Where the arts and science meet
I had the opportunity to speak on a panel at one of the largest conferences hosted in the U.S. each year: SXSW (South by Southwest®). Founded in 1987, SXSW is an event that brings together thousands of creative minds from around the world to the city of Austin, Texas, to meet, learn and share ideas. What started as a conference focused on the music and film industries has evolved into an event that draws attention to the intersection of technology and the arts.

I have always believed that science at its root is an artform. At its most fundamental level we design and create new science that has the power to deeply impact those around us. That is why I was excited to participate in SXSW’s Health & MedTech track this year, which aims to highlight emerging new ideas that address how technological and social changes are impacting the field of medicine. While there, I discussed ������Ƶ’s mission to expand access to life-saving cell therapies by leveraging a tool that people typically see as dangerous – viruses.

Reimagining viruses as medicine
In 2020, the world quickly became aware of the impact viruses can have on human health. For me, this realization came early on during my time as a physician and pediatric immunologist. I was treating children who were becoming sick due to the heavy burden of infections. These first-hand experiences motivated me to develop novel treatments for patients who had genetic defects in their blood cells, making them unable to fight off those infections. This led me to study the different types of technologies that could facilitate gene transfer to replace the defective gene in these patients.

After many years at the bedside treating patients, mentoring students, and advancing new technologies at innovative biotech companies, at about 55 years old I decided to take one last giant swing of the bat: I co-founded ������Ƶ with the goal of advancing practice-changing cell therapies. At ������Ƶ, we are pioneering a way of using viral vectors to deliver new genes into tumor fighting T cells to treat cancer. Through years of work by many in the field, we know how our T cells recognize and attack cancer cells. We can replicate this by manually placing a new gene, called a chimeric antigen receptor (CAR), into our T cells to train them to recognize cancer and kill it – which we now call CAR T cell therapy.

CAR T cell therapies are very effective, however, only one in five people can access the treatments. At ������Ƶ, we have set out to solve this problem. This has required a fundamental change in how we deliver CAR T cell therapies to patients. Rather than removing cells from a patient’s body before spending a month manipulating them in a laboratory, we have engineered a way to deliver the CAR gene directly to the patient’s T cells in vivo using a viral vector. These versions of viruses are the perfect vehicle for transferring a piece of genetic information into a cell to reprogram it. Knowing this, we have modified lentiviral vectors in a way that allows them to do the necessary gene transfer inside the patient, delivering the CAR gene, so that the patient can manufacture their own cancer-fighting therapy inside their body.

We are currently manufacturing our viral vectors, which are used in our gene delivery platform called VivoVec™, at our Colorado facility, The CLIMB, and look forward to initiating our first clinical trials this year. Our mission is to overcome the limitations of approved CAR T cell therapies including the challenges of ex vivo manufacturing, difficult administrative processes that are a barrier to care, and the limited reach of current treatments. What I have come to realize over the course of my medical career, and life, is that we are all touched by serious medical issues at one point or another – at ������Ƶ, one point we emphasize over and over is that patients are waiting.

Listen to the SXSW panel “From Adversary to Ally: Reimaging Viruses As Medicines” featuring Andy Scharenberg, M.D., Steffanie Strathdee, Ph.D., and moderator Vincent Racaniello, Ph.D. here:

Andy on the stage at SXSW 2024

Andy at SXSW 2024

Ultimately, Emily was the first child to receive a revolutionary new therapy called CAR T cells, which had been engineered from her own (autologous) white blood cells to recognize a protein on her cancer cells and, hopefully, clear her body of her leukemia. She received the CAR T cells in 2012 and had a very rocky clinical course. This included a potentially fatal side effect called cytokine release syndrome, or CRS. Further innovations in the care of patients receiving cellular therapies identified interleukin-6 (IL-6) as an important biologic mediator of this and other side effects. Importantly, scientists and researchers discovered that blockade of IL-6 from its receptor could help ameliorate the symptoms of CRS and potentially save lives. In the case of Emily, it did just that.

Now ten years later, Emily remains in remission from her leukemia, and the field of cellular therapy has made huge strides in treating patients, both children and adults, in the treatment of hematologic malignancies. There are now five products in the US approved for the treatment of such cancers, including some leukemias, lymphomas, and multiple myeloma. As these products have moved forward from clinical trial to commercialization, many roadblocks to patients receiving these therapies have arisen. These include the need for cell collection, a manufacturing time that can be anywhere from days to months, potentially requiring alternate therapies to keep their cancer “in check” while that uncertain manufacturing takes place, and the need for so-called “lymphodepleting” chemotherapy or conditioning to ensure the cells are accepted by the patient. Finally, the significant cost associated with this process and labor/resource-intensive manufacturing processes limit the number of patients who might benefit from these therapies in the long term. Still, to date, many people like Emily have benefited from the development of these groundbreaking treatments.

In terms of sheer numbers, solid tumors such as breast, lung, and others are much more common than blood cancers in the overall population. Unfortunately, getting these cellular therapies to solid tumor patients has faced many roadblocks, both biologic and logistic. As clinical trials have been initiated with so-called “ex vivo” autologous cell therapies, like the ones approved for blood cancers so far, researchers have discovered that solid tumors are much more complex in terms of the environment in which solid tumor cells “live”. This tumor environment makes them much more resistant to cell killing by CAR T cells, as they tend to suppress the activity of the immune system in general, which is how they take hold in the first place. This puts CAR T cells at a disadvantage in the treatment of these tumors. Many researchers and private companies are working very hard to unlock the key to this suppressive tumor environment to make CAR T cells more effective in solid tumors.

Unfortunately, even if the biologic hurdles are overcome for these cancers, the burden of manufacturing and administering autologous cell therapies along with preparative lymphodepleting chemotherapy must be addressed. At ������Ƶ, we are taking a unique approach to conquer these challenges and are carefully designing a platform to address each of these issues. Our VivoVec™ technology is designed to be off-the-shelf, ready when a patient needs it. It should allow patients’ own bodies to make CAR T cells, without the need for ex vivo manufacturing. Next, the rapamycin-activated cytokine receptor (RACR™) system, delivered to the patient’s immune cells by VivoVec™, works in concert with rapamycin, an FDA-approved medication, to provide both a proliferative signal to transduced T cells as well as allowing for suppression of a potential immune response to the patient’s new CAR T cells. This should remove the need for lymphodepleting chemotherapy associated with most cellular therapies. Finally, a portfolio of bispecific engagers, or TumorTags™, are being developed to allow the CAR T cells to attack multiple targets simultaneously on both tumor cells as well as the tumor environment to give CAR T cells an advantage biologically to overcome CAR T cell suppression and, ultimately, lead to better efficacy while maintaining patient safety.

We and others around the world are working very hard to combat cancer in a way that is safe, effective, and equitable for all members of society. We stand on the shoulders of patients and scientists who have contributed to the body of knowledge that guide our efforts, and we are committed to transforming the treatment of blood cancers and solid tumors.

While chimeric antigen receptor (CAR) T cell therapies have revolutionized the treatment of blood-forming tissue cancers (i.e., hematologic malignancies), major limitations hinder their widespread application. Decades of CAR T cell therapy efforts, starting with “first generation” CAR T cell therapies in the 1990s and leading to the first CAR T cell therapies receiving FDA approval in 2017, have produced successful results in treating B cell malignancies, with long-term remission achieved in 30-40% of certain patient populations. Despite the promising clinical efficacy of CAR T cells in hematologic malignancies, significant challenges remain, including patient access, complex manufacturing, and high cost. ������Ƶ is focused on developing “off-the-shelf” cancer therapies to overcome these challenges.

Introducing ������Ƶ’s Engineered iPSC Platform

As part of ������Ƶ’s mission to deliver “off-the-shelf” therapies for cancer, we are developing an Engineered induced Pluripotent Stem Cells (iPSCs) platform. While the cell therapy industry has demonstrated the transformative potential of using gene-engineered, patient-derived cells for treating specific disease indications, many challenges with using patient-derived materials remain, including limited expansion capacity and scalability, manufacturing complexity, high cost, variability from patient to patient, and patient access. ������Ƶ’s Engineered iPSCs platform is designed to overcome these challenges by instead utilizing iPSCs. iPSCs are pluripotent stem cells, a type of cell theoretically capable of differentiating into any other cell type – including lymphocytes such as T cells and natural killer (NK) cells that are applicable to the treatment of cancer. Using iPSCs, we aim to enable scalable and simplified manufacturing of cancer-fighting cells like NK cells and T cells, thus reducing costs and improving patient access to cutting edge cellular cancer therapies.

iPSCs possess an unlimited expansion capacity, meaning they can reproduce and proliferate indefinitely, potentially generating a nearly endless supply of differentiated immune cells for cancer therapies. iPSCs are also amenable to precision multiplex genome editing, allowing introduction of multiple genetic modifications to enhance the cancer-fighting capabilities and safety of the immune cells they eventually become. iPSCs can similarly be engineered with the goal of protecting them against allogeneic rejection by the patient’s own immune system, improving both their initial expansion and duration of engraftment.

Furthermore, while either patient-derived or donor-derived blood materials are inconsistent, iPSCs provide a consistent starting material originating from a single cellular clone, which we believe will enable genomic consistency and integrity in the final cellular product. Taken together, we believe that our Engineered iPSCs platform offers solutions to many of the challenges of using blood-derived materials for the generation of cellular cancer therapies by providing an approach to create a precisely-edited, consistent, scalable cell therapy manufacturing process with reduced manufacturing complexity.

Overview of ������Ƶ’s integrated platform detailing how the RACR-iCIL cells are engineered to express the Rapamycin Activated Cytokine Receptor to create the RACR-TagCAR iPSC line that can be induced by infusion of rapamycin to increase engraftment and persistence. These can be co-infused with TumorTag small molecules to universally label tumor and stromal tissue for precise targeting by RACR-CAR T cells.

������Ƶ’s Technology Enables a Differentiated iPSC Therapy Platform

������Ƶ’s engineered iPSCs are designed to provide an “off-the-shelf,” or ex vivo and allogeneic, immunotherapy treatment option by creating precisely engineered iPSCs, outside of patients, that express both our RACR cytokine receptor system and universal TagCAR.

Rapamycin administration in patients who already have received infusions of RACR-iCIL cells have a multimodal effect: 1) promoting engraftment with a protective effect against host versus graft responses and, 2) promoting expansion through activation of cytokine signaling pathways.

Engraftment and persistence of therapeutic cells are key challenges in the cell and gene therapy space that are commonly achieved by treating a patient with highly toxic chemotherapy prior to administration of the cell therapy. Persistence is key to achieving durable tumor remission and has proven to be a challenge in the allogeneic cell therapy space in part due to the anti-allograft response against the therapeutic cells. To address the challenge of achieving sufficient persistence of therapeutic cells, ������Ƶ is developing a synthetic cytokine receptor system, the rapamycin-activated cytokine receptor, or RACR platform. The potential benefits of the RACR system are realized both in the manufacturing process and in the patient. During manufacturing, RACR activation is used to drive differentiation of cells with potent cancer killing function, and to eliminate the need to add expensive growth factors and other raw materials. Once these engineered cells, or iPSC-derived RACR-induced cytotoxic innate lymphoid (RACR-iCIL) cells, are administered to the patient, RACR activation can be used to support the engraftment, persistence, and effector functions of therapeutic cells.

This fluorescence microscope image shows iPSC-derived NK cells engineered to produce ������Ƶ’s RACR and universal TagCAR (clear cells; brightfield) cultured together with breast cancer cells (red) tagged using TumorTag (green). To watch the NK cells in action – recognizing and destroying the cancer cells – see the video below.

The capacity of the RACR system to support therapeutic cell expansion and survival may allow therapeutic RACR-iCIL cells to be administered without the need for toxic lymphodepletion. RACR-iCIL cells are expected to expand in number in vivo when rapamycin, an FDA-approved drug, is administered to the patient. Rapamycin also has the native capacity to suppress the activity and expansion of immune cells that are not expressing the RACR system. Thus, treating patients with rapamycin is expected to not only bolster the survival and expansion of the therapeutic RACR-iCIL cells, but also inhibit immune responses which might target and limit the persistence of the therapeutic cells.  

Once in a patient’s body, these engineered RACR-iCIL cells are designed to target and destroy tumor cells through a universal TagCAR that engages tumor cells labeled with ������Ƶ’s TumorTags. While a significant challenge in the immunotherapy field is unpredictable efficacy of solid tumor treatments due to hostile tumor microenvironments and tumor heterogeneity, our TumorTag platform aims to improve efficacy by labeling multiple targets in the tumor environment with a cocktail of bispecific small molecule adapters (TumorTags) that are recognized by our universal TagCAR.

As shown in the video here, when RACR-iCIL cells (clear/brightfield) producing TagCAR are cultured with breast cancer cells (red) tagged via TumorTag (green), these RACR-iCIL cells can recognize and destroy the cancer cells.

Cautionary Note Regarding Forward-Looking Statements
This blog contains forward-looking statements about ������Ƶ, Inc. (the “Company,” “we,” “us,” or “our”). The Company has based these forward-looking statements largely on its current expectations, estimates, forecasts and projections about future events and financial trends that it believes may affect its financial condition, results of operations, business strategy and financial needs. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. These statements are subject to risks and uncertainties that could cause the actual results to vary materially, including, among others, the risks inherent in drug development such as those associated with the initiation, cost, timing, progress and results of the Company’s current and future research and development programs, preclinical and clinical trials, as well as the economic, market and social disruptions due to the ongoing COVID-19 public health crisis. Except as required by law, the Company undertakes no obligation to update publicly any forward-looking statements for any reason.

That’s why as part of our mission to create innovative cancer treatments, we incorporate manufacturing as an integral part of our process from start to finish, taking efficiency and accessibility to new levels. Our reimagining of manufacturing from the ground up begins with the recent groundbreaking of our new facility located in Louisville, CO just outside of Boulder and 20 miles from Denver. This facility is an important step towards fully integrating ������Ƶ’s platforms, giving us the potential to develop processes and manufacture therapeutics at a pace that keeps up with our scientific innovations.

Manufacturing as a therapeutic keystone

The current manufacturing models in the cellular immuno-oncology space have significant challenges. First, early generation cell therapy platforms have shown many challenges to scale to meet available demand. Companies have “solved” this problem through a combination of building internal manufacturing capabilities on a global scale and by partnering with contract development and manufacturing companies (CDMOs). This strategy allows for increased capacity, but comes at a cost. These facilities are competing with not only themselves, but also others for limited supply chain, infrastructure, and the trained personnel to run plant operations. Having overseen and led a cell therapy CDMO myself for many years, I am very thankful that these facilities  enabled the first movers, but I also firmly believe we have a great mission in front of us to unlock the potential of cellular therapies through scalable manufacturing.

Secondly, scientific innovations and product understanding are happening faster than the current cell and gene therapy product development and manufacturing models can keep up with. Changes in manufacturing processes due to findings from lab optimization or clinical trial results are common in early phase clinical trials. Lifecycle management is an important tool we can utilize to implement these changes. However, process changes come at an increased risk to the manufacturing success through the need to retrain CDMO operators or having multiple sites attempting to adhere to the same process. Often, manufacturing improvements are not implemented to minimize risk in an attempt to expedite products to the market.  This comes at a tradeoff with suboptimal manufacturing processes leading to lack of innovation, scalability, and access for patients.

From bottleneck to opportunity

������Ƶ is innovating the way we think about drug development manufacturing. The manufacturing mindset starts in early discovery and builds through shared knowledge and personnel resources, resulting in a seamless transition from the bench to the manufacturing facility. By internalizing our manufacturing processes, ������Ƶ can control the entire product pipeline.

We believe our manufacturing capabilities, in combination with the advanced properties of our VivoVec, RACR/CAR, and TumorTag platforms, puts us in a unique position to provide the benefits of immuno-oncology in a highly scalable, consistent manner. This single manufacturing facility is designed to provide thousands of therapeutic doses globally while maintaining the flexibility to efficiently implement optimized processes.

And while our current focus is on building a facility that fully integrates process development and manufacturing for VivoVec-based drug products, we believe that our RACR/CAR and TumorTag platforms offer significant benefits across a range of cell therapy modalities. With that in mind, we have built in the flexibility needed to expand into other types of cell therapeutics as our pipeline expands.

Manufacturing reimagined

Our innovative approach to drug development takes inspiration from the scenic Colorado landscape. In the pursuit of new and exciting vistas bigger than us, we remember that we climb higher—and smarter—when we go together.

We are not just investing in our process development and manufacturing capabilities with the creation of our facility; we are investing in enabling our pipeline for ������Ƶ and the global community. The establishment of our development and manufacturing facility in Colorado is an important part of our story.  It will enable us to efficiently develop and optimize processes to manufacture innovative treatments that we believe will allow our pipeline of cancer therapeutics to treat any cancer at any time. It is an inflection specifically designed to launch our clinical pipeline forward and put patients on an expedited path toward overcoming the burden of cancer.

As we establish roots in Colorado, we are tapping into a flourishing hub of diverse scientists and engineers and capitalizing on a rich history of drug product manufacturing. Our team is already expanding with a staff of highly experienced, dedicated individuals who are aligned on ������Ƶ’s long-term mission and eager to build it with us to benefit cancer patients. I feel very fortunate to be part of this brilliant team and look forward to unlocking the scalability challenges so far inherent to cell and gene therapies by leading the field in manufacturing innovation and execution. Patients are waiting.

Sincerely,

Ryan Crisman, Ph.D.,
Co-Founder and Chief Technical Officer of ������Ƶ

This year has had no shortage of major accomplishments for the company. Topping the list is our recent closing of an oversubscribed $210 million Series B funding round. We view our success in this financing round as affirmation of not only the value intrinsic to ������Ƶ’s technologies and our mission to develop new approaches to treating cancer, but also the team we have built to deliver on that mission. We are continually grateful for the ongoing support of our investors and partners.

A close second in significance has been our growth and maturation as an organization. We made critical hires onto our senior leadership team, including Nushmia Khokhar as Chief Medical Officer, Irena Melnikova as Chief Financial Officer, and David Fontana as Chief Business and Strategy Officer. The knowledge and experience that these individuals bring have massively enhanced our organizational capabilities. Just as important, they have each been able to attract cadres of highly qualified individuals onto their teams, giving ������Ƶ an exceptional depth of talent extending to our youngest associates. Finally, we have achieved an extraordinarily high retention rate of our existing talented employee base – no small feat in the competitive Seattle and Boulder/Denver life science industry hubs. I believe that the capacity to attract and retain the highest quality people reflects on both the impact of our mission and a commitment across the organization to sustaining a positive and empowering culture reflective of our values and aspirations. 

With the growth in our personnel has come concomitant growth in our facilities. This growth kicked off in August with an expansion of our R&D footprint in Seattle through the opening of our 410 W. Harrison site. In Boulder/Denver, we will shortly bring on line critical R&D and process development space at our Walnut facility, and we recently broke ground in Louisville, CO on a 150,000 square foot state of the art manufacturing facility we call UB One. We’re excited to share more details about these sites and the work undertaken in each of them soon.

All of this vital growth and expansion is in service of our ultimate goal to overcome the longstanding hurdles in delivering the transformative potential of engineered cell therapies to more patients. Our R&D teams have continued to individually progress and further integrate our VivoVec, RACR CAR, and TumorTag technology platforms, and to advance our lead clinical programs. We are also excited to report soon on applications of RACR/TumorTag platforms for supporting ex vivo manufactured allogeneic cell therapies, an area we see as complementary to our fully integrated in vivo cell therapy approach.

Working on new approaches to treating cancer is challenging. The mindset we bring to our work is that the obstacles encountered in the past and new obstacles we may encounter in the future represent opportunities for creative solutions to help patients. I am honored to be working alongside my fellow Umojians, unified in purpose to make the most advanced immunotherapies accessible to all patients with cancer. Looking ahead to 2022, I believe the best is truly yet to come.

Sincerely,

Andy Scharenberg