Gamma Delta: Two Phase 1 INDs Approved Announces Jeff Liter CEO Luminary Therapeutics
By Jeff Liter, MBS, CEO of Luminary Therapeutics
We currently have two Phase 1 INDs approved: one for non-Hodgkin lymphoma and the other for multiple myeloma. The CAR we’re using for these therapies is very unique and novel, as we are using a ligand-based CAR instead of a single-chain CAR. Our CAR is called a BAFF CAR, which has three different antigen receptors (T-cell receptors). We designed this CAR construct to overcome the primary reason for relapse in many blood tumors, which is antigen escape. In fact, up to 30% of CD19 therapies for non-Hodgkin lymphoma and about 12% for multiple myeloma result in relapse due to antigen escape. We believe that our CAR, with its three antigens, will overcome antigen escape and provide a more durable response for a larger population of patients treated with CAR T therapies.
What sets Luminary Therapeutics apart in a crowded space of cell therapy companies?
Currently, there are likely around 800-900 companies specializing in cell therapy, exploring various therapeutic indications. However, what distinguishes us is our selection of immune cells, specifically gamma delta (T-cell). This immediately reduces the number of potential competitors to roughly 12-15 companies. Moreover, we employ a unique approach to using gamma delta cells that affords us additional advantages, which we will discuss later in this interview.
Tell us about your Gamma 2.0 allogeneic platform and what’s included in the process?
Returning to the topic of gamma delta (T-cell) therapy companies, our approach is unique, and we call it our “triple play” for building an allogeneic cell therapy based on gamma delta cells. Firstly, unlike other companies that choose only one of the two primary subsets of gamma delta cells, we use both V-delta1 and V-delta2 in our final therapeutic product. We believe that this combination provides a robust approach that combines the rapid response of NK innate killing with the adoptive and tissue-resident approach of normal alpha-beta cells.
Secondly, we can incorporate an immune cloaking agent into our CAR design, which down-regulates both MHC 1 and MHC 2 restrictions. This allows our cells to persist and provide a more durable immune response by avoiding recognition as foreign cells by the patient’s immune system.
Finally, we use non-viral gene engineering, which we developed in a previous company, to genetically modify the cells. This gives us a significant advantage in terms of time to clinic, cost, and cargo size that can be incorporated into the cells. This triple play approach sets our allogeneic gamma delta platform apart from others.
Tell us about the solid tumor program.
This is an exciting development, perhaps even more exciting than our Gamma Delta manufacturing platform. We have obtained a license for innovative technology from the University of North Carolina and Gian Petro Doty. It involves a two-CAR program in which we combine two CARs and utilize a unique signaling approach. We share the (cell) activation domain but split off the costimulatory domain, allowing us to regulate the persistence of the engineered T-cells and achieve a more durable immune responses.
Doty’s paper in Nature Communications demonstrated successful clearance of 4-5 solid tumor programs in mice, including head and neck cancer, neuroblastoma, and certain types of glioma cancers, with clearance lasting up to 80-90 days. We are thrilled to bring this technology to our allogeneic gamma delta (T-cell) platform in about three months and look forward to advancing it into clinical trials.
Where are you in building out your allogeneic clinical trials?
As previously mentioned, the first two trials we approved are autologous, which I didn’t mention earlier. However, we anticipate bringing at least three, and possibly four, clinical trials from Luminary to the market between November 2023 and March 2024 through our allogeneic programs. We plan to submit two solid tumor cancer trials, one for head and neck cancer and another for esophageal cancer. Furthermore, we will select the best performer from our blood tumor programs, specifically non-Hodgkin lymphoma or multiple myeloma, and transfer it to our allogeneic platform to file for an IND. We aim to file all three INDs between November 2023 and March 2024. We are very excited about the progress of all three of these programs.
Please talk to us about your autoimmune program.
Returning to the BAFF CAR that we have, it features a single CAR with three different antigens: BAFF, TASSIE, and BCMA. These antigens are capable of effectively clearing out an entire B-cell compartment, a detail I omitted in my initial response. For patients with conditions like lupus, where their B-cells are producing autoantibodies and causing problems for the immune system, we can use the BAFF CAR to not only eliminate normal CD19 B cells but also long-lived plasma cells. Unlike other CD19 therapies designed for autoimmune diseases, ours has this capability. As a result, we believe our treatment will provide a more complete response for these patients. We plan to file an IND for our autologous manufacturing platform-based autoimmune lupus treatment in late fall of this year.
Has that been a traditionally challenging disease to treat?
Before the potential application of CAR T therapy against autoimmune diseases, this was a new field and a new opportunity for many CAR T therapy companies. All the treatments that existed were designed to only treat the symptoms and were not curative. The beauty of CAR T therapies is that they clear out the entire B-cell compartment, which contains the mutated B-cells that create autoantibodies that attack the autoimmune system. This process acts like a reset, similar to an “Alt-Control-Delete” on a computer. The B-cells in the blood are refreshed and tend to return to a more normal state. Therefore, CAR T therapy is a more curative approach compared to other therapies available for lupus, systemic scleroderma, and other autoimmune disorders that only treat the symptoms.
What challenges are you trying to overcome in cell therapy development?
When we started our company, we focused on three primary challenges. The first challenge was to demonstrate that an allogeneic platform could be as effective as autologous CAR T therapies, which have had tremendous success from 2014 to the present day. Many different allogeneic approaches have been tried, from NK cells to alpha-beta cells to knockout cells. However, we believe that using gamma-delta cells is the right approach to achieve allogeneic treatment. Our goal is to create an allogeneic product that is easily accessible and significantly less expensive. We are confident that we can reduce the cost of cell therapies from half a million dollars to one hundred thousand dollars.
The second challenge we took on was that CAR T therapies have not effectively treated solid tumors to date. We believe that dual targeting, where we split off the costimulatory domains, is a first step towards demonstrating that CAR T therapies can work in solid tumors. A few researchers have shown success by tuning CAR signaling, and we are on a good path to making this happen.
The third challenge is related to blood cancers, where CD19 therapies and CAR T therapies have successfully treated 55 to 60% of patients. However, 30 to 40% of patients still experience relapse. We believe that a significant portion of this is due to antigen escape, and we believe that our BAFF CAR with the three ligands will start to reduce those numbers. It is essential for patients to consider multi-antigen CAR constructs to fully treat their cancers.
How are you addressing relapse in patients?
As mentioned earlier, the most notable blood diseases being treated with CAR T therapies are non-Hodgkin lymphoma and multiple myeloma, primarily using CD19 CAR constructs. Attempts have been made to combine CD19 and CD20, but the signaling conflict that can occur when two CARs are combined hasn’t been resolved, rendering them ineffective.
In non-Hodgkin lymphoma, despite the availability of commercial products for the last 5 years, 30% of patients experience relapse because CD19 no longer expresses on the cancer surface. On the multiple myeloma side, the relapse rate is around 12% to 15%. However, there are challenges in producing this particular product because it involves engineering with viruses, which we avoid. Consequently, we can bring products to the clinic much faster than our competitors, which is how we aim to address antigen escape and relapse rates in blood tumors.
This is also a non-viral allogeneic platform compared to a virus-based platform. Tell us why that’s important.
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“This is a transposon system that was developed by our previous company. In fact, we were able to develop a brand new transposon system that achieves around 60% integration, which is equal to or better than virus-based systems. We can achieve this at a cost of only 25% to a third of the cost of virus-based systems, and we are able to obtain clinical-grade reagents in four months or less. This allowed Luminary to obtain the first two phase 1 INDs within just 19 months of in-licensing that technology. We believe that we know this technology better than anybody else since we developed it at our former company, Demogen Biotechnologies. When we sold that company to another company, we in-licensed the technology right back because we knew the power of that tool.
Is this a new approach, or has the viral approach developed in parallel to the non-viral approach?
Viruses, specifically lentiviruses or retroviruses, have been present since the inception of CAR T therapy. The use of CAR T therapy gained significant momentum in 2013, during my tenure as Chief Operating Officer of a sizable CDMO. During my tenure, we processed approximately 25 different CAR T therapies, and even today, around 90% of these therapies employ lentivirus or retrovirus. Before the non-viral method we developed, two transposon systems, Sleeping Beauty (SB) and Piggyback (PB), were utilized. However, both of these systems are proprietary to a single company.
When we developed Demogen and our new transposon system in 2017-2018, we aimed to create a technology accessible to everyone. Our non-viral system is novel and still relatively new. Presently, many CAR T therapy companies are exploring non-viral methods because they offer several benefits, such as reduced costs, shorter timelines to the clinic, and greater cargo capacity compared to viral systems.
And gamma delta cells a reasonably new approach for allogeneic CAR-T therapies?
Yes, they are. If you look at where the industry is headed, when people first tried to build allogeneic therapies, they had two choices: either using NK cells, which, like Amit Delta, are inherently allogeneic, or they took alpha beta cells and worked on knocking out all the various NHC restrictions required to make them an allogeneic cell. It’s a more understudied cell type, but if you look at the particular gamma delta cell therapy companies out there today, they’re starting to have pretty promising results in the clinic. As I mentioned, none of them have the components that we have where we use non-US engineering. We are able to preserve both V-Delta 1 and V-Delta 2, and in fact, we have an immune cloaking. So, yes, this is new on the scene, but I think it shows the most promise of all the three different ways you can approach allogeneic manufacturing.
We are confident that, and our data every day is telling us more about this, we are solving these three problems that we set out to solve. The first being the manufacturing challenges of autologous therapies and turning that into an allogeneic therapy that actually works as well as autologous. Secondly, is to be able to show that CAR T therapy can work in solid tumors. And finally, that we have an answer to those relapse patients of the 30% magnitude in blood tumors. That’s Luminary in a nutshell, covering off on those three very big challenges that the industry is facing. By Jeff Liter, MBS, CEO of Luminary Therapeutics
What is Gamma Delta in CAR T-cell therapy?
Gamma Delta (γδ) T cells are a type of white blood cell that can be utilized in CAR T-cell therapy. CAR T-cell therapy involves collecting a patient’s own immune cells, genetically engineering them to produce a chimeric antigen receptor (CAR) that targets cancer cells, and then infusing the CAR T cells back into the patient’s body to attack the cancer.
Traditional CAR T-cell therapy uses alpha beta (αβ) T cells, which are the most abundant type of T cells in the human body. However, recent research has shown that γδ T cells may have unique advantages for CAR T-cell therapy. γδ T cells can recognize and kill cancer cells in a different way than αβ T cells, and they may also be more resistant to certain types of cancer treatments.
Overall, the use of γδ T cells in CAR T-cell therapy is an area of active research and holds promise for improving the effectiveness of this cutting-edge cancer treatment.
How has CAR T-cell therapy changed in the past 10 years?
CAR T-cell therapy, a form of immunotherapy, has undergone significant changes in the past decade. Here are some key developments:
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Expanded Approval: In 2017, the US Food and Drug Administration (FDA) approved the first CAR T-cell therapy, Kymriah, for the treatment of certain types of leukemia and lymphoma. Since then, the FDA has approved several other CAR T-cell therapies, including Yescarta and Breyanzi, for the treatment of various blood cancers.
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Targeting New Antigens: Originally, CAR T-cell therapy was limited to targeting a few antigens found on cancer cells. However, in recent years, researchers have identified new antigens that can be targeted by CAR T-cells. This has expanded the number of cancers that can be treated with CAR T-cell therapy.
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Improving Safety: Early versions of CAR T-cell therapy were associated with severe side effects, such as cytokine release syndrome and neurotoxicity. However, researchers have made significant strides in improving the safety of CAR T-cell therapy. For example, they have developed methods to control the activity of the CAR T-cells, such as by using switchable CAR T-cells, which can be turned on and off using small molecules.
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Using Allogeneic CAR T-cells: Initially, CAR T-cell therapy used a patient’s own T-cells, which were modified in the lab and then infused back into the patient. However, researchers have also been exploring the use of allogeneic CAR T-cells, which are derived from healthy donors. This approach could potentially make CAR T-cell therapy more widely available and less expensive.
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Combining CAR T-cell Therapy with Other Treatments: Researchers are exploring the use of CAR T-cell therapy in combination with other cancer treatments, such as checkpoint inhibitors, to improve outcomes. They are also investigating the use of CAR T-cell therapy for solid tumors, which have been more challenging to treat with this approach.
Overall, these advancements in CAR T-cell therapy have greatly expanded its potential applications and improved its safety and efficacy.
Luminary Therapeutics – About the Company
Luminary Therapeutics is a biotechnology company that is focused on developing next-generation gene therapies for the treatment of rare and serious diseases. The company is based in Cambridge, Massachusetts, and was founded in 2017 with the mission of advancing cutting-edge science to help patients in need.
Luminary Therapeutics’ approach is based on the use of adeno-associated viruses (AAVs) to deliver therapeutic genes to specific cells in the body. This approach has the potential to provide a long-lasting and potentially curative treatment for a wide range of genetic diseases.
The company’s pipeline includes programs for the treatment of rare diseases such as Pompe disease, Fabry disease, and Huntington’s disease. Luminary Therapeutics is also working on developing gene therapies for diseases that affect the central nervous system, such as spinal muscular atrophy and amyotrophic lateral sclerosis (ALS).
In addition to its gene therapy programs, Luminary Therapeutics is also developing novel technologies to enhance the safety and efficacy of gene therapies. The company’s team includes experts in gene therapy, molecular biology, and drug development, and is dedicated to advancing the field of gene therapy and improving the lives of patients with rare and serious diseases.
Jeff Liter – About The Author, Credentials, and Affiliations
Jeff Liter is a seasoned executive with over 20 years of experience in the biopharmaceutical industry. He currently serves as the Chief Executive Officer of Luminary Therapeutics, a clinical-stage biotechnology company focused on developing innovative gene therapies for rare diseases.
Prior to joining Luminary, Jeff served as the Chief Operating Officer of AVROBIO, a clinical-stage gene therapy company. Before that, he held various leadership roles at Biogen, where he was responsible for leading the company’s global manufacturing operations and supply chain.
Throughout his career, Jeff has played a key role in advancing multiple gene and cell therapies into clinical development and commercialization. He has a deep understanding of the challenges and opportunities involved in developing and bringing gene therapies to market, as well as a strong track record of building and leading high-performing teams.
Jeff holds a Bachelor of Science degree in Chemical Engineering from the University of Michigan and a Master of Business Administration from Harvard Business School. He is a recognized thought leader in the biopharmaceutical industry and has been featured in various publications and conferences.
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