September 5, 2023 PAO-08-23-CL-04
Beau Webber (BW): Luminary started in 2017 in Minneapolis, Minnesota with a new vision for how to utilize technologies that we had developed at a prior venture. Previously, Jeff Liter, Branden Moriarity, David Largaespada, and I had started a genome-engineering company called B-MoGen Biotechnologies where we developed a novel, nonviral transposon-based technology. That company was acquired, but we retained a license to use this nonviral transposon technology for cell and gene therapy applications. We saw an excellent opportunity to leverage nonviral genetic modification to accelerate cell therapies into the clinic.
This work was driven in part by our early recognition that the use of viral vectors was ultimately very limiting. Viral vectors take a long time to source at clinical grade, and they pose scalability challenges as well, particularly when you start to think about allogeneic products. Within our vision to leverage the nonviral technology to rapidly accelerate cell therapies into the clinic, we sought to tackle a few big problems. One major challenge in this sector is antigen escape — the ability of tumors to basically stop making the target antigen. This happens particularly in CD19 chimeric antigen receptor (CAR-)T cell therapies: the cancer cells quit making CD19, which means that the engineered CAR-T cells can’t see them anymore, and the cancer comes back.
We began by looking into novel CAR technologies that are able to bind to multiple antigens natively. We in-licensed technology for a B cell activating factor (BAFF) CAR product that we were able to move quite quickly into the clinic, moving from the preclinical study to IND authorization in roughly 18 months. That speed is pretty remarkable for a start-up, and we accomplished that without even having a classic Series A funding round. We demonstrated the feasibility of moving rapidly utilizing these nonviral technologies to accelerate cell therapies into the clinic.
The other big area that we’re focused on is the solid tumor space. We have a number of different technologies primarily focused on utilizing a novel allogeneic platform based on gamma-delta T cells.
BW: In addition to the viral/nonviral aspect that we already touched on, another big limitation right now involves the complexity in the manufacturing and delivery of some of these cell therapies, especially autologous therapies. Making individualized cell products, particularly with cells from sick patients, is very challenging and costly. While there have been successes with CD19 and other CAR-T therapies, this issue is hindering the more widespread application of these cell therapies. There’s a big push toward allogeneic therapies where you can manufacture large batches of cell products from healthy donors who have been prescreened for beneficial qualities in the cell type of interest. You can make a large batch of a quality-controlled, essentially pre-validated product, rather than taking cells from sick patients, which inevitably leads to some manufacturing challenges, because you not only have to isolate the cells from that person and move them offsite but also make the product and then ship it back. You also end up with quite variable outcomes because these patients have gone through many lines of pretreatment. The autologous approach is a big challenge — and that’s why Luminary is very focused on the novel gamma-delta T cell platform.
The other big challenge is in the solid tumor space: how do you effectively target solid tumors without targeting normal, healthy tissues? CD19 works great because it’s highly specific to B cells, and you can administer CAR-T products and specifically hit leukemias quite well. But it’s been really challenging to identify antigens in the solid tumor space that are very specific to the cancer, and even when they can be found, you still run into this problem of antigen escape. As a result, it’s not merely a question of developing strategies to target the solid tumor selectively but also finding ways to target it in a way that minimizes its ability to essentially evolve or evade or mutate its way around what is essentially a selective pressure exerted on the tumor by the immune cells.
The solid tumor microenvironment itself is very complex and very suppressive — there are suppressive cytokines, suppressive molecules, suppressive immune cells. From our perspective as genetic engineers, we realize that tackling the solid tumor space will require engaging some of that complexity to fight fire with fire by increasing the complexity of the cellular product as well. Using the nonviral transposon approach is really advantageous because it’s very good at mobilizing large, complex genetic cargo, which gives us an advantage. There are some approaches and genetic constructs that can be delivered with a transposon that you likely could not with a virus.
BW: Gamma-deltas are a bit of an enigma, and they have been for quite some time. One of the big reasons is that they’re less frequent than alpha-beta T cells, particularly in the blood: between 1% and 10% of CD3+ lymphocytes in the blood. The vast majority of the rest of them are in tissues, primarily mucosal and epithelial tissues. Compared with alpha-beta T cells, they are still relatively poorly understood in terms of how they recognize antigens. Gamma-delta T cells have a wide variety of ways to be able to recognize target cells and activate a cytotoxic program, but they are still being studied.
A further challenge is that human and mouse gamma-delta populations don’t parallel each other. There are many different subsets of gamma-deltas, largely based on the receptor that they express, but they’re not synched between mice and humans. Mice still are useful in studying gamma-delta T cell biology, but the knowledge is less easily transferred to humans than it would be for other cell types: subset A in mice doesn’t necessarily equate to subset A in humans. That’s one of the main reasons why gamma-delta T cells have lagged: our basic biological understanding of them is behind the curve compared with alpha-beta T cells. As a result, our ability to develop effective manufacturing and engineering protocols has also lagged behind.
BW: You can already see the signs that there’s a growing interest in gamma-delta cells. We know that these cells play a big role in monitoring our bodies for cells that may be becoming cancerous or are virally infected, and we also know that their inherent biology can be exploited for therapeutics. Now that some of the understanding and the challenges of manufacturing are being overcome, we are seeing growing interest in leveraging them. I mentioned earlier that there are different subsets of gamma-delta T cells: currently, a number of companies have developed their pipelines around a single subset for one reason or another: whether because of their R&D or their intellectual property.
At Luminary, we know that gamma-deltas as a whole play important roles in targeting cancer cells and virally infected cells. Evidence suggests that the different subsets all have unique and complementary biology. So why throw all of your eggs in one basket, essentially? At Luminary, our approach utilizes a polyclonal manufacturing process. For instance, the Vδ1 and the Vδ2 are the two big subsets that are really being pursued in industry, and so our process actually maintains both of them throughout the whole process.
Alpha-beta T cells are part of the adaptive immune system. The alpha-beta T cells start out as naïve T cells and become activated when they see antigens, after which they differentiate through stages, becoming like a memory cell and then an effector cell, and so on. Whereas natural killer (NK) cells are more innate, so they’re kind of just primed to kill right from the start; they basically elicit a rapid cytotoxicity but don’t persist for very long. In contrast, alpha-beta T cells can become a memory subset that persists for years.
The gamma-delta subsets exhibit a blend of these properties. To make things simple, you can think of Vδ2s being more innate or NK-like, whereas the Vδ1 subsets and some of the others are more adaptive and can potentially persist longer. We’ve seen this in some of our preclinical animal model studies, where we manufacture a polyclonal population that has a mix of Vδ1s and Vδ2s and watch this progression over time, which results in a flux of the different cell types throughout the course of the treatment. Not only is this potentially beneficial in terms of long-term or sustained efficacy, but it’s also really informative from a biological standpoint because we’re able to learn so much about these different subsets in the process. Down the road, it’s going to open up opportunities for us to be able to either tweak the manufacturing or modify it or home in on subsets that are potentially beneficial in certain settings.
In terms of efficacy and manufacturing, I think there will be opportunities to learn as we go forward. Luminary is currently working with a cell composition of gamma-deltas that’s different from what other gamma-delta companies are pursuing, which gives us the best of both worlds in terms of the inherent properties of gamma-deltas. Additionally, because of our nonviral manufacturing protocol, we can work with more complex cargo.
One of the big challenges with all allogeneic therapy approaches right now is that when you put these cells into a third party in an allogeneic setting, the recipient’s immune system recognizes the incoming cells as foreign and works against them. We’ve in-licensed novel cloaking technology from Harvard that we’re incorporating into our engineering strategy. The complexity of the engineering is such that we’re able to put in not only multiple CARs plus cytokines to armor these gamma-deltas, but also a cloaking technology to help prevent their rejection by the recipient. Altogether, Luminary has a very unique and robust gamma-delta program.
BW: I’ll use CD19 as an example. We know that about 30% of patients relapse with CD19 loss ultimately. The primary way that this is being addressed is by identifying secondary antigens to target. For instance, the combination of CD19 with anti-CD20 CARs or anti-CD22 CARs in basically dual-CAR setups is one approach being pursued, which is essentially what we are doing in the solid tumor space using technology that we have in-licensed from the University of North Carolina. We call our unique configuration of CAR design our Split Co-Stim CAR configuration.
That represents one approach to targeting multiple antigens, but there are different ways to go about it. For the solid tumor space, we are focused on a dual CAR-targeting approach. For our hematological programs, we’ve in-licensed a ligand-based CAR — instead of being part of a single chain variable fragment from the antibody, it’s a natural ligand, the BAFF ligand, which can bind to BCMA, TACI, and BAFF receptors. So, it is one CAR entity that can bind to all three of these receptors, and we’ve shown that, as long as the cancer cell expresses one of these receptors, it can be recognized and killed by the BAFF CAR.
We’ve also shown that you can take a population of leukemic cells, target them with this BAFF CAR, and kill them — and it doesn’t matter if they lose CD19, because they still express all three of those other receptors. If they lose one or two of any of those receptors, the others will still be recognized. We know from other areas in biology that if you target three pathways, it becomes very hard for these cancer cells or viruses to really evolve to elude the targeting. We’re very excited about that BAFF CAR, which is currently in the clinic in an autologous setting, but we’re quickly moving it toward an allogeneic gamma-delta platform.
BW: That’s really interesting. There have been a few really nice reports now on the use of CAR-T cells in the autoimmune space for lupus, including a recent paper that made a big splash using a CD19 CAR. But there are also other autoimmune diseases, like systemic scleroderma and others, that may be relevant. These diseases are ultimately caused by pathogenic B cells that are producing autoantibodies, which target normal tissues and cause disease pathology.
We know that CD19 CAR-T cells will just essentially wipe out the B cell compartment, which could produce some benefit. With Luminary’s BAFF CAR platform, the receptors to which the BAFF ligand binds are expressed on a slightly shifted spectrum of the B cell differentiation pathway. So, while CD19 will take out B cell progenitors earlier in differentiation, it is not expressed on some of these longer-lived plasma cells that are producing large amounts of autoantibodies.
Because the BAFF CAR targets BCMA, BAFF, and TACI, which are expressed on plasma blasts and plasma cells, it may have a better therapeutic effect on the pathogenic cells that are causing disease without creating such deep B cell aplasia that is sometimes seen with CD19 CAR. You can think of this as a more nuanced and hopefully more selective approach. We’re conducting studies to vet that out right now. We know that some inflammatory cytokines that are expressed in these autoimmune diseases are linked to the receptor in the pathways that are targeted by the BAFF receptor. There are a number of lines of evidence to suggest that the BAFF CAR can be more effective in the autoimmune space.
The other interesting question in the autoimmune space is whether long-term persistence of these cell products is necessarily needed to have a significant impact on the disease pathology. It’s interesting to think about how an allogeneic product may actually be very effective in the autoimmune space insofar as challenges remain in the solid tumor space regarding the need for these cells to persist for a long period of time, and part of that is evading the recipient’s immune system. But in the autoimmune space, you may not need quite as long of a persistence to reset the B cell compartment and eliminate a lot of these pathogenic cells.
BW: From the standpoint of manufacturing and engineering, I don’t see any really insurmountable hurdles ahead. Most of the manufacturing components are available and readily sourced, and we understand how to do that part of it. The biggest uncertainty we are facing with our first-line autologous BAFF program is that the BAFF CAR has not been used clinically until now. We need to see an acceptable safety profile and signs of efficacy at this point. Efficacy isn’t typically considered too closely in early-phase trials, but it’s something worth keeping an eye on in the cell therapy space.
Right now, we’re hoping to gather those data on the autologous front. As long as things go as expected and the BAFF CAR is safe and shows clinical signals of efficacy, then moving that CAR into gamma-delta cells should be relatively straightforward.
The profile of the input cell product is also critical: if you’re going to make a batch of cells that can treat 200, 300, or 400 people, you want to make sure that the donors that you’re sourcing from and the cell population that’s being used are the most effective that you can obtain. We have quite a bit of work going on in biomarkers on the gamma-delta T cells and the profiles of donors that we would want to use in the gamma-delta setting.
BW: As I mentioned previously, as part of our BAFF CAR program, we are also looking at non-Hodgkin lymphoma and multiple myeloma. We also have some potential lead indications for the gamma-delta solid tumor program, such as head and neck squamous cell carcinoma. There are a few other indications under consideration on the solid tumor side, and we’re in the process of conducting the preclinical studies that will help inform our decision.
It’s been extremely interesting and exciting over the past few months as we’ve taken this dual CAR platform from Gianpietro Dotti’s lab at the University of North Carolina and put into our gamma-delta T cell chassis. Dotti’s group had a really nice paper in Nature Cancer showing this dual CAR approach in alpha-beta T cells, but it had not been applied in gamma-delta T cells. Over the past few months at Luminary, we’ve taken our generalized design principle for lead CAR candidates in the solid tumor space and put them into this dual CAR configuration in gamma-delta cells.
Remarkably, we’ve found that the benefits that Dotti reported in alpha-betas seem to be magnified in gamma-deltas. We’ve pushed these forward and found compelling evidence that there may be broad applicability across quite a wide range of solid tumor types. I think there are real opportunities for broader application. Right now, head and neck cancer is our primary candidate, but I’m very excited about where this could potentially go in the future.
BW: Like I mentioned, Luminary’s founders had worked together previously on the industry side. I actually wear a second hat: I’m an associate professor at the University of Minnesota in the department of pediatrics. My colleague and cofounder Branden Moriarity is also an associate professor at the University of Minnesota. David Largaespada, another cofounder, is a full professor at the University of Minnesota. We all have academic backgrounds as well as experience in the industry space, both through starting our own companies — spinout companies and start-up companies — and partnering with industry through our academic roles. We’ve all worked together before. As I mentioned, B-MoGen Biotechnologies was our first company together, along with Jeff Liter, who was the CEO of B-MoGen. I think we have a team that has a strong background spanning all the way from basic cancer biology to cell therapy, immunotherapy, and immunology.
We all have strong backgrounds in the genetic engineering side as well. This core competency around genetic engineering and then complementary expertise spanning cancer biology to immunology is very advantageous. We’ve also had some translational experience on the academic side, and Jeff has translational experience on the industry side. Merging this all together, we have expertise in understanding how to move things efficiently from the bench to the clinic. I think all that has worked to our advantage in terms of our efficiency and ability to execute that bridge from the bench to the bedside.
As a Midwestern company, we’ve faced challenges that companies on the coasts might not face, particularly in terms of fundraising. I think we’ve shown that you can be efficient, in terms of capital, people, and resources and still be innovative and successful in moving things into the clinic.
It is a tough time in the biotech space right now. Think about the model: you bring in and license a technology or two. You generate some prelim data, a little bit of seed funding. You go out and then you raise a big Series A and hire a lot of people and build and then move toward the clinic. As we’ve seen, that doesn’t always work out so well. I don’t know if the model’s going to change or if it just needs a little bit of a reset.
Things have been challenging for us. We’re looking to finalize a Series A to move some programs forward on the clinical side. We’ve also been able to be really efficient at writing grant proposals, and we’ve been quite successful in securing nondilutive grant funding. We’ve also really made the most of the seed money and the other money we’ve raised, which I think is a testament to our team and the technologies and the approach that we’re taking. Ultimately, clinical trials are expensive. We’re in the process right now of bringing in the money to do the next step, particularly on the autoimmune and the solid tumor side.
You always have to prioritize and be focused. It is easy to have many ideas and want to pursue them all, but I think you need to be very diligent, prioritizing where your potential for success is highest both from an efficacy standpoint and from the standpoint of being successful on the science and clinical side. Where is there opportunity and an opening to carve out a space that isn’t overly trodden? I would say that the hematological space with CD19 CARs is very competitive, and autologous therapies have a well-established footprint there. It’s still an area that can be challenging to make headway in unless you have a really novel and effective approach, which we think we do with the BAFF combined with our gamma-delta platform.
At the same time, we also have a novel and potentially interesting combination of technologies for our gamma platform for allogeneic solid tumor therapy as well. I think we have to be very focused, particularly on the solid tumor space, because the overall platform has so much potential that you could point it in multiple directions. But we realize that we need to be very focused on the direction where we see the highest probability for success.
BW: I think the direction is fundamentally laid out. We know that these therapies need to become more cost-efficient to produce and more scalable in terms of being able to generate large batches of cells that can be given to patients with more consistent outcomes and a much lower cost profile, while maintaining the high efficacy that’s been set forth by some of the real big successes in the hematological space, with CD19 CAR and now with BCMA and CD20 and others. I think both on the scaling and the engineering side, the complexity has to ratchet up in order to tackle the solid tumor space. In the next five to 10 years, I think it’s likely that cell types that have been engineered in multiple different ways and scaled in allogeneic fashion will become reasonable from a cost standpoint to manufacture and produce. I think that’s a big thing. Most are aware that that’s where the direction is heading.
I think there’s a lot of interest as well in in vivo engineering and ways to circumvent the need to actually manufacture the cells outside the body. I think that’s still a little ways off, but you could imagine how that would impact the accessibility of these therapies. Right now, most of these therapies are given and administered at hospitals — which are mostly larger medical centers — where they have the expertise and infrastructure to be able to deliver the cell therapies and deal with potential side effects. But the cell products have to be manufactured at dedicated manufacturing facilities offsite. I think you could imagine that opportunities to make these more accessible at a broader range of facilities could open the door for more people to receive these therapies. I think that’s always on the mind, where some of these in vivo–based approaches might have an advantage. But I think they’re still a ways behind.
In the near term — the next five years — the direction is really moving toward an allogeneic, scalable sort of system where large batches are manufactured at scale almost like a traditional pharmaceutical and can be given across many people. A lot of the work right now is finding ways to do that effectively while at the same time identifying ways to actually generate success in the solid tumor space because solid and epithelial cancers are the most common cancers.
I think there’s a long way to go just from an efficacy standpoint on that front. Most of the manufacturing in the allogeneic setting and some of those questions will probably be tackled in the hematological space. Whereas on the solid tumor side, I think the field is still looking for the next really robust platform or product from an efficacy standpoint that generates reproducible, durable responses in solid tumors. The focus there is probably not as much yet on trying to scale and other activities closer to commercialization. It’s just finding a way to generate efficacy.
Ten years down the road and beyond, I think that we’ll probably start moving away from ex vivo manufacturing and toward technologies for in vivo engineering — but that presents a whole other realm of challenges that you have to face.
Dr. Webber’s laboratory is focused on synergizing genome engineering, stem cell biology, and adoptive cellular therapy to develop novel treatments for genetic disease and cancer. Research projects in the lab currently fall into two broad areas: the application of genome engineering to develop improved cell-based immune and gene therapies, and the development of “bottom-up” cancer models using human pluripotent stem cells.
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