Guest Column | September 20, 2023

Allogeneic Cell Therapy: Our Strategy, Learnings, & Advice

A conversation with Robert Hariri, M.D., Ph.D., CEO, Celularity

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Celularity is a Florham Park, NJ-based biotech company developing off-the-shelf placental-derived allogeneic cell therapies, including genetically modified and unmodified NK cells, engineered T cells (including CAR T cells), and mesenchymal-like adherent stromal cells (ASCs), targeting indications across cancer, immunologic, infectious, and degenerative diseases. We caught up with Robert Hariri, CEO, founder, and chairperson of Celularity, to discuss the company’s facility site selection strategy, how they transformed the property into a GMP facility, lessons learned in allogeneic cell therapy preclinical and early clinical development, and their advice for allogeneic cell therapy startups.

1. What was the strategy behind the selection of your property in Florham Park?

Robert Hariri, M.D., Ph.D., CEO, Celularity
HARIRI: In 2018, Celularity made the decision to create a purpose-built cell and biomaterial manufacturing facility capable of supporting our existing and future clinical development and commercial programs. We assessed multiple properties over several months, settling on one in Florham Park, NJ. This three-story, 150,000-squre-foot structure was an ideal candidate to repurpose as a cGMP/cGTP manufacturing facility at which we could consolidate under one roof all operations that previously were split between two nearby legacy sites.

Florham Park was the geographic center of the Celgene locations where our team worked prior to the 2017 spin out, so we avoided retention concerns that a more distant location no doubt would trigger. As a pharmaceutical and biotechnology hub, our region has an experienced, highly trained workforce supported by many research institutions and STEM-oriented colleges and universities. This environment acts as a catalyst for innovation and collaboration that has the active support of state and local government, all of which combines to create the conditions necessary for a biotech company to thrive and grow.

The region’s network of teaching and community hospitals has always been a key consideration for us because our technology platform is based on the use of postpartum placentas obtained from informed consent donors. That’s why I founded our legacy Lifebank biobanking business here over 20 years ago. We use these ethically sourced biomaterials as a source of cells and biomaterial products that are the basis of advanced therapies targeting a multitude of indications in autoimmune, infectious, and degenerative diseases and cancer.

2. What did Celularity need to do in order to get the property transformed from its previous use into a GMP cell therapy manufacturing facility? Can you tell us about the facility design strategy? Did Celularity find a way to keep costs down during the project?

HARIRI: I’ve always believed that controlling manufacturing is not only essential to the security and integrity of your intellectual property, but it’s also the best place to learn and make improvements that will ultimately help to differentiate and distinguish you from your competitors. Within that context, we recognized the importance of manufacturing and having our R&D co-located with it and other elements of our business.

Once you get good at producing cells from a particular source material, such as the placenta, all you need to do to change the product and, ultimately the clinical candidate is to modify an element of the manufacturing. You can keep the “backbone” of the manufacturing process stable and introduce only one or two modifications, which is cost-effective because you don’t have to re-engineer your entire process all the time.

Because Celularity is a spin-off of Celgene Corporation, we occupied some legacy Celgene real estate at the time, which we took over. While it was a beautiful home for our developing company, we needed to move toward late-stage clinical trials, and, ultimately, commercialization. The project involved converting the 170 Park Avenue three-story suburban building from a mixed-use office to a biomanufacturing facility to include a cGMP-ready manufacturing center, along with dedicated research and office spaces and space for shared services.

And since we manufacture both cellular therapeutics and advanced biomaterial products from the postpartum human placenta, our facility needed to enable parallel, vertically integrated processes and operations that leverage a shared infrastructure and workforce. New mechanical, electrical, and plumbing engineering systems were installed in the facility, including air handling units and curbs, chillers, pump house, generators, and boilers to support operations of nine Grade C/ISO-7 and six Grade D/ISO-8 manufacturing suites.

It also meant we needed biorepository capabilities for storing and retrieving cryopreserved cells and cell products, as well as pharmaceutical-like inventory management and distribution operations, all within one building. This required major structural modifications to accept 10 large new air handling units on the roof, plus lab services, including nitrogen and compressed air for cryo-storage facilities.

3. What are Celularity’s facility plans for scaling up for the future?

HARIRI: 170 Park Avenue was built with scalability in mind, so the facility itself doesn’t require additional investment to support our future growth plans. For example, we’re scaling operations now to support product distribution opportunities in the Middle East for our Halal certified advanced biomaterial products, which entails adding the variable components like workforce and so on. While many companies remain years away from generating revenue, income from our commercial suite of advanced biomaterials products helps supplement the costs associated with our clinical development programs. We had identified the Middle East as our first location for international expansion since the region has long lacked broad access to biomaterials compatible with religious and cultural practices. This is because, unlike Celularity’s products, some biomaterials used for regenerative medicine in the West are from xenogeneic sources, which are almost entirely of porcine and bovine origin. Muslim traditions generally prohibit use of such products, which leaves the Muslim world with an acute shortage of biomaterials for wound healing and regenerative medicine.

Our facility at Florham Park can accommodate all of this anticipated growth in a way that is cost efficient and sustainable, so we do not anticipate a need to expand our U.S. facility footprint.

4. What is the biggest challenge in allogeneic cell therapy preclinical development that you’ve encountered and how have you approached that challenge?

HARIRI: One of the main obstacles to developing successful allogeneic cell therapies is the human immune system — how do you make a cell-based treatment that the patient’s immune system does not reject as foreign? Overcoming immune histocompatibility challenges associated with allogeneic therapies remains an ongoing area of focus for scientists, clinicians, and industry professionals to address limitations and improve patient outcomes. Many prominent cell therapy industry players are prioritizing gene editing technologies, like CRISPR-Cas9, which hold promise for modifying cells and tissues to reduce the risk of immune rejection. By modifying specific genes, it may be possible to make donor tissues more compatible with the recipient's immune system. While gene editing technologies hold promise, it's important to note that their clinical applications are still being extensively researched and refined. Persistent challenges such as off-target effects, delivery efficiency, and long-term safety concerns demand additional scrutiny and substantial capital commitment.

Our strategy involves natural material that possesses a low potential for provoking an immune response, the human postpartum placenta, to develop allogeneic cell and tissue therapies that can be used without the need for matching the patient to the donor. The placenta has a fundamental role in maintaining fetomaternal immune tolerance. It is rich in immune-privileged cells that secrete anti-inflammatory and immunomodulatory factors preventing the maternal immune attack. As such, placenta-derived cells hold a unique promise in the allogeneic cell therapy field. Their pluripotency and self-renewal capacity are somewhere between embryonic and adult cells isolated from bone marrow, fat, and other tissues. Isolated from plentiful discarded post-partum placentas, their recovery does not require invasive procedures for the donor, and their use does not cause ethical quandary.

Another safety concern currently plaguing the allogeneic cell therapy field is the expression of tissue factor CD142, which may trigger thrombosis when the cells are administered intravenously. Human placental stromal cells are culture-expanded, undifferentiated mesenchymal-like cells derived from full-term postpartum placenta and possess immunomodulatory and pro-angiogenic activities; however, they also express the tissue factor CD142. We at Celularity have performed CRISPR/Cas9-mediated tissue factor gene knockout in these cells, leading to significantly lower expression, activity, and thrombotic effects. The genetic modification does not impact cell properties, including expansion capability, the expression of phenotypic markers, and the secretion profile. Moreover, the immunomodulatory activities, which are functionally relevant to therapeutic applications, are not affected by tissue factor knockout, further improving the clinical safety features of our placental-derived stem cells.

5. You have a number of candidates in your pipeline in stages that range from discovery to Phase 1/2. How has the data you’ve collected early on informed your strategy on moving forward?

HARIRI: Given the rapidly emerging landscape in natural killer (NK) cell science, we felt it was important to evaluate the tolerability and biological activity of our unmodified placental-derived NK cells in patients.

For this, we conducted a Phase 1 trial of CYNK-001, our investigational unmodified placenta-derived NK-cell therapy for the treatment of resistant/refractive (R/R) and measurable residual disease (MRD) positive acute myeloid leukemia (AML). Treatment with CYNK-001 showed biological activity and it was generally well-tolerated, with no dose-limiting toxicities observed with even the highest dose of the cells. This trial also yielded important insights into the optimal approach to lymphodepletion, the role of IL-15 and IL-2 in NK-cell persistence, and the importance of baseline lymphoblast count in achieving better responses. A trend toward better outcomes was observed in patients with lower lymphoblast counts in R/R AML patients in the trial.

Based on the encouraging preliminary data and the observations from the broader scientific community, we decided to work on developing CYNK-301. CYNK-301 is our preclinical investigational next-generation chimeric antigen receptor-transduced natural killer (CAR-NK) cell therapy candidate that has the potential to overcome some of the challenges faced by NK therapies in treating R/R AML, including minimizing the burden of lymphodepletion while improving proliferation, persistence, and efficacy. This product candidate incorporates membrane-bound IL-15 to enhance NK cell activation, proliferation, and persistence, marrow homing, and a targeted CAR to enhance potential efficacy further.

6. It’s advised that companies start with the end in mind when establishing their manufacturing process. What are one or two best practices you would encourage allogeneic therapy companies to prioritize in establishing their own cell therapy process, and in what ways has employing this practice been important to your success to date?

HARIRI: Designing a manufacturing process that is robust and scalable is essential, as is setting the bar high with respect to regulatory compliance and similar considerations since those standards go up, not down, over time as a rule. You also can’t shoehorn advanced manufacturing processes into old infrastructure or research-scaled facilities and expect good outcomes. Investing in human capital is essential to develop and retain the skilled workers necessary to execute advanced manufacturing processes. Lastly, companies have to understand and optimize their supply chain and build infrastructure that’s accommodating.

7. What is any additional advice for allogeneic cell therapy startups that you’d like to share?

HARIRI: We’re past the point in time when early research findings alone are sufficient to succeed in the allogeneic cell therapy field. Raising the amount of capital to support the development of allogeneic cell therapies through clinical trials and regulatory processes represents probably the biggest challenge, aside from the obstacles posed by the human immune system. This is especially the case for cancer-focused cell therapies for which the development pathway can be long and expensive, but less so in regenerative and longevity-focused indications. The most important piece of advice I want to share is to identify your niche market and demonstrate the value of your therapy to stakeholders early on. The recent financial market downturn and investor sentiment have significantly affected the biotech space, with cell therapy hit particularly badly.

The journey of a cell therapy startup can be long and challenging, but the potential to make a positive impact on patients' lives is significant. Surround yourself with a skilled and passionate team, seek collaborative partnerships with leading industry players, and remain committed to your vision.

About The Expert:

Robert Hariri, M.D, Ph.D. is a surgeon, biomedical scientist, and serial entrepreneur. He is the chairperson, founder, and CEO of Celularity, Inc., a cellular therapeutics company. He uses stem cells to treat a range of diseases and makes contributions across immuno-oncology, cell therapeutics, tissue engineering, and functional regeneration. He discovered pluripotent stem cells derived from the human placenta and helped discover the physiological activities of tumor necrosis factor (TNF). Hariri holds 170+ issued and pending patents and has authored 150+ published chapters, articles, and abstracts.