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

Introduction
In the fast-paced landscape of biotechnology, the demand for advanced tools and techniques is on a relentless rise. Lentiviral vectors (LVVs), which are a cornerstone in immunology and cell and gene therapy, have garnered significant attention due to their versatility and potential applications in cancer, genetic diseases, vaccine development, and academic research. ������Ƶ seeks to harness the full potential of LVVs to overcome the challenges in the current CAR-T space by using LVVs to directly modify a patient’s immune system in vivo to fight cancer – and potentially treat certain forms of auto-immune diseases as well. To unlock this vast potential, establishing a dedicated LVV manufacturing facility was not a choice, but a necessity. In this blog, we’ll delve into the reasons why ������Ƶ built our own LVV manufacturing facility and how it is paramount in advancing access to life-changing therapies.

Accelerating benchtop to commercial
There are less than 50 contract development and manufacturing organizations (CDMOs) that can manufacture cGMP LVVs, most of them focusing on autologous cell therapy. About half of them are supplying active pharmaceutical ingredients (APIs) for commercial product. As a start-up with a long time to wait before a commercial launch, we were not a priority within these facilities.

Of the remaining, many did not have a customer yet, and we were not comfortable being the first, especially with our enhanced surface engineering of our viral particles and analytical needs as a novel direct injection drug product.

We were left with a handful of CDMOs that had 16+ month lead times for one cGMP run.  They offered minimal flexibility during that window if we wanted to make changes or needed another batch. Additionally, we would be required to transfer to a commercial facility if we showed clinical success.

By building our own facility, we have the flexibility and adaptability that is critical during early-stage drug development and a clear line of sight to commercial scale production.  

Novel recipe vs high throughput production
CDMOs are critical to the success of the biotechnology industry. Most are great at taking a known recipe and repeating as needed. However, the production and release of our surface-engineered LVVs is a novel process that requires a deep understanding of the interplay of the biology, analytics, and how the process impacts the product. This requires strong collaboration from our early discovery Vector Biology team through our Manufacturing and Quality organizations to make sure we maintain consistency in vector production and ensure reproducibility in experiments and clinical trials. A dedicated facility with deep scientific knowledge of our drug product, a robust analytical platform, and trained personnel could only be met by building out our own internal capabilities.

Scalability and Cost Efficiency
The demand for LVVs is projected to increase significantly as cell and gene therapies progress from research to clinical applications. Competition for capacity at CDMOs continues to rise, resulting in less flexibility and adaptability for start-up companies. Additionally, trained personnel who know how to produce these complex biologics are becoming more and more scarce. Building our internal manufacturing facility allows us to hire and retain a team with the flexibility needed for early clinical trials while providing us the adaptability for scalability, enabling production to meet growing demands efficiently. Additionally, economies of scale can be realized, reducing production costs in the long run and making these therapies more accessible to patients.

Attracting Talent and Collaboration
Establishing an internal cutting-edge LVV manufacturing facility has been a significant factor that has allowed us to attract the top talent in the cell and gene therapy sector. Those of us who have lived the comparability challenges in the autologous cell therapy space know that having trained personnel that control our manufacturing destiny allows us to move our products forward while still providing the flexibility needed in the early stages of clinical trials. Skilled researchers and technicians are drawn to facilities that own their own products and are equipped with state-of-the-art tools and resources. Moreover, such facilities encourage collaboration with academic institutions, big-pharma companies, and other research organizations, fostering innovation and knowledge exchange.

Ensuring Supply Chain Reliability
The COVID-19 pandemic highlighted the fragility of global supply chains for critical medical resources. By having a dedicated manufacturing facility, we reduce reliance on external suppliers and ensure a stable and uninterrupted supply of LVVs, especially during times of crisis.

Conclusion
As we pave the way in a new class of immunotherapies, being a leader at the intersection of scientific innovation and commercially viable drug products is crucial. The establishment of our own LVV manufacturing facility is both a strategic move and an imperative step towards realizing the full potential of LVVs in cell and gene therapy. With our facility, we will accelerate a new class of cancer therapies, enabling our team to work together to provide the best product and process to have the biggest impact on patients. The next question for us was where to build our facility. In my next blog post I will discuss why we chose Colorado as our location to change the way we think about cancer immunotherapy.

Last fall, I felt a lump in my breast. After debating for a few days about what to do – Had it been there before, and I just hadn’t noticed it? Should I be concerned about it? – I ended up calling my Obstetrics and Gynecology (OBGYN) physician’s office. They encouraged me to get it checked out and managed to get me an appointment for a few weeks later. Waiting was suspenseful and stressful. I thought of my mother-in-law, who died of breast cancer in 2014, and my own mother, who is a breast cancer survivor. Fortunately, after a quick examination, my OBGYN found everything to be normal.

For many women, their story has a different ending. Breast cancer can present itself as a lump in the tissue that is usually painless¹, making it easy to be ignored. Other symptoms include tissue thickening or a change in the shape or appearance of the nipple or breast (which may involve dimpling or redness or other skin changes, or an unusual nipple discharge). Even if symptoms are painless – which malignant lumps typically are – it is highly recommended that someone with any of these symptoms quickly visit a physician within 1 to 2 months of symptom onset for an examination. Early detection is crucial for having the most successful treatment and outcome.

Worldwide, breast cancer is the most common cancer type, and there are more cases of breast cancer diagnosed than any other cancer type. In 2020, there were more than 2.3 million new cases, and 685,000 people died^1,2. If cases progress along their current trajectory, it’s predicted that by 2040, there will be more than 3 million new cases and 1 million deaths annually².  

Available options to treat breast cancer have evolved over the years from primarily invasive options such as complete breast removal to more current treatment options, including radiotherapy, chemotherapy, less invasive surgery options (such as partial mastectomy, or lumpectomy) and targeted breast cancer immunotherapies. The first immunotherapy drug approved by the FDA (in the 1990s) for breast cancer was Herceptin (trastuzumab), developed by Genentech. Herceptin is a monoclonal antibody that targets HER2, a cancer biomarker expressed by ≈20-30% of early-stage breast cancers. A cancer biomarker is typically a surface protein that is more highly expressed in certain cancer types compared to healthy cells, allowing targeted treatment of cancer cells specifically.

Today, treatments for breast cancer can be highly effective, especially if diagnosed early, with probabilities of patient survival for ≥5 years reaching ≥90% in high-income countries¹. However, survival rates are decreased in lower-income countries with limited resources, dropping to 66% in India and 40% in South Africa¹. If the diagnosis does not occur early, survival rates decrease. There is still a need to develop new and innovative targeted therapies that improve long-term survival, decrease cost, and increase accessibility worldwide to help overcome many of the major challenges we still face today to successfully treat people with breast cancer.

To bypass adverse effects of conventional chemotherapy that can leave patients feeling very sick and unable to complete treatment, more targeted immunotherapy approaches are being pursued. One such promising cancer biomarker is the folate receptor (FR). FR is expressed in many different cancer types, including breast cancers³. In particular, FR expression is relatively increased in estrogen receptor (ER)/progesterone receptor (PR) negative and triple-negative breast cancer (≈15-20% of patients), a devastating subtype that carries a relatively poor prognosis^3,4.

New technologies are offering hope for these hard-to-treat cancers and at ������Ƶ, we announced in May 2022 the Seattle Children’s activation of the Phase 1 ENLIGHTen clinical trial, which is targeting FR in cancer patients. This trial uses chimeric antigen receptor T-cell (CAR-T) therapy, which uses the patient’s own T-cells that are reprogrammed to recognize and kill cancer cells, along with a TumorTag , ������Ƶ’s proprietary small molecule that targets tumor biomarkers. Specifically, this TumorTag (UB-TT170) selectively binds to FR on tumor cells, labels them with fluorescein, and marks them for destruction by specially-designed CAR T cells. While a significant challenge in the immunotherapy field is the unpredictable efficacy of treating solid tumors such as breast cancer due to the hostile tumor microenvironments and tumor heterogeneity, ������Ƶ’s TumorTag platform aims to improve efficacy by labeling multiple targets in the tumor environment with a cocktail of TumorTags. UB-TT170 and other TumorTags are also used in ������Ƶ’s upcoming therapeutic candidate, UB-VV200, with an IND submission being targeted as soon as 2024.

While the Phase 1 ENLIGHTen clinical trial is assessing safety and tolerability in patients with osteosarcoma, it is paving the way for targeted therapies for other cancers where FR is overexpressed, such as the triple-negative breast cancer subtype. One of the limitations of current CAR T therapies on the market is the need for lymphodepleting chemotherapy, which can be toxic and leave patients feeling too sick to complete treatment. To address this, ������Ƶ has developed another approach that uses our Rapamycin-Activated Cytokine Receptor (RACR) platform to selectively enrich and expand engineered CAR T cells inside a patient’s body and enhance the anti-tumor response. ������Ƶ recently published on the RACR technology in .

While breast cancer treatments – especially when the cancer is caught early – can be highly effective, challenges remain in developing treatments with fewer adverse side effects and improved affordability and accessibility. By overcoming such challenges, new therapies offer hope to the millions of people diagnosed with breast cancer each year.

References

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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.