The revolution of CAR-T technology: an interview with Jalil Hakimi
Jalil Hakimi, is an experienced and visionary biotech and pharmaceutical professional with more than 25 years of experience in clinical immunology, cancer genetics and vaccine research and development (cancer and prophylactic). He graduated from the Ivey Business School and completed the Project Management course at the University of Toronto (Canada) to sharpen his life science background.
He is currently Global Product Manager for the Advance Therapy team at Sartorius (Göttingen, Germany). His previous roles included work as a key member of the discovery, research, and development team at Sanofi Pasteur (Toronto, Canada) for 20 years, meanwhile, he established and successfully managed the genotyping core facilities for the Sunnybrook Research Institute (Toronto, Canada) and University Health Network (Ontario Cancer Institute) affiliated with the University of Toronto to support scientific cancer community.
In this interview with Jalil Hakimi, Product Manager at Sartorius, we discussed the main challenges associated with the development and manufacture of CAR-T therapies and how we can work to overcome them. Jalil also gave his insight into how utilizing CAR-T-specific media is a key factor for generating CAR-T therapies with optimized efficacy and minimized toxicity, which could support a broader range of applications.
This interview is part of the RegMedNet In Focus on CAR-T cell therapy. Discover expert opinions on this topic by visiting our feature homepage.
How has the CAR-T space changed since you began working in this field?
In July 1997, when I had the privilege to work at Ontario Cancer Institute (Canada), I learned that the lab beside us belonged to Tak Mak, a noble Canadian scientist who cloned the T-cell receptor (TCR) for the first time in 1983. His discovery opened the door of opportunities for TCR editing by genetic engineers. I remember how excited scientists were about this.
Initially, the idea was to generate CAR-T therapeutics for HIV-infected patients but a few years later Carl June at the University of Pennsylvania (USA), the father of CAR-T, pioneered the concept further and teamed up with Bruce Levine to start the first CAR-T clinical trials for children with acute lymphoblastic leukemia.
In 2012 Emily Whitehead was the first pediatric patient to receive CAR-T therapy and the first patient of any age to receive the treatment for acute lymphoblastic leukemia. Ten years later, Emily remains cancer-free, and even more patients have gotten significant benefits from different CAR-T treatments. Patients with CD19 lymphoma get up to 97% cancer-free thanks to CAR-T therapy. This is an amazing advancement. At present, we have 6 FDA-approved CAR-T therapies and I can imagine the numbers will rapidly grow due to the continuing technological advancements and support from the regulatory bodies. More CAR-T generations will come over time but to me, every child who is saved is a milestone on this journey!
What has been the greatest technological breakthrough for CAR-T therapies?
There are many, but to name a few:
Other cancers. The application of CAR-T to other cancers, such as solid tumors, is on the way to becoming another breakthrough in the fight against cancer. Although CAR-T therapies have been successful in liquid cancers, its application is very challenging for solid tumors due to the inhibitory microenvironment. Learning from tumor-infiltrating lymphocytes, scientists are trying to hybridize both concepts and come up with more powerful CAR-T therapies for solid tumors.
Bioreactors. When we are talking about generating millions and billions of potent T-cells, it is not feasible by culturing cells manually in plates. The demand to scale up cell proliferation in cGMP prompted biomedical engineers to design bioreactors for a more robust and reliable system to grow the cells in large amounts.
Transduction efficiency. For advanced therapies, particularly cell and gene therapies in clinical phases, regulatory bodies want to get rid of viral-based technologies. Surprisingly the lentivirus is still the standard transduction method for CAR-Ts. However, alternative non-viral techniques such as mRNA, CRISPR and enzymes are promising. We can thank the COVID-19 vaccine!
Safety and efficacy. Any therapy has benefits and risks. It is important for clinicians to minimize the risk of side effects such as CAR-T-induced cytokine storms. Today, scientists are considering using other immune cells, including natural killer cells, regulatory T-cells, or T-cell progenitors such as gamma delta T-cells that potentially, due to their activation mechanism, are less dangerous.
Other unmet medical needs. The application of CAR-T for other unmet medical needs, including autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, pemphigus and many others are on the horizon.
What factors hold the greatest influence on finished product efficacy?
Generating powerful T-cells that can recognize cancer cells and kill them requires a smart design process. To generate powerful T-cells, you need to engineer the right receptor, use right T-cell culture media for proliferation, and use the right growth and activation factors at the right concentration. Those are the pillars of a robust protocol, from small scale to large scale. Consistency is a big factor. If the finished products are aimed for clinical application, then utilizing GMP products in this process is a great advantage. Using GMP cell culture media or cytokines from the pre-clinical stage makes life much easier when preparing to meet regulatory requirements at later stages.
Where do you think the greatest challenges lie in the development and manufacture of CAR-T-cell therapies?
The cost is the most challenging part. CAR-T treatment is very expensive at approximately US$0.5 million on average. The sad part is it is a promising treatment for cancer, especially leukemia, which affects mainly children. But the cost makes it inaccessible to many. If the cost of discovery and manufacturing is reduced the final product will be more affordable.
The time to produce and upscale the cells is also lengthy. For a cancer patient every day counts as cancer progresses, while it takes weeks and months to produce enough therapeutic cells to transplant into the patient.
We must accelerate this technology in order to maximize its value.
How can we work to overcome these challenges?
CAR-T manufacturers, in partnership with suppliers, are trying to come up with advanced tools to accelerate the process by implementing automation systems and GMP-grade bioreactors for mass production at each step. For autologous CAR-T therapy, since the cells are limited and it is considered a personalized therapy, it is very costly and time-consuming. Scientists are trying to generate a kind of universal cell therapy – allogeneic cell therapy – from sources other than primary cells, such as induced pluripotent stem cells or human pluripotent stem cells. These cells have the ability to grow faster and are more viable to overcome the challenges of cost and time.
I believe it will happen eventually, but it takes time!
How does CAR-T-specific media support T-cell growth in culture?
As I mentioned earlier, the quality of a good and powerful CAR-T depends on many factors. Most importantly, well-defined media that does not require additional serum or animal components to be added has great advantages. Such media creates significant value and can be very beneficial to cell growth with minimal manipulation.
Furthermore, cell culture media must be compatible with other cell growth factors or activation cocktails and easy to use within different bioreactors. A good cell culture media must be reliable from research to clinic with the same high performance and consistency.
If the cell culture media is optimized and, more specifically, has been developed for CAR-T, that is a huge advantage. It provides the ability to power up cell growth from small numbers to large numbers, and progress to the large-scale manufacture necessary for clinical development. A good cell culture media is a key factor to generating the CAR-T with optimized efficacy and minimized toxicity and could support broader applications of T-cell adoptive cell therapies.
How do you see the CAR-T industry evolving in the next 5-10 years?
The CAR-T paradigm is shifting to applications beyond only T-cells for many reasons. The strongest reason is to reduce the toxicity and side effects. Scientists are considering generating other engineered cells, such as CAR-natural killer cells, macrophages and CAR-TCR cell therapies, with the notion that HLA recognition is minimized to prevent the cytokine storm or the host versus graft phenomena. Making a safe CAR-T therapy is the number one priority. Results from research into CAR-natural killer cells, CAR-TCR and gamma delta-based CAR therapies are promising, and they will be at clinical trial within the next few years. We will also see the applications of CAR-T therapies for other unmet medical disorders such as autoimmune diseases escalating.
Regulatory approval easiness is a stimulant to the industry as well. The number of CAR-T therapies approved not only by the FDA but also by other global health regulators has increased. China is moving quickly towards generating so-called off the shelf allogeneic CAR-T therapies due to its public health demands. As of today, over 50% of global clinical CAR-T trials are happening in China! The CAR-T market is growing at a compound annual growth rate of 24.5% from around US$ one billion in 2021 to a predicted market size of US$ five billion in 2028.