According to the American Society of Gene and Cell Therapy (ASGCT), gene therapy involves the transfer of genetic material, usually in a carrier or vector, and the uptake of the gene into the appropriate cells of the body. Cell therapy, on the other hand, involves the transfer of cells with the relevant function into the patient. There is crossover between the two, as some protocols utilize both gene therapy and cell therapy. But the differences between gene therapy and cell therapy are vast, and as such, it is important to address and discuss them separately. And so, to garner a clear outlook for 2022 and beyond, I spoke to André Choulika, CEO at Cellectis, and Michael Mehler, director, global site operations, at Immatics. Choulika provided me with perspective for gene therapy, and Mehler provided me with the same for cell therapy. Here’s what they had to say.
(Editor’s note: Cellectis, in 2020 and 2021 respectively, completed construction of two manufacturing facilities: an 82,000-square-foot GMP manufacturing facility in Raleigh, N.C., and a 14,000-square-foot manufacturing facility in Paris.)
Other Than Covid-19, What Have Been The Biggest Changes To Face CGTs In 2021?
CHOULIKA: The gene therapy field is thriving. The changes we have seen over the last year are aligned with what we have seen in years past, where some therapies are having tremendous benefits to patients, while there still seem to be some safety risks with other treatments. The biggest thing to come out of the past year is a challenge to improve safety for patients who are trusting us with these new kinds of therapeutics.
MEHLER: With successful products and companies comes the welcomed challenge of rapid growth, leading to the effort of filling roles with talented cell and gene therapy experts. Like the rest of the world, the cell and gene therapy sector is still very much in need of specialized talent. Especially during the last 18 months, clinical sites were overwhelmed with the number of cell and gene therapy trials, products, and processes that were coming through their institutions/facilities. The explosive growth of CGT is exciting, yet it challenges us all to keep up with the advancements. We are still several years away from being able to catch up on filling roles with CGT experts on both the sponsor and clinical site sides of the sector.
From A Clinical Development Standpoint, How Has The CGT Field Improved In The Last 12 Months?
CHOULIKA: Oncology and rare diseases are the most active therapeutic areas of research (preclinical through pre-registration), with more than 1,300 gene and cell therapy candidates in development for oncology, and a total of 75 clinical trials initiated in 2021.
There are five autologous CAR-T therapies approved for various hematologic malignancies. The next great clinical milestone to meet is the development of allogeneic CAR-T therapies, which could offer off-the-shelf for on-demand therapeutic options for patients with high unmet medical needs and expand the use of allogeneic CAR-Ts to solid tumors.
MEHLER: Cell therapy clinical development continues to make great strides in identifying what works and eliminating what does not. While CAR-T has revolutionized the way in which hematological malignancies such as acute lymphoblastic leukemia and B-cell lymphomas are treated, solid tumors present different problems where the tumors can be inaccessible to cell therapies and the identification of targetable antigens can be challenging. Over the last 12 months, companies such as Immatics have been treating patients with improved targeted immunotherapies with an emphasis on solid tumors.
In What Ways Will Manufacturing Be Key To The Success Of CGT Growth And Innovation?
CHOULIKA: When you are addressing rare genetic disorders or relapsed/unresponsive cancers, there will be no one “quick fix” that can be applied to a multitude of disorders and patient sub-populations. To consistently reproduce high-quality batches, companies will need to have specific requirements of the modified cells and the key starting materials needed for gene editing.
We believe that bringing manufacturing in-house could contribute to eliminating some of the risks for inconsistencies among treatments, ensuring that lead times are met so patients are never waiting for their treatments, and improving adaptability, as each disease targeted by advanced therapeutics may require great innovation at the level of our manufacturing capabilities. Importantly, having our manufacturing in-house means that we can rapidly “version” promising therapeutic candidates as we monitor clinical responses, leading to the best possible product at registrational filing.
MEHLER: Flexibility and adaptability are critical when transitioning a cell therapy from research to early clinical manufacturing. Many companies will be faced with the decision to either build their own manufacturing facility or utilize a centralized approach. Also, implementing a GMP mindset from the earliest point of the project will help ease the transition from research to early clinical and commercial manufacturing. However, to achieve significant cost savings, the sector must move from the manual ad-hoc hospital labs, where the early therapies have been delivered, to scaled-up and far more automated processes that are faster and more reliable. A key to this new approach will be dedicated facilities and extensive process automation that removes bottlenecks.
Regarding The Evaluation Of Investigational CGTs, How Have CGT Companies Worked To Bring Safe And Effective Therapies To Patients In Accordance With The FDA?
CHOULIKA: It is evident from recent events, such as the FDA Cellular, Tissue, and Gene Therapies Advisory Committee, that all parties are committed to evaluating the evidence as it becomes available by examining ways to improve upon first-generation gene therapies.
At Cellectis, the FDA and EMA have been brought in as early as possible in the development of our UCART products, and we have worked together to assess risks and define paths forward. We anticipate this will be the same for all our gene therapies currently in development. Early interaction with the FDA is crucial as there could be several versions of these products that can be tried before a pivotal trial could be started. Also, the nimbleness that internal manufacturing brings can be a key success factor when filing for a Biologics License Application (BLA).
MEHLER: Both the FDA and cell therapy companies are still figuring out how best to oversee all the cell and gene therapy development. From a company and product perspective, I think it is important to identify your technology, pick your targets, and execute. Many of the cell and gene therapies now in testing are the first of their type, so it is not always clear from the beginning what characteristics or attributes are most important for reliably assessing clinical impact. We often get very excited about the fact that a product produces an important effect but maybe don’t worry as much about reproducibly making that product on a global scale for patients.
Based On Your Tenure And Experience, Describe CGTs’ “Next New Normal.”
CHOULIKA: Over the next few years, we hope everyone will understand that gene therapy is poised to become a rational approach for genome modification, and current random intervention in genomic DNA will disappear over time. Nuclease-based gene editing has been the founding concept of new medicines, starting with Meganucleases and Zinc Finger Nucleases. TALEN and CRISPR have opened the door for gene editing to blossom, but what will be vital going forward will be developing cell and gene therapies that are engineered with precision, avoiding all genomic toxicities. This means looking at gene editing tools that can provide the highest efficiency, precision, and safety for patients.
MEHLER: Specific to CGT progress, we will see the beginning of automated manufacturing, a breakthrough in solid tumors, and more combination therapies in the clinic with cell therapies and immuno-oncology products over the next few years. Issues of scale-up, automation, and commercialization that are unique to autologous cell therapy will continue to be addressed to create the infrastructure required for the widespread availability of cell therapy strategies. Several approaches in the development of optimized next-generation T cells that display better tumor selectivity, better tumor access capabilities, and increased activity in an immunosuppressive context will emerge.
What Are The Trends That Will Shape The CGT Industry In 2022?
CHOULIKA: Vector technologies that can target specific tissues and can bring all the needed external gene editing tools to perform the right genomic surgery in cells in vivo is the next challenge. There are the critical success factors for in vivo gene editing: the gene editing technology, the vector that will take it to the right cells, and safety. As more patients have received these therapies, it has become clear that three fundamental challenges will restrict the applicability of vectors — getting past the immune system, controlling the dose, and controlling expression.
Additional trends include:
The development and use of stem cells.
Regulatory bodies such as the FDA must become more flexible in their approval timelines.
There will be continued discussions around access and ensuring these therapies will be affordable, reimbursable, and profitable for biopharmaceuticals companies that develop them.
MEHLER: New models of academia/industry collaboration will continue to expand and grow with noticeable impacts on approvals of products. Specifically, speaking outside of the CGT topics we usually cover (e.g., clinical development, manufacturing, talent crunch), I think what is most encouraging and noticeable is the trend toward collaborative efforts among companies in this space, both large and small. It truly feels like a global effort amongst a small community to change the way we treat, for example, cancer. We see partnerships among academia, global pharmaceutical companies, and small biotechs advancing these therapies, which is the most progressive approach for clinical development and patient care. This collaborative effort will continue to shape the CGT industry as we share data and next steps.