The next generation of oncology treatments will likely require a personalized approach wherein a patient’s own immune system will be harnessed to specifically tackle their unique cancer cells. Mark Shlomchik, M.D., Ph.D., co-founder and Chief Scientific Officer at BlueSphere Bio, discusses how the company’s new platform technologies enable the rapid development of effective personalized T cell receptor (TCR) T cell therapies for the treatment of solid tumors with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.
David Alvaro (DA): Can you explain what you see as the critical limitations of CAR-T cell therapy with respect to solid tumors and the advantages that a TCR approach presents?
Mark Shlomchik (MS): To me, the division is between targeting tumor-associated or tumor-enhanced invariant antigens versus neoantigens. CAR-T cell therapies are designed to bind to monomorphic antigens that are associated with a given class of tumor. The classical example is CD19, which is of course present on tumor cells, but also on normal B cells. Although there is a pathway to making off-the-shelf CAR-T cell therapies of this type — which is certainly viewed as being easier and cheaper — there are problems with this approach.
One of those problems is that these tumor targets may also be expressed elsewhere in the body, in normal tissues. I worry about on-target, off-tumor effects, which give rise to toxicities. This on-target, off-tumor effect has been seen in both CAR-T and TCR T cell therapies.
There is also the issue of autoimmunity in some patients. One case in point is CAR19-T cells, which destroy normal B cells. We live with that, because it is ultimately better to have that problem than to have leukemia or lymphoma. If an analogous problem occurred with, for example, epithelial cells, which are the source of many solid tumors, though, there would be a real issue.
Another problem with monomorphic antigens is escape. Because CAR-T therapies typically target just one antigen that may not be important to the cancer cell’s survival, especially in leukemias, the cancer cells are able to lose the CD19 (or other targeted) receptor. This can also happen with solid tumor CAR-T targets and is a real issue.
Finally, with CAR-T cell therapy, the antigen space is not very diverse because the antigens that can be targeted must be tumor-specific, on the surface of the tumor cell, and expressed at a high enough level to activate the CARs.
With TCRs, it is possible to access a much broader and more diverse antigen space. The challenge with TCRs is HLA (human leukocyte antigen) restriction. Every TCR must be considered in the context of not only the target antigen but also the HLA alleles that the patient carries.
DA: How does targeting neoantigens overcome those issues?
MS: I am really excited about this approach, because I believe that neoantigens are undoubtedly the Achilles heel of tumors. Tumors are comprised of cells that, in order for them to be malignant, must have a number of mutations. Even a tumor classified as having a relatively low number of mutations truly has quite a large number of mutations. Because of those mutations, tumor cells produce mutant proteins that are visible to the immune system. The immune system then recognizes these mutant proteins and will engage T cells specifically driven to target and kill those cells expressing the mutant proteins. Except for a limited list of driver mutations, which I think are very interesting and are a class of monomorphic but truly tumor-specific mutations that produce specific fusion proteins, peptides, or other unique biomolecules, many of the mutant proteins are going to be unique and idiosyncratic to the individual patient.
Creating TCR T cell therapies to target those mutations offers several advantages. The most important is that there isn’t a risk of autoimmunity. Those T cells targeting the neoantigens will not kill the patient due to adverse effects, regardless of how “charged up” they are. They only target and kill the tumor. That makes TCRs a great approach in general. It does, however, mandate personalization, as off-the-shelf neoantigen therapies are difficult to develop, as most neoantigens are unique to a particular patient and tumor. To target recurrent neoantigens, there would need to be an extremely large data set available to understand specific clusters of shared neoantigens across patients. That is one reason I think that larger movers and players are not yet showing that much interest, given that this approach has yet to be proven. There are smaller companies focusing on this area though, such as Neon and Gritstone. They are largely looking at vaccine development and TIL (tumor-infiltrating lymphocyte) expansion.
DA: How is this approach applied to cancer vaccines?
MS: With vaccines, the goal is to get the patient’s own immune system to destroy tumor cells. It is a promising concept, because we know how the checkpoint blockade — which has efficacy in a lot of people — works. There have been many great publications from a number of labs demonstrating that what happens at the checkpoint blockade is the re-emergence or the expansion of neoantigens for specific T cells. We thus have some proven biology that these cells are there.
Unfortunately, not enough patients respond, and that’s probably because they don’t have enough of the right T cells, or their T cells are too exhausted. As a result, cancer vaccines today have limited success. Cancer is immunosuppressive, and patients receiving these therapies are generally older and have had chemotherapy and other treatments that tend to make them nonresponsive. In addition, the cells that you want to respond are stuck in the tumor microenvironment, which is unfriendly to T cell responses.
DA: You also mentioned TIL expansion — what is driving interest there?
MS: TIL expansion was pioneered by Steve Rosenberg and others and has led to the generation of some pretty significant companies like Iovance. The work done by these investigators and companies has provided excellent proof of principle, because they have shown that — at least in some patients, for some tumors — you can get T cells out of the tumor, expand them in vitro, administer them back to the patient, and achieve long-term remission. I think that really demonstrates the viability of the fundamental biology.
Unfortunately, TIL expansion as performed to date fails in a large percentage of patients. It’s not standardizable. I believe there have been issues with this in terms of defining what a product really is, because it is difficult to know exactly what is undergoing expansion. Furthermore, expanded cells for some people may work great, but for others may be exactly the wrong cells. There is also the challenge of needing a relatively large tumor biopsy with enough T cells in it to begin creating the therapy. That isn’t always available for a number of patients for various clinical reasons across the broad spectrum of potentially responsive tumors.
TIL expansion is a great idea, and there has been terrific proof of principle, but I think it is very difficult to implement as an adoptive cell therapy. However, I do think that it has potential for personalized therapy. What I love about it is that, instead of relying on the patient’s own immune system to be vaccinated, it involves boosting the patient’s immune system with T cells. I like to refer to is as pushing TCR therapy or pushing T cell therapy. In the end, even if the T cells are not the best, you can probably outnumber the cancer cells and get rid of minimal residual tumors — at least, that’s the theory.
DA: What can you tell me about the approach that BlueSphere Bio is taking to overcoming these issues?
MS: Instead of taking the T cells out, we wanted to capture the T cell receptors and use them to modify a patient’s own unexhausted primary T cells in a more CAR-T cell–like manufacturing process. In this way, we can leverage the progress that has been made — and continues to evolve — for adoptive cell therapy. The industry continues to make improvements to the manufacturing of cell therapy products; we still have a way to go, but I have little doubt that we’re going to get better at it and it’s going to become cheaper and faster.
The missing ingredient was getting the TCRs out, matching them to patients, and finding the important neoantigens. Until BlueSphere Bio introduced the TCXpress™ technology, I think most people felt it would be too expensive, too slow, and impossible to personalize. Our platform, however, makes it possible to do all of this a couple of orders of magnitude faster and more cheaply than previously thought possible.
Our technology allows us to take T cells out of a tumor and sort them. Because the process is so efficient and we aren’t growing the T cells, we only need a few thousand cells, which means that even a needle biopsy is sufficient. We take the TCRs out of the individual T cells and convert them into functional T cell receptors in a few days at a cost of less than four dollars per TCR. The process is ultra-small-scale and performed by a series of pipetting robots with minimal human intervention, which makes it robust and reliable. At the same time, we also sequence the tumor and perform RNA-Seq, because we are only interested in moving forward with TCRs that target antigens that we know are expressed within the tumor. This analysis of the tumor using modern genomic techniques is combined with well-established informatics tools to enable us to understand what the mutations are for a particular patient’s tumor and to predict which will be immunogenic.
Our second platform — NEOXpress™ — identifies the sequences that are different in the tumor from the sequences found in the patient’s normal T cells and that are predicted to be presented by their HLAs. A series of antigens is then created and placed into antigen-presenting cells that are then cross-screened against the TCRs derived from TCXpress™. As a result, in a period of a few weeks and without much hands-on work, we can identify the TCRs that are specific and matched to the neoantigens in the patient’s tumor.
DA: What would you say are the key differentiators of your approach at the clinical level?
MS: First of all, our approach provides multiple neoantigen hits for a single patient. Just like we wouldn’t treat cancer with a single chemotherapy agent because it is likely to escape (the problem I mentioned with monomorphic TCRs), with our approach at least three targets are identified per person, increasing the likelihood of preventing escape. I don’t have any illusions that we’re always going to cure everybody, because nothing works that way, but I think that by going after multiple targets you do have a better chance. Second, because we have identified the neoantigens, we can demonstrate for safety purposes that the TCRs for those neoantigens do not react with the native peptides found in the rest of the body.
With this approach, we create primary T cell products that are personalized for the patient. Given the data that has been gathered on TIL expansion at checkpoint blockades, we expect that this approach will be synergistic with checkpoint inhibitors. Such a therapy could also be given with a variety of the other amazing drugs people are developing to make the tumor microenvironment more amenable. I believe this is how we are going to cure cancer eventually — with a combination of personalized approaches. We are providing the missing link to make that accessible in a timely and cost-effective way.
DA: What challenges will you need to overcome to make this approach a reality? Are there any technological advances yet on the horizon that will be crucial to your success?
MS: I’m hoping that, as cell therapy advances, we will be able to manufacture products more cost-effectively and easily. We are still a few years away from deploying this personalized solid tumor therapy, but I think that developing nonviral editing approaches where you don’t have to expand the T cells as much will be beneficial to the success of this program. This approach allows the T cells to retain a lot more of their capabilities.
In general, there is also a lot of optimization that must take place to make the process faster, cheaper, and more efficient. To best develop this process, we are doing what we call “virtual patients,” where we practice on tumors. One question we must answer is how many T cells we really need to screen per patient. Literature estimates that T cells in a tumor that are neoantigen-reactive range from 1% to 20%. That means that we should screen maybe hundreds up to a thousand T cells for each person. That is one to four 384-well plates. That’s not that hard to do, but we might find that we don’t need to screen that many. I also think the informatics are still imperfect; the prediction algorithms can be improved. Experience will tell us that. As we practice more and more, we might get better at that.
Overall, I believe it is really an evolving process that will improve as we study it. I want to get to where it is efficient enough to introduce into real patients. Given what we have seen thus far, we believe that this approach is feasible, and so we will continue to develop it with the goal of achieving significant speed and cost optimizations.
DA: What about from a regulatory perspective? What potential hurdles do you see facing such novel and personalized therapies?
MS: With any new therapeutic approach, there is a need to introduce regulators to the concept. You have to think of cell therapies differently from pills. I think we have to take even another step and recognize that, if we really want to offer people with incurable lung cancer something that could cure them, we’re going to have to be more flexible about how we define the product. You simply can’t spend months validating such a personalized therapy, because the patient is likely to die during that time.
However, there is still a lot of opportunity to provide extensive information to regulators on the products that we will be developing, and I am optimistic that it will be sufficient. The T cells that we will be working with will have come from patients and therefore will not be foreign to them. We will also be able to show regulators that these T cells react with tumor-specific mutations but not with the patient’s own cells. That is a real advantage of our approach, because we can demonstrate safety.
That is another reason why I want to get away from viral delivery using lentiviral vectors. Viral vector delivery has been clearly demonstrated, but there are risks associated with it that can be avoided by using an easier, nonviral TCR knock-in approach. We have seen proof of principle for these approaches in the literature already, and at BlueSphere Bio we are working on optimizing the process.
In general, I believe that everyone understands that solid tumors are different and that personalized solutions are going to be required. The key will be to show the right amount of efficacy using the right approach with demonstrated safety. If that can be achieved — and we think it can be with our technology platforms — it will be a real breakthrough and will be welcomed by the regulators.
DA: Given the multiple technological aspects of your approach, it seems that collaborations with partners that possess different skillsets would be valuable. Do you have any notable partnerships in place?
MS: We are interested in partners who can offer something to help improve our process or the efficacy of our products. We would love to work with a company that has an effective nonviral TCR knock-in approach, for instance. That is one example of aspects on the manufacturing side where we would be excited to collaborate.
On the other hand, BlueSphere Bio has a great platform for very quickly and inexpensively finding many, many TCRs for various applications. Just in the last four months, we’ve produced TCRs for five different targets — four of them in the minor histocompatibility antigen space. Our ability to provide a panoply of TCRs for any target makes it possible to identify elite and different TCRs that are more sensitive and that have the right qualities. We are looking for somebody who wants to partner with us to access our platform. We in turn want to partner with companies that have a therapeutic hypothesis for which they require a TCR — not on a fee-for-service basis as a service provider, but as a true development partner working together to bring impactful new therapies to patients.
DA: Do you have any products in development that you would like to highlight?
MS: We have a first-generation product that is semi-off-the-shelf. It is designed to treat blood cancers in the context of allogeneic bone marrow transplant. It is an important product, because it is going to get BlueSphere Bio into the clinic by early next year with a product for which we have used our TCXpress™ platform. Instead of looking for neoantigens, however, the platform was used to find minor histocompatibility antigens, which are like neoantigens.
Usually, transplants involve donors who are HLA-matched (for example, siblings) with many allelic proteins. We are getting TCRs that target allelic proteins that we have selected because they are only expressed in the hematopoietic system. For this therapy, we engineer a TCR from donor T cells and reprogram them with a TCR specific for an allele that the patient expresses but the donor does not. These engineered T cells kill the host bone marrow and the leukemia because these cells are hematopoietically derived, but they do not touch skin or liver cells. As a result, the anti-leukemia product we are developing does not cause graft-versus-host disease and also allows the stem cell transplant to engraft. It is developed using minor antigens analogous to solid tumor neoantigens that segregate in the human population and are thus reusable from one patient to another.
Our first target is HA-1 and will cover 15–20% of bone marrow transplants. Our manufacturing process has been standardized — much like the process for CAR-T cell therapies, and we anticipate filing an Investigational New Drug (IND) application with the FDA by the end of this year.
DA: I’d love to close with your thoughts on how disruptive or transformative you think this approach to cancer therapy will ultimately be.
MS: Immune cells travel throughout the body. It is very likely that, in most adults, many cancers have been edited out by our immune systems. Part of the reason why humans today live as long as they do could be because our immune systems are pretty good at editing out nascent cancers, at least until they become somewhat senescent. The process is very natural. We also know from checkpoint inhibitor and TIL infusion therapies that these types of treatments can be very effective in certain patients.
There are 230,000 new cases of lung cancer every year in the United States alone. Only maybe 10% or 15% of them are going to get treated in a way that will result in a definitive cure, because lung cancer is typically caught very late and there is a high tumor mutation burden. That’s a lot of people still dying from this disease.
In my opinion, targeting neoantigens in a personalized way is the best way to fight solid tumors, and I think we really have found a great way to make that approach work. In the end, these personalized products should be nontoxic and relatively easy to manufacture. It is an autologous product, which is immunologically safe and sound. While I know that there is great interest in allogeneic products because of perceived ease of manufacture, there is risk in that approach of both rejection and even graft versus host disease. The biggest problem to practically producing autologous therapies is going to be how to scale up the process. That’s why we have to make it more efficient. At BlueSphere Bio, we are developing technology that will make it possible to personalize these therapies so that they will be effective for a large number of patients.
I truly believe that this personalized approach will become the mode of treatment in the future. The reason I founded BlueSphere Bio is because I realized that we could use this technology to develop therapies that meet a huge unmet need. BlueSphere Bio now has 55 employees and we’ve already raised $120 million. The reason I have put so much time and effort into the company is because I thought it could be really disruptive. Actually, transformative is the better word.
If we are successful like I anticipate, then between 5 and 10 years from now, the approach being developed by BlueSphere Bio will be an effective way to treat cancer. In 15 years, I think our approach will supplant chemotherapy in some settings, because using these systemic treatments comes with such high toxicity. At the end of the day, it needs to be the immune system that fights cancer, and because of that, therapies must be personalized.