Early Data Shows Potential of CAR T Cells Beyond Cancer


In an interview with Targeted Oncology, Daniel Baker, PhD candidate at the University of Pennsylvania, discussed the growing role for CAR T-cell therapies outside of the oncology field.

Daniel Baker, PhD Candidate

Daniel Baker, PhD Candidate

Chimeric antigen receptor (CAR) T cells have demonstrated remarkable progress and greatly impacted outcomes for patients with blood cancers for the better. With 6 CAR T-cell therapies currently approved by the FDA, experts are now looking to see where else they can produce encouraging results.

Investigators have reported promising early results with CAR T-cell therapy in a group of patients with the autoimmune disease systemic lupus erythematosus. According to Daniel Baker, PhD candidate at the University of Pennsylvania (Penn), CAR T therapies could continue to have broad applications based on their great results in patients with cancer.

In an interview with Targeted OncologyTM, Baker discussed the growing role for CAR T-cell therapies outside of the oncology field.

Targeted Oncology: Can you discuss the role of CAR T-cell therapy in the oncology field and what your research focused on?

Baker: In the last decade, CAR T cells have been deployed throughout blood cancers and have seen remarkable effects, essentially leading to, at least in a subset of patients, cures in patients who essentially had refractory untreatable disease. It's been amazing and exciting. There's been a lot of enthusiasm to apply CAR T cells to other blood cancers and throughout solid tumors. That's where the majority of focus and emphasis has been.

What's been kind of percolating for some of those years is the potential for this modality in a wide array of diseases [and] the idea that you could go after pathologic cells in any context and potentially treat something like a chronic disease or something like an acute infectious disease. What our work focuses on is, can we actually use this platform, CAR T cells, beyond cancer to treat diseases? My work focuses on using it on aging or chronic-associated diseases, essentially targeting a pathologic population going after the CAR T cells and seeing whether or not we can ameliorate that long-term disease.

What recent successes with CAR T-cell therapy shaped this research?

I think it's been paramount. In oncology, cell therapy, especially CAR T-cell therapy is labor-intensive [and] very resource-intensive. The idea of proof of concept going into some of these more chronic diseases that are manageable, but have serious long-term morbidity, would be challenging. What has happened is because the field has shown in blood cancers that potentially a single infusion can be curable for a subset of patients, it's caused a lot of enthusiasm for the fact that although this is complicated and resource-intensive, if we can create a better therapy, there's at least the potential to treat some of these long-term diseases. I think the successes in blood cancers, and the recent successes in solid tumors have been paramount for CAR T cells to go beyond cancer.

Additionally, there is now just a smattering of clinical reports of CAR T cells being successful in an autoimmune disease context. In lupus [and] myasthenia gravis, those 2 have been critical to show that there is proof of concept that this specialized form of cellular therapy does have promise beyond just cancer. I think these early days, the first patients that are still less than 2 years out from being treated. It's early to be able to tell what the long-term effects of these are going to be, but these early signs of efficacy are promising as we're looking at the full disease spectrum of what might be able to be treated.

The article discussed the emerging technologies and platforms to enhance the potential of CAR T-cell therapy. Can you discuss these technologies and how they contribute to expanding the applications of CAR T-cell therapy?

One of the things that's exciting about CAR T cells is it's a good platform where we can multiplex technology. The reason is because CAR T cells are produced ex vivo. What that means is we take a patient's cells, take it outside of the body, and the manufacturing process happens outside of the body. The reason why that's exciting is because it allows us to ask some of the cool questions of whether we can use CRISPR editing or [CRISPR]-based editing ex vivo rather than having to engineer that in a patient and see whether it's therapeutic. For example, like a proof of concept is this is CRISPR was first described just around the same time when the first patients were being treated with CAR T cells. CAR T cells that have been CRISPR-edited have already made it into the clinic. It's a cool platform for T cells to kind of innovate and ask whether some of these emerging technologies can be useful.

T-Cell cancer cell © catalin - stock.adobe.com.jpg

T-Cell cancer cell © catalin - stock.adobe.com.jpg

There's a couple of different interesting platforms that could really potentiate the expansion of CAR T-cell therapy throughout cancers and beyond cancers. Gene editing, whether it's CRISPR-based editing, prime editing, all of these things are being explored and have a lot of potential. Another thing that's really important is CAR T cells are a living drug, which means that we can try to engineer them beyond just seeing t[them kill the target]. People are making things like synthetic switch systems, where essentiallyyou can require your CAR T-cell to see not just 1 antigen, but 2 antigens, to actually kill the cell of interest. That's important because we know CAR T cells are powerful and specific. The field has shown that if you design a CAR Tcell to go after a particular target, but that target is present on other tissue, vital tissue, you can see pretty severe toxicity. This could be a powerful way to essentially try to alleviate some of that toxicity.

I think that there's a lot of synthetic engineering that's going on. There's gene editing, which we address particularly in that article, though, it says there's a lot of work being done trying to improve the scalability of CAR T-cell therapies, or T-cell therapies right now are highly personalized. We need the patient's own T cells in order to actually produce the product. There's a whole bunch of innovation, trying to make [an] off-the-shelf route, generic CAR T cells, whether you do that from stem cells, whether you do that from a healthy donor.

A couple of interesting emerging technologies is the potential to make CAR T cells in the patient, what we called in the vivo CAR T-cell generation. Rather than going through this expensive and resource-intensive process of taking T cells, isolating them, shipping them somewhere, engineering them ex vivo, shipping them back infusing them, if there was a way to actually generate CAR T cells in a patient's own body, that would obviate the need for all of that work. It would greatly reduce cost and potentially has some safety benefits.

There's 2 major ways that this is being explored right now. There is in vivo viral delivery, where essentially, we can send a targeted virus to a particular Tcell, and transduce the CAR in the patient. There are benefits with that approach, but also some pretty serious considerations. That will also be probably a pretty expensive way of addressing the problem. Another approach that we're particularly excited about is the approach of transducing CARs with lipid nanoparticles. Lipid nanoparticle technology was deployed successfully with the COVID vaccines, kind of showing widespread possibility of scalability, and it was done relatively cheaply.

What a group at Penn did is demonstrate that if you took lipid nanoparticles and put an antibody on their surface and made them go to T cells and delivered CAR mRNA, what you could do is you could give a single injection of that targeted lipid nanoparticle and produce CAR T cells in a mouse. Those CAR T cells were able to work and function. Importantly, as we think about CARs moving beyond cancer, those CAR T cells actually go away after a period of time, because they're only being transduced with mRNA. Only as long as that mRNA is producing that protein do you have a functional CAR, and then it goes away. For context, where we don't want CARs persisting forever, it's attractive, this idea of like a single injection of lipid nanoparticle particles, producing a response, and then having the CARs go away. I think there's a lot of interesting technologies and platforms that might be useful for CAR T-cell therapy. Only time is going to tell what's really going to be successful, and what will show the broadest application, but I think it's pretty clear that there's going to be ways to improve the scalability and reduce the cost of this approach.

What measures are being taken to ensure the safety and precision of CAR T-cell therapy?

This is a very important area of research. This is something that the FDA takes extremely seriously, like CAR T cells and CAR T-cell patients to be tracked for a period to ensure that there's long-term safety for cell and gene therapies. I think safety is of the utmost consideration as CAR T cells are being developed. That's the thing that all of us as researchers and clinicians care about, whether the cells that we're producing are either going to improve patient safety or improve patient disease burden, or is it going to cause harm to patients? Many of these engineering approaches are being explored. Are there ways to kind of augment that safety profile? Can we reduce the number of cells that we need to infuse into patients? Are we able to essentially have greater control over our CAR T cells?

Now in the clinic, we have CAR T cells that have been engineered with Suez Light switches. If we start seeing toxicity, we can give a synthetic drug and essentially eliminate the CAR T cells. I think there's a lot of engineering approaches, as well as scientific approaches, to get greater understanding of what's causing some of these safety concerns, and what are the different strategies that we can do to modulate those concerns. Again, I think it's an exciting time as we're getting greater control over a living drug, and that's exciting.

The fact that it's a living drug is kind of this double-edged sword because we know that [there are] very small proportions of cells. There's a case report from our hospital here where essentially a single patient was treated, and the vast majority of the CAR T cells produced from that patient came from 1 single T-cell and was able to cure that patient of cancer. It's amazing that a single cell can do that. But as we discussed earlier, the idea that that same cell might rapidly proliferate, and cause toxicity is also dangerous. This is a different class of disease modalities. There's lots of things that we're doing now in cancer that are exciting and innovative, but cell therapy is kind of its own unique category. That comes with its potential benefits from an efficacy standpoint, and it does come with serious concerns from a safety standpoint. I think it will take both science, technology, and engineering in order to grapple with all of the possibilities that might actually come out as a result of what we're doing.

Looking ahead, what are some promising avenues for CAR T-cell therapy beyond cancer?

I think the clearest place where CAR T cells beyond cancer are the most mature is autoimmune disease. Particularly severe refractory autoimmune disease, you have patients who essentially are on long-term chronic immunosuppression. What some of these emerging clinical reports are showing is that, essentially, CD19 CAR T-cell therapy is able to eliminate these B cells. At least for all the patients that have been treated, today we're seeing a pretty remarkable reduction of autoinflammatory disease. I think that similar to the way that blood cancers paved the way for autoimmune disease, autoimmune disease will pave the way for a variety of other diseases.

We're in the early days of where CAR T cells have been explored. Even from a preclinical perspective, just a handful of reports explore the potential for using synthetic T cells to treat disease. But there's been some interesting work done on targeting cardiac fibrosis. Essentially, after a heart attack, your heart begins to put down a dense extracellular matrix. That kind of prevents your heart from rupturing when you have cardiomyocyte death. As you can imagine, the job of your heart is to pump. Having this dense tissue in your heart over a long period of time leads to severe morbidity and mortality. One of the approaches that we've taken is the idea that you could go in after and get rid of that cardiac fibrosis, post-heart attack, and see whether you can ameliorate some of those effects. This has been done in mice and there's been 2 studies. It's shown pretty remarkable effects of being able to do that.

There's some exciting clinical translation of seeing whether these CAR T cells could be therapeutically applicable for some of these failing heart patients. Similarly, there's been some reports of CAR Ts and senescence-associated diseases. Senescence cells are associated with a whole bunch of chronic diseases, and a group at [Memorial Sloan Kettering] showed that you could build a CAR Tcell that was able to treat a couple of forms of liver disease. It's early days of what all could potentially be treated, but I think 1 of the interesting things is there's a wide swath of diseases from the ultra-rare, like rare forms of lung fibrosis, to things that are common to all of us. It's been speculated that pathology associated with aging might be treated with CAR T cells. It's an exciting time for the field to see what within cancer and beyond cancer might be able to be used by particle technology.

What else can you note about the potential use of CAR T in autoimmune disease?

It is rather remarkable that we're seeing these early responses. So far, the safety profile has looked great. But it's still too early to tell exactly what the long-term effects will be or if there will be a subset of patients that are either nonresponders to this disease therapy or that do have serious safety concerns associated with it. We're talking about 10 to maybe 50 patients at this point that have been treated and reported on. Larger and multicenter trials will need to be done to fully elucidate what's going on in autoimmune disease. An interesting point [that is] important for people to understand is the fact that CAR T cells have been successful in cancer. This is exciting for the potential beyond cancer.

Cancer is a uniquely difficult disease. Cancer is rapidly proliferating. You have a cell that is undergoing this rapid expansion, it's rapidly mutating, especially at the time of CAR T-cell infusion. A huge number of CARs have cancer cells. Most of these things are not true of other diseases. When you come to cardiac fibrosis or senescence, the target population is exponentially lower than in cancer. You don't have these cells located in a dense microenvironment or immunosuppressive environment. They're accessible to the normal immune system, they are not rapidly mutating. In fact, senescence cells are essentially growth-arrested. One of the interesting points is, CAR T cells might in fact work better in noncancerous disease, based on the fact that they have worked in cancer. Some of the mechanisms of resistance for cancer are like antigen escape, where your target cell loses the target that the CAR is going after. The likelihood of that happening in non oncology settings is much lower because you don't have a rapidly proliferating subset.

We've speculated that because your target burden is much lower in non cancerous diseases, and we might not see some of these severe response safety responses that we see in oncology, like cytokine release syndrome [CRS] or immune effector cell-associated neurotoxicity syndrome [ICANS]. To date, there have been no reports of severe CRS or severe ICANS and these patients have been treated with CD19 CARs or BCMA CARs for autoimmune disease. Again, it's still early to understand what's the full spectrum of these effects, but I do think it's promising that we have seen efficacy in cancer, and it is likely that we will see efficacy and safety in some of these other diseases. Again, only time will tell what diseases and what will need to be changed to actually go after those disease contexts, but I think it's an exciting time for the field.

Zmievskaya E, Valiullina A, Ganeeva I, et al. Application of CAR-T cell therapy beyond oncology: autoimmune diseases and viral infections. Biomedicines. 2021;9(1):59. Published 2021 Jan 9. doi:10.3390/biomedicines9010059
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