Cell therapies, particularly chimeric antigen receptor (CAR) T cell therapies, are highly complex and autologous therapies, and those on the market today require weeks to manufacture from the time a patient sample is obtained. One of the major challenges facing CAR-T cell therapy is the cost and complexity to deliver these treatments. EXUMA Biotechnology’s “logic-gated” technology leverages the unique nature of the acidic tumor microenvironment to activate CAR-T cells when they are near the target tumor. The company’s next-generation rapid point-of-care (rPOC) platform is being developed for subcutaneous autologous CAR-T administration in a matter of hours following blood draw, making the potential for same-day CAR-T a reality for more patients. Driving these advances are industry leaders in cell therapy technology committed to increasing the efficiency and reducing the cost of cell therapies, thus expanding patient access.

Q&A: Pharma’s Almanac Scientific Editor in Chief David Alvaro, Ph.D., spoke with EXUMA Biotechnology’s Chairman and CEO Gregory Frost, Ph.D., and Vice President, Oncology, Research & Development Sid Kerkar, M.D., about their earlier experiences with cell therapy, the genesis of EXUMA Biotech, and the success they have had so far in developing rPOC CAR-T cell therapies.

DA: You both have extensive backgrounds in the cell therapy field. What experiences in particular drove you to establish EXUMA Biotechnology and led you to the solutions you are pursuing today?

GF: When we were building Halozyme in the late 1990s and early 2000s, cell therapy was a new field, and it was challenging to get a handle, not only on the regulatory science, but frankly on the overall process. However, we all agreed that it made sense to develop cell therapies for patients, providers, and payers. I thoroughly enjoyed that experience, and I love what’s been done. When a medicine is launched in a hundred countries around the world, you know it is a leading-edge technology.

Stepping back, I can say my fascination with the cellular therapy space started around 2013–14, when it struck me that everyone was really excited about achieving great efficacy, but there wasn’t sufficient focus on the inefficiencies in the process. I realized that people didn’t spend enough time thinking about providing greater access, because creating safe and effective medicines is a sufficiently difficult challenge by itself.  And I couldn’t imagine a better place to spend my time than trying to make something that’s phenomenally effective easier to achieve, so more people could have access to these therapies. 

We set out to tackle that concept about five years ago, and truthfully in the beginning we didn’t know if we’d be able to get over some of these scientific hurdles, because no one had really done it before. Doing so requires a long-term investment, time, and a foundation of strong science.

That is where my experience in cell and gene therapy and transplantation came into play, as well as my knowledge of the work coming from academia, particularly MD Anderson and the National Cancer Institute (NCI). The issues we saw were that viral vectors were thought to not be able to modify white blood cells without getting them to start dividing, and that sufficient cells had to be manufactured and preparative chemotherapy had to be performed before the cell therapies could be administered.

We knew that, in organ transplantation, making something that can actually engraft and stay as a living medicine for a long period of time is really difficult. We decided to tackle that piece first, with the goal of harnessing all of the benefits of using patient cells, but with additional properties using vectors that overcome the manufacturing issues of current modified cell therapies. 

Our goal was to take drawn blood and achieve cell modification within four hours, because we wanted the process to allow patients to be treated and discharged in a single day, as is the case with standard chemotherapy treatments. Moving from intravenous to subcutaneous injection was one aspect. 

Transferring production from a central manufacturing facility to synthetic lymph nodes on the patient’s skin was another. T cells are normally localized in lymph nodes, where they see all of the antigen-presenting cells, after which they expand and enter the bloodstream. With this approach, we reduced the volume of blood required and the gene vector dose, and the cells are produced within the patient, eliminating the need for commercial production and all of the logistical difficulties associated with that. 

From the beginning, we were laser-focused on building that technology, and each of the pieces that had to come together are interrelated workstreams. In each case, though, we focused on the patient and the provider to ensure that we were developing a solution that actually overcame existing issues and fit into the existing system. 

SK: I would like to start by stating that I’m truly excited to be working with Greg and the EXUMA team on a journey to bring new innovative CAR-T therapies to patients. Thinking back 20 years ago, the plan after graduating medical school was to become a surgeon. However, this all changed during my second year of Residency at the Detroit Medical Center, now 16 years ago, after I saw a documentary about cancer immunotherapy research being done by one of the pioneers in the field, Dr. Steven A. Rosenberg, Chief of Surgery at the National Cancer Institute (NCI, part of the National Institutes of Health (NIH)). I sent him a cold email expressing interest in a surgical oncology fellowship at the NCI, and, much to my surprise, he responded.  In 2006, I left Michigan to become a clinical fellow on Dr. Rosenberg’s cancer immunotherapy service. These were early days for immunotherapy where most of the patients being treated were in clinical trials. I had the privilege of providing medical care to the inspirational individuals willing to come to the NIH Clinical Center to get treated with an experimental immunotherapy.  This was a career-defining moment for me, as I came to realize that immunotherapies offered a hope for a cure. 

Despite the promise of cancer immunotherapies back then, the majority of the patients we took care of did not respond to their treatment. This too was a career-defining moment, as I remember desperately wanting to come up with better treatments, and it was this passion that led me to the lab. I spent the next eight years doing basic postdoctoral research and training in pathology to gain a better understanding of the tumor microenvironment, and worked on developing a new and more potent gene therapy. One of the most rewarding experiences I’ve had professionally was watching my postdoc project get taken into a clinical trial. 

Following my 9 years at NIH, I made the transition to industry and have held positions in discovery, translational research, and clinical development at some of the larger global pharmaceutical companies. Today, one of the major hurdles for gene and cell therapies is the time and cost it takes to generate a treatment. EXUMA has developed innovative technology to potentially overcome these obstacles. My road to EXUMA actually began when I met Greg during my postdoc years at the NIH. I admired and respected his entrepreneurial success at Halozyme. We kept in touch during my time at pharma, and we decided that the timing was right to join EXUMA last year at an important inflection point for the company as we look to further our scientific foundation and take new promising programs to patients in the near future.

DA: Sid, you made a significant transition from academia to industry. Can you talk a little bit about how that came about? 

SK: During my time with Dr. Rosenberg, the Surgery Branch conducted one of the first CD19 CAR-T clinical trials. It was very much a “eureka!” moment when, in patient after patient, the tumors were melting away. During our Monday morning rounds, it was incredibly rewarding to see the hope CAR-T was bringing to patients and their families. At the time, I began to think about what it takes to ensure that patients with hematologic malignancies around the world could have an opportunity to be treated with a potentially curative new therapy. This is when I started to become seriously interested in Industry.  I witnessed how Dr. Rosenberg licensed this transformative new treatment to  Kite Pharma (now part of Gilead Sciences) and how the executives and scientists at Kite developed the treatment into Yescarta^® (axicabtagene ciloleucel), a marketed drug with the potential to save hundreds of thousands of lives across the globe.

I came to EXUMA after speaking with Greg about the exciting work the company is doing and to be in a very “hands-on” biotech environment with scientists committed to developing an innovative technology. The early discovery work initiated five years ago has matured to the point now where promising preclinical data exists. The ability to genetically modify white blood cells after only four hours of exposure with viral vectors is truly remarkable and a scientific feat that was not thought possible only a few years ago. I am excited to lead EXUMA’s R&D team as we look to bring these innovative technologies to patients. 

DA: What are the key drivers for the work being done at EXUMA today?

GF: For patients with advanced cancers, their greatest need is more time. For CAR-T cell therapies today, the time from apheresis to treatment is weeks, and a lot of patients cannot wait that long. Our technology doesn’t just increase potential access in terms of reduced cost and complexity; it can get treatments to patients more quickly so those CAR-T cells can get to work rather than sitting in a reactor at a central manufacturing facility.

Achieving expansion of the modified T cells without lymphoid-depleting chemotherapy prior to treatment is another important driver for us. Doing so avoids immunosuppression and adverse events, particularly infections, associated with such pre-treatment. If we can do this right, the administration process can be very simple from a deployment perspective, and follow-up checkups can be performed at home, because there isn’t a high infection risk. 

Overall, we are taking two new approaches: pushing from liquid to solid tumors and moving from a centralized manufacturing process to the individual patient. With these two new approaches, we’re really trying to push the direction of cellular therapies across the board. They’re tough to implement from the scientific perspective, but they are both really important things to do to move the field forward. 

DA: EXUMA’s logic-gated technology seems to be an intuitive and ideal approach to ensure appropriate tumor targeting. Can you provide some mechanistic details on how you achieve the “gate?”

GF:  With solid tumors, one of the biggest hurdles is achieving precision. The current approach is to identify unique cancer mutations with new antigens that can be targeted. While this approach has been successful, it is complex and leads to therapies that may treat very few patients. In addition, many solid tumor antigens — when placed in a CAR setting — cannot always distinguish cancerous versus normal cells, and off-target effects are an issue.  

Our basic premise for the “logic-gated” technology was to engineer the binding domains of CAR-T cells so they are only turned “ON” to attack antigens that exist within the TME. Our logic-gated CAR-Ts require both the target antigen and the TME to become fully activated and will therefore only work in tumor — not normal — tissue, thereby reducing potential on-target, off-tumor toxicity.

SK: Tumor acidity is a byproduct of the high metabolic rate of cancers and is a well-known characteristic of the TME. EXUMA’s CAR-T cells are engineered to take this biological phenomenon into account. The logic gate refers to CAR-T cells designed to be optimized to recognize tumor antigens at a lower pH that is characteristic of the TME.  The process is also reversible so that, when CAR-T cells leave the TME, normal tissue expressing a target antigen will not be targeted due to the more physiologically normal and non-acidic environment outside of the TME.

A tremendous benefit of this approach is that it enables targeting of shared antigens that are present in normal and tumor cells. Harnessing the differences of the TME therefore enables us to target a common antigen that is expressed on normal tissue, but also highly expressed on tumor cells. 

This approach addresses multiple roadblocks for cell therapies in solid tumors and expands the possible antigens that can be targeted, including antigens that are very well known and well developed. If you look at the entire landscape of solid tumors, you could cover the whole landscape with shared antigens. Based on EXUMA’s internal bioinformatics models, up to 90% of solid tumors could be targeted with only 10 logic-gated CAR-T constructs. So it’s an exciting, clinically enabling technology. 

DA: Can you explain how it is possible to produce target CAR-T cells in an inpatient setting within just four hours?

GF: In addition to addressing concerns about on-target, off-tumor toxicity, we also needed to develop the ability of the cells to expand without the use of lymphoid-depleting chemotherapy. Both required new viral vector technology: a synthetic component that can fit into a small vector to allow those cells to expand without chemotherapy and additional components in standard SIN lentiviral backbones that could selectively enter T cells in the blood.

What we established is a process in which the gene vector is placed into freshly drawn blood. Within four hours of exposure, it enters and genetically modifies the T cells. These modified CAR-T cells are then captured and transferred subcutaneously to beneath the patient’s skin. Cell expansion up to 10,000-fold occurs, and within two weeks the number of cells in the blood is increased sufficiently that they reach the tumor. Interestingly, what we have observed is that the white blood cells in the bloodstream, which are there because we do not perform lymphoid-depleting chemotherapy, really drive the cell expansion.

I also want to note that part of the work we have completed over the last three to four years has been to develop a chemically defined media suspension-based lentiviral manufacturing process that enables GMP material to be produced in such a high quality that its product quality attributes can be characterized very carefully, rather than treating it as a critical intermediate. 

DA: Why did you choose subcutaneous administration?

SK: The preclinical studies of our engineered vector designs repeatedly show that subcutaneous administration is more effective than intravenous treatment. Our studies showed that the subcutaneous environment transforms into a synthetic lymph node and provides an environment for the in vivo proliferation of CAR-T cells generated from our vectors. Importantly, subcutaneous delivery can also potentially provide a better patient experience. It involves a single injection that is quick to administer and can be performed in most medical settings across the country without the need for infusion ports or catheters.  

DA: Beyond the safe and effective delivery of CAR-T cells to the right tumors, it is clear that EXUMA is attempting to address the many logistics and other issues associated with the production and administration of these therapies to patients by leveraging existing infusion clinic infrastructure. Can you explain your approach?

SK: The leap in technology that EXUMA has made is the ability to develop a gene and cell therapy in less than six hours and to go from blood draw to subcutaneous injection in one day at one site. It is a kinder, gentler, more patient-friendly cell therapy that we envision can one day be performed at outpatient oncology infusion centers where pharmacists and nurses can readily reconstitute the gene vectors with fresh whole blood and produce a subcutaneous injection within a normal day’s workflow.

GF: Cell therapies are tremendous, but if they cannot reach many of the people who need them, they don’t offer maximum value. Patients with solid tumors are treated by a network of community oncologists. We looked at the tools and systems in place and thought about how we could make cell therapy treatments more efficient. If we can be successful, we can eliminate all of the logistics, complexity, and time involved in central manufacturing, reducing the cost and complexity of care while driving patient access. 

Of course, cell therapies must be safe and effective. But once you pass through that gate, it is essential to develop a means for getting the treatments to as many people as possible. We have taken the approach of starting with that end in mind — getting cell therapies out to all of the patients that need them.

We believe that our rPOC platform based on our proprietary centralized CCT3 CAR-T process can dramatically change the CAR-T landscape; eventually, rPOC could use the community oncology infusion clinic infrastructure and be administered without lymphodepleting chemotherapy or long-term immunosuppression.

DA: What can you tell me about the status of the rPOC program?

SK: We presented preclinical data for our rPOC, subcutaneous, autologous CAR-T platform in November 2020. In animal models, exposure of peripheral blood to our CD3-directed lentiviruses encoding a CD19 or a CD22 CAR for just four hours followed by subcutaneous injection to create a synthetic lymph node resulted in robust CAR-T cell expansion with regression of established tumors. The entire process of genetic modification of peripheral blood mononuclear cells and subcutaneous dosing can be completed in less than six hours, resulting in targeted genetic modification of T cells without prior activation.

Importantly, logic-gated HER2 CAR-T cells were also capable of completely regressing large established gastric carcinoma xenografts that had progressed on prior trastuzumab therapy. In addition, compared with ungated HER2 CAR-T constructs, logic-gated HER2 CAR-Ts did not eliminate normal hepatocytes with HER2 expression in mouse livers. These results demonstrate that a logic-gated HER2-targeted CAR-T can eliminate established HER2-amplified malignancies in a xenograft model, while mitigating potential on-target, off-tumor toxicity.

In January, we entered into a strategic collaboration with Moffitt Cancer Center to develop the first rPOC subcutaneous product for the treatment of B cell malignancies targeting CD19 and CD22. Moffitt will provide regulatory support, gene product characterization, and analytical testing to support first-in-human studies. We are looking to get this program into clinic with our first targets toward the end of 2021 and the beginning of 2022.

DA: What needs to occur before cell therapies are commonplace? For CAR-T cell therapies specifically and immunotherapies more generally?

SK: We need the acceptance of cell therapies as part of the oncologist’s armament and their comfort in delivering this type of treatment to patients. It is outside of the traditional oncology box and requires specific experience from the oncologist’s end. Getting that comfort from the delivery of the treatment for patients will be a key driver for advancing the field. Then it will be about building better treatments and improving on the cell therapies that exist today, including improving efficacy and safety and managing side effects specific to immunotherapies.

GF: There are liquid and solid tumors and central manufacturing and off-the-shelf approaches. Autologous treatments for hematologic malignancies are the most mature space, but now many people are trying to develop cell therapies for solid tumors. The next move will be toward off-the-shelf treatments for both liquid and solid tumors, with the latter being the most difficult to achieve.  

In the meantime, finding autologous cell therapies that treat solid tumors will be a big win. So will allogeneic treatments for hematologic malignancies. I am encouraged that this industry continues to be getting great scientists onboard; that we’re still attracting some of the best and brightest people in science and medicine to move things forward. 

DA: Within that context, where do you see EXUMA positioned five or ten years from now? 

GF: Medicines that can reduce cost and complexity and drive access are relevant around the world. As we develop the platform to do that, we are maintaining a hybrid business model that includes business-to-business alliances in which we can help advance centralized cellular therapy technologies and products through the clinic and to patients. 

We will continue to maintain a blend of partnerships and internal development efforts, with success in the partnerships helping to fund the development of our rPOC platform. We are mastering viral manufacturing, because even today there really aren’t any CDMOs that can take a completely new process like that and raise the quality standards. With the infrastructure we have and continue to build, including wholly owned manufacturing facilities, we will be positioned to support our internal programs and progress partnerships with the ability to manufacture materials for others, from bulk drug substance to fill/finish.

Five years from now, the goal is to move our solid tumor programs into registration trials. We will also look at our platform to determine which other development products we should keep and where we should partner with the intent of leveraging relationships that bring us strategic strengths in particular therapeutic areas. It is too early at this point to be more specific: we could be forward integrated in Asia, partnered in the United States or Europe, or the other way around for each product. 

SK:  Five years from now, we would love to see our CAR-T science advance even further and see our treatments helping cancer patients live longer and better lives. It will be a tremendous reward to bring new medicines to the oncology community.