whether they were different in their composition. And then we made them into research-grade CAR T-cells targeting BCMA, and we looked at how they manufactured, whether there were differences that we could see, the phenotype of those CARs, and then ultimately how those CARs worked. And what we were able to show was that basically, from the very beginning of starting material, there’s differences in the earlier treatment lines versus the later treatment lines, the earlier T-cell looking more fit, more robust, having better proportions that are more favorable for making into CARs. When we made them into CARs they manufactured better, they had a better looking phenotype, known associations with better outcomes when you put them into patients that have been shown previously. And then we also were able to show that they were metabolically different, that the earlier T-cells were more metabolically robust, they were fitter, they were able to handle the stress of killing and they actually killed better after serial stimulation. So just really lending some background research into this idea that if you bring the CAR-T therapy forward, as has recently happened with the changes in the FDA approvals, that probably they’re going to do a better job, make a better product, and do a better job at killing the cancer for patients. 

Saar Gill

That’s a great summary. Thank you, Ciara. How do you contrast your findings? How do they complement what people should understand about myeloma therapy with what you heard from Ciara? Francesco? 

Francesco Maura

I think it’s myeloma, we often study different labs study areas when they are more expert than others. But the fact is that everything is interconnected. So the fact that we have better fitness in front line is also because we collect the cells probably when patients are in response after Dare-VRd, for example. So the level of inflammation and the chronic stress or active stress that the myeloma provides to the immune system, it’s just reduced. T-cells are more free to be naive, to, you know, come back to what they should be and not be hijacked by the tumor. So, and as well, you know, all the other factors we see. So, in principle, I do think that everything I listened today from my colleagues, great presentations, is somehow interconnected. The more tumor you have, the more aggressive, the more proliferation, the more metabolic changes you have in your body, the more inflammatory status you have, the less T-cell effective are. And so how we can revert this of course moving therapies earlier in line is one strategy but also a lot of patients are already treated in front line so we don’t have to forget the one that you know are still in that stage. So I think investigating alternative strategy like you know try to modulate the immune status through alternative approach that are not necessarily therapies or optimizing our bridging therapies before getting CAR and doing something after CAR to promote this better efficacy over time in terms of disease control. So we have a lot of strategies. I think we’re just at the beginning of something like a big journey where we just need to learn how to use better our drugs in terms of timing and schedule. 

Saar Gill

And Francesco, I thought some of your work has been really fascinating with respect to comparing and contrasting the differences between CARTS and BiTeS and between GPRC5D and BCMA. So for people who are watching this and thinking about myeloma therapeutics, how would you summarize the sort of few top lines from what you’ve found over the last few years? 

Francesca Maura

So I think there are a few bullet points that can summarize my work. The first is that GPRC5D, it’s an excellent target, but myeloma doesn’t need it necessarily for its biology, it’s not essential. So that’s why for myeloma losing GPRC5D it’s something that they can do without any problem and that’s the main mechanism of resistance for patient that respond to GPRC5D bispecific and CAR-T, loss of GPRCD5 is the main mechanism of resistance. For patients with the BCMA CAR-T because the stimulation is short in time, because the persistence is limited in its effect, what myeloma needs to do is just down-regulate temporary BCMA and the myeloma that can do that are the one with the stronger fitness in term of NF-κB or less dependencies on BCMA and we know that highly proliferating tumor cells usually have additional hits on the NF-κB pathway. So they can either lose or down-regulate BCMA enough to just survive the CAR-T. That mechanism doesn’t work well with bispecifics, so patients with bispecifics that respond needs to develop something which are these mutations on the BCMA that we don’t see in the CAR-T because it’s a matter of how long the tumor cells is exposed to the selective pressure. The refractory patient, the ones that don’t respond at all, it’s a mixture of very high disease burden, very aggressive disease, a bad T-cell, and so for those patients like EMD, oxidative stress, there are so many confounders and factors that interplay together that for them of course we need to find other therapies. But as someone said, some patients even with very aggressive disease respond. So I think it’s not just disease burden. We should always remember that Burkitt lymphoma is probably the tumor that grows faster and is the tumor that grows every 48 hours, duplicate its size, but is one of the most sensitive tumor and genomically simple that we have, the aggressive lymphoma. So we should keep that in mind that disease burden doesn’t necessarily mean that the tumor doesn’t respond. 

Saar Gill

Sure and Mike can I ask you to help us think about, you’ve done more fundamental work about metabolism and the microbiome. How do we for again those of us who are thinking about treating patients and sequencing therapies and maybe the context of the patient the disease the everything else that they’ve gone through how should we think about the contribution of the microbiome not necessarily in myeloma but with respect to cellular immunotherapy? 

Maik Luu

Yeah thank you for your question. I think we are at the beginning of the connection between microbiota and cancer entities because I guess the key will be to have more robust profiles of different disease entities, the microbiome profile and the metabolism or the metabolites that are secreted by the certain profiles. Because I guess it’s not like there is a golden microbiome standard that you have for each entity. We have the data from lymphoma and myeloma because that is an accessible cohort that we had at hand. For lymphoma and myeloma, interestingly, the data that we had with predicting the success of the therapy with pension weight as one of the biomarkers was nicely fitting into the preclinical models in solid tumors, but that could be a coincidence. We can’t expect that the phenotype that we cause in the T-cell will be applicable for every disease entity but what we are currently thinking is that, which is also why I was so inspired by your talk, that fitness and the way the T-cell response that might be kind of defined very early on. I mean when we look at the patient cohort that we had and we see abundance of pentanoid is very predictive for the patient outcome, why is that? I mean most probably it is because there’s something in the patient that is already influencing their pharesis product, right? It must be somewhere in the starting material, because otherwise where should the microbiome interact with the T-cell, although there’s no other intervention? And then we need to ask ourselves, what should we do? If the abundance of such biomarkers is low, should we not do the therapy at all, or should we modify the T-cells or supplement it? And if we go into supplementation, how would we do that? I mean, going for stool transplantation, that might be the closest way, but there are so many additional factors that you introduce to the patient who is probably also suffering from other infections later on. So I guess it’s a bit too early to think about these global aspects, but seeing the microbiome as a pool of tools, as a pool of metabolites that could be used at least in those entities that we have tested, yeah, that might be a good idea to do so. 

Saar Gill

Do you think, maybe it’s the last question for this session, do you think, Mike, that you can take what you’ve learned from the metabolic profile and its effects on T-cells to teach us how we can maybe engineer next generation T-cells to take advantage of those pathways?

Maik Luu

Definitely, I think so. I mean, what it requires is that we have a very close mechanistic point of view because every metabolite will work differently on different immune cells subsets. I think for T-cells we have a very good feeling what those can do, but only for the main classes. For some short-chain fatty acids are the major classes, they are well known, but there are hundreds of other metabolites that can also have contradictory effects, right? So I guess we are at a stage where we need to kind of have a more detailed view into which metabolites are there, which have a beneficial response, which don’t, and in which way can we apply that to the subproduct. So we have found that using the modification right before the gene transfer is most efficient because it’s an epigenetic modulation that happens. It gets weaker if you do that later on, but I guess if we know how it works then it’s easy to apply and probably also to put this into a genetic modification to get rid of the metabolites and that might be the way to go. 

Saar Gill

Good, thank you. Thank you all very much.

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