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. ÃÜÌÒÊÓƵ 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 ÃÜÌÒÊÓƵ 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 ÃÜÌÒÊÓƵ, 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 , ÃÜÌÒÊÓƵ’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, ÃÜÌÒÊÓƵ’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 ÃÜÌÒÊÓƵ’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, ÃÜÌÒÊÓƵ 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. ÃÜÌÒÊÓƵ 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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