With greater than 30 million cases and 946,000 deaths reported from COVID-19 worldwide, the novel Coronavirus represents one of the largest pandemics in modern history. Thankfully, it also represents the largest cooperative effort in human history.
Globally, scientists are exploring every potential weapon to suppress the threat, including vaccines, repurposed drugs, combination therapies, and as we explore here, cellular therapies with promising cell types such as natural killer (NK) cells and mesenchymal stem cells (MSCs).
In this interview with Dr. Robert Hariri, CEO of Celularity, Inc., we discuss the company’s cell therapeutics pipeline against COVID-19. Enjoy!
Interview with Dr. Robert Hariri of Celularity, Inc.
Cade Hildreth: I noticed that Celularity announced a partnership with Sorrento Therapeutics related to COVID-19 in January 2020. How early were you tracking the spread of the disease and what caught your attention?
Dr. Robert Hariri: From the early news we were hearing from China, I understood that COVID-19 would be problematic at least in Asia, and potentially, worldwide. Given the spreading threat, there was an opportunity to explore a cellular immunotherapeutic approach to treating viral infections. Cade, I’ve always felt that we are surrounded by trillions of viruses and particles every moment of our lives and the appearance and spread of novel viruses is just part of life on this planet.
Everyone has been worried over the last ten years after the SARS and MERS outbreak that another one of these viruses could pop up at any time and create the same type of havoc, creating consequences similar to the Spanish Flu. Despite these fears, we still do not have a way of coming up with, for lack of a better phrase, a generic antiviral strategy.
When you think about it, the way we deal with seasonal flu ― where we’re constantly coming up with a new vaccine every year ― it’s impractical. In my mind, it doesn’t afford the kind of protection required for diseases that change more rapidly than the commercial cycle of development. Nor does it address that in the early stages of a pandemic, we often have yet to predict how lethal or pathogenic a disease could be.
Naturally, I was looking at the natural history of viral illnesses from the lens of a company that is working in immunotherapy (Celularity). It was clear to us that if the mechanisms of our natural killer (NK) cells could be useful in viral infections, then we would be well-positioned to enter clinical trials, because we are the beneficiaries of clinical safety data and experience from conducting prior cancer trials.
This clinical experience would be invaluable if undertaking development work with the same product in viral illnesses. That’s how it all came about.
Cade: How interesting.
Dr. Robert Hariri: As you know, we know a lot about our placental NK cells. Much of that knowledge came in preparation for its use as a cancer treatment. However, our scientists have also worked tirelessly to understand how some of these fundamental markers of disease or illness, are programmed. These targets are programmed into the natural killer cells and it’s one of the reasons why the fetus is protected during gestation and the immediate postnatal period.
We recognized a long time ago that in addition to the placenta being a “stem cell factory”, the placenta is also a remarkable defense system for protecting the developing fetus from lethal illnesses ― not only the transmission of malignant cells, but also the transmission of certain viral diseases.
The fetus does not develop any adaptive immunity in utero, but at the moment of birth, it is exposed to an environment filled with all kinds of pathogens. Despite these environmental threats, postnatal infection mortality is essentially zero. This suggests something is “priming the immunological pump” for newborns, positioning them for defense against dangerous environmental pathogens.
We looked at this observation and said, “Well, the one thing we do know is that these placental natural killer (NK) cells are part of the fetal innate immune system. What’s their functionality against viral infected cells?”
When our team did the work using certain viral models ― the team looked at influenza and CMV and a few others ― what they found was that a stereotypic event in virally infected cells is the upregulation and expression of stress antigens. Many of those stress antigens are the same ones that are expressed on cancer cells.
Our thesis was, perhaps newborn defense is provided by NK cells primed against stress antigens that can identify and destroy virally infected cells in order to keep viral burden down. That was the thesis behind exploring the potential use of Celularity’s placental derived NK cells in COVID-19 infection.
We decided to align with Sorrento because of their capabilities around developing engineered T cells and their capacity around manufacturing. We created a working plan on how we would approach the emerging COVID-19 threat together. That’s how it started.
As the pandemic continued to evolve throughout January and February, the news kept getting more and more ominous. The COVID-19 virus appeared to have high lethality rates, be very transmittable, and potentially have long incubation periods. Thus, our involvement became of greater and greater relevance, and we began to invest more “intellectual horsepower” in how we could contribute.
Understandably, we worked to create an IND package to submit in order to test our clinical stage NK assets in COVID-19. We submitted that and then worked with the FDA to get through all of their concerns about the use of a cell therapy in a viral illness. We got our IND accepted on file at the beginning of April.
We believe that we have a strategy that has a good biological rationale and is supported by strong science in viral-infected cells. It is supported by good human safety data in cancer. We know how to manufacture the product. The product is scalable, and ultimately, the product is delivered via a very simple administration protocol, intravenous (IV) infusion, which means it goes well with virtually any treatment environment.
When you think about what the factors are that make a potential COVID strategy valuable, it is all those things. It is scalability, economics, ease of administration and it is a strong biological rationale. We had all those factors, so it satisfied the FDA’s review and I am happy to say we are starting to treat patients now.
Cade: That’s fantastic. Can you tell me about Celularity’s clinical study design, where the Phase I study is taking place, and the timelines involved? Also, I believe you are working with Seattle’s Infectious Disease Research Institute as a partner. Is that correct?
Dr. Robert Hariri: Yes, that’s right. We’re working with Dr. Corey Casper in Seattle at the Infectious Disease Research Institute. Corey is also a Cornell alum, so we have that similarity. He’s an exceptional investigator, extremely knowledgeable of the technology, and in agreement with our approach, so he’s the principal investigator.
We have enrolled, four or five trial sites, and we have many, many more that are in review because there is so much interest in this approach. The clinical trial design for this Phase 1 trial is 84 patients.
The product will be administered to patients who are confirmed to be COVID-19 positive but who are showing early symptoms. Meaning, we will not be treating patients who are on ventilators, because the objective of the trial is to try and augment a patient’s immune response against the virus. The goal of the trial is to keep a patient’s viral burden from exceeding their immunologic capacity.
The way I look at it, this is kind of a numbers game. If you are forced to allow viral burden to grow beyond a threshold, then it will exceed the innate and adaptive immune response of the patients. Regrettably, that is what gets people into serious complications like acute respiratory distress syndrome (ARDS) and multiple organ system failure. Ideally, we would prevent disease progression from reaching this critical, life-threatening stage.
Our Phase I study is going to look at patients who are confirmed to be COVID-19 positive with early symptoms, so our objective is to determine if we can prevent these patients from progressing to advanced stages of the disease. We also want to demonstrate a reduction in viral burden and improve overall outcomes.
In my opinion, it’s a clear, straightforward study and with clinically relevant endpoints.
Cade: Excellent. Do you know the timeline for treating the first patient?
Dr. Robert Hariri: Yes, we treated our first patient earlier this month in a Phase I/II study of human placental hematopoietic stem cell derived NK cells (CYNK-001) for the treatment of adults with COVID-19 as part of a national clinical trial. The patient was treated at UC Irvine in California, the first CA site to open for patient enrollment with support from a COVID-19 Project grant awarded to Celularity by the California Institute for Regenerative Medicine (CIRM).
As you know, we announced early last month that we were awarded a $750,000 COVID-19 Project grant by the California Institute for Regenerative Medicine, one of the three clinical awards targeting the coronavirus.
Cade: Excellent. If all goes well, when could you potentially have early stage data to report?
Dr. Robert Hariri: That’s a great question. In a crisis like this, the results are being watched very carefully. We believe that the safety component of this study will be evident within the first week of treatment of patients. I’m thinking that within the next two to four weeks, we’ll have a very good handle on safety.
The principal safety signal is that you can give the product to patients and not “trip” them into a cytokine storm. Understandably, we don’t want to worsen the situation with a product that’s an immunotherapeutic.
Then, in terms of the effect on conversion rates and preventing patients from needing ventilators and assisting them with release from the hospital, that’s going to take a longer period. Because the average hospitalization right now for COVID-19 patients is around 21 to 24 days, we will need several weeks to assess these metrics.
My hope is that within 60 to 90 days, we’ll be able to say whether we’re seeing promising clinical evidence of efficacy, along with safety.
Cade: Excellent. If all goes well with the trial and you’re able to move forward, what would Celularity’s timeline be for manufacturing of your NK cell product, scaling up production, and eventually, initiating distribution?
Dr. Robert Hariri: Fantastic question. As you know, over the last year we invested very heavily into building a world-class state of the art GMP manufacturing facility that we are now occupying. We just initiated the first manufacturing cycle in that facility. The facility is designed to enable us to produce multiple products all under independent isolated GMP conditions. It’s our objective to be producing clinical-grade products from this facility.
That will add to our current inventory of product, which is enough to support our 84 patient Phase 1 study, plus the treatment of a significant number of Compassionate Use and Expanded Access patients.
My objective is to be capable of producing our own product and meeting all the developmental requirements. Because we are anticipating that our NK cell product (CYNK-001) is going to have utility within one or more indications, we will be scaling up our manufacturing.
The rationale behind that is two things. First, we believe we are going to have a useful therapeutic for use against COVID-19. That’s number one.
Second, in the event that our NK cells (CYNK-001) are not an effective therapeutic for COVID-19, we have the ability to inventory it under cryopreservation. As you know, CYNK-001 has a shelf life which is measured in decades. It’s a product that will either find its way into either this type of treatment or a cancer indication or a solid tumor indication.
Cade: That makes a great deal of strategic sense. One of the things that I have found interesting is that Celularity has been actively exploring partnerships related to the development of CYNK-001. You’ve partnered with Sorrento Therapeutics, Lung Biotechnology PBC (a subsidiary of United Therapeutics), and now Seattle’s Infectious Disease Research Institute.
What’s the importance of these partnerships and what other types of partnerships might you seek out?
Dr. Robert Hariri: As you know, we’ve always seen ourselves first and foremost as a platform technology company. We have far more clinical potential than we have bandwidth to handle ourselves. As you also know, we created Celularity by establishing strategic partnerships with investors, such as United Therapeutics, Bristol-Myers, Sorrento, and others. We’re very fortunate, because we’ve proven these relationships to be beneficial to all parties.
For example, United Therapeutics has expanded our relationship to proceed with co‑development of our placental-derived NK cells (CYNK-001) in both COVID-19 and acute respiratory distress syndrome (ARDS) ― caused by COVID origin or by any other etiology. As you know, United Therapeutics is a world-renowned company in pulmonary disease with great expertise. They round off our clinical development capabilities and they’re an exceptional partner. The way I envision it is that United Therapeutics will continue to be a critical partner to us in the pulmonary space and in COVID-19.
It will serve as a model for other development partnerships that could occur with other pharma companies in numerous clinical areas and with other assets.
Cade: Makes perfect sense. What are other approaches to the prevention, treatment or management of COVID-19 that could be synergistic with your immunotherapy, CYNK-001?
Dr. Robert Hariri: You always ask the best questions. I love it. You’re thinking the way I’m thinking.
For us to pigeonhole ourselves hoping for a “silver bullet” in this disease, it’s not only unreasonable, it’s illogical. The beauty of immunotherapy it that it’s a unique and complementary approach.
To date, most of the studies which have been filed for COVID are for a vaccine, for ways to contain and compartmentalize disease in a preventative way, or for antiviral therapies ― which again, take a long development cycle and are an extremely different clinical approach.
The beauty of our approach is that it can be used in conjunction with any of these other therapies. We don’t see any reason why we shouldn’t be looking (especially in a trial environment) to potentially combine approaches in patients.
Let me give you one perfect example. You know that convalescent serum is now being tested. Meaning, patients who survived the disease can be donors of blood and convalescent serum or plasma that potentially are a good source of antibodies against COVID-19. The beauty right there is that an infusion of that product not only primes the immune system, it might even make our NK cells more effective, because the antibody bound to virus could increase the sensitivity to a natural killer cell.
That is just one example of how I think our approach could be very useful in a complementary way to other approaches.
Cade: This is a final question and one that I am personally curious about. With your access to placental-derived MSCs through LifebankUSA, are you considering the development of an MSC-based therapeutics against COVID-19?
Dr. Robert Hariri: I tell you; I could not set up better questions if I tried. As you know, you and I talked about this for a long time. We are very, very confident that our placental pluripotent stem cells ― which have both immunomodulatory and pro-regenerative behaviors ― can be used in lots of indications.
With United Therapeutics, we are about to file an IND for one of those products, a placental-derived product, PDA-001. It will be tested in patients who experiencing the advanced complications of COVID-19, such as ARDS. We believe this approach could help to control and manage the cytokine and pro-inflammatory effects of the illness, while supporting a recovery after the virus is cleared.
We’re seeing some evidence ― there are reports from other companies ― that MSC-like cells can be beneficial for resolving COVID-19 related complications. We think we have a product that can work in concert with our NK cell therapy and other therapies, while being administered at a different stage of the disease.
I’m hopeful that we’ll soon be the only company to have two independent cellular therapeutic products in the fight against COVID-19.
Cade: Wow. That’s fascinating. It there anything else related to the global pandemic or your involvement in flattening the curve that we should address?
Dr. Robert Hariri: I really do think that cell therapeutics can play a critical role in the management of viral diseases.
While this pandemic has been a horrible thing for people to live through, I think that we have the potential to come out of this global crisis with a better understanding how to deal with viral illnesses. If we establish that cellular immunotherapeutics are useful for this purpose, then we could reshape the future of how we treat infectious disease.
As you know, everyone’s concerned about antibiotics and antibiotic-resistant pathogens, so it would be incredible to have another tool to use in our fight against infectious disease.
If we can show that in a serious lung-damaging illness, like COVID, that other cell types could improve remodeling and recovery of the lungs or lung tissue, then these products could have applications in other respiratory conditions as well ― such as COPD, asthma, or emphysema.
We’ve got to keep our eyes open. We’ve got to be good observers. We need to notice what we’re learning from this crisis and how it could be applied elsewhere.
Cade: I agree. As always, this was a lot of fun and I can’t wait to come see your new facility in Florham Park. Thank you for your hard work, service, and contributions toward this global pandemic.
What questions do you have for Celularity about their cell therapeutics pipeline against COVID-19? Ask them in the comments below.