Cellectis, a clinical-stage biopharmaceutical company focused on developing immunotherapies based on allogeneic gene-edited Chimeric Antigen Receptors (CAR) T-cells (UCART) which are specifically designed to seek to harness the power of the immune system to target cancers, and Lonza, have signed a manufacturing service agreement covering clinical manufacturing of Cellectis’ allogeneic UCART product candidates targeting hematological malignancies.
Chimeric antigen receptor (CAR) T-cells are designed to detect and kill cancer cells that present a specific, predefined antigen. However, over the last decade, these engineered therapeutics have attracted a great deal of interest due to their potential in treating a wide range of diseases, beyond cancer and autoimmunity.
Meeting high quality standards
Based on the agreement, Lonza is in charge of implementing Cellectis’ manufacturing processes as per current Good Manufacturing Practices (cGMP) in a way that meets the highest quality and safety standards outlined by the U.S. Food and Drug Administration (FDA). The manufacturing will take place at Lonza’s GMP facility in Geleen, The Netherlands.
“Working with Lonza, a world-class solutions provider with deep experience in the biotech and pharma industries increases our global capabilities and allows Cellectis to further strengthen its manufacturing expertise,” noted William Monteith, Executive President, Technical Operations, Cellectis.
“This agreement not only bolsters our product supply for clinical trials, but it ensures that we are producing first-rate product candidates so that we can potentially deliver new hope to patients living with certain blood cancers,” he added.
“Early-stage innovators with great science, like Cellectis, can find an ideal partner in Lonza as we bring great value in technical development and manufacturing, industrializing processes and enabling the journey to commercialization,” said Alberto Santagostino, Lonza’s Senior Vice President, Head of Cell & Gene Technologies.
“We will draw on the experience at our cell and gene therapy center of excellence in The Netherlands, ideally equipped to support Cellectis in bringing their promising pipeline of allogeneic CAR T-cell therapies to people around the world in need of life-saving products.” Santagostino further noted.
Lonza’s supply will complement Cellectis’ ongoing collaboration and in-house manufacturing sites which are currently under construction.
The manufacturing process of Cellectis’ allogeneic CAR T-cell product line, Universal CARTs or UCARTs, yields frozen, off-the-shelf, non-alloreactive engineered CAR T-cells. UCARTs are intended to be readily available CAR T-cells for a large patient population. Their production is industrialized with defined pharmaceutical release criteria.
A key to the effort of harnessing the power of the immune system is a type of white blood cell known as the T-cell, which plays an important role in identifying and killing cancer cells.
Unfortunately, in many cases cancer celles are able to develop specific mechanisms to evade the immune system. Chimeric Antigen Receptors or CAR, engineered receptors that can be expressed on the surface of the T-cell, provide these T-cell with a specific targeting mechanism. This enhances their ability to seek, identify, interact with and destroy cancer cells bearing the selected antigen.
Within the last 24 months the FDA has approved the first two CAR T-cell therapies, including tisagenlecleucel (Kymriah™; Novartis) for the treatment of patients with acute lymphoblastic leukemia (ALL) and axicabtagene ciloleucel (Yescarta®; Kite Pharma), a treatment for large B-cell lymphoma, a type of non-Hodgkin lymphoma, that has failed conventional treatment.
Tisagenlecleucel and axicabtagene ciloleucel are both autologous therapies. This means that they are patient-specific and are manufactured from the patient’s own T-cells collected from their own blood, preserved and shipped to a manufacturer, genetically engineered to recognize and attack the patient’s cancer cells by modifying the T-cell’s receptors. These new treatment, following manufacturing, called chimeric antigen receptor T-cells, are then reintroduced into the patient.
While this type of personalized therapy is revolutionizing the treatment of cancer, one of the major limitations of this approach is that it is hyper personalized, requires a labor-intensive manufacturing process and takes about 3 -4 week production time.
Hence, a technique that produces T-cells without relying on collecting them from patients would be an important step toward making CAR T-cell therapies more accessible, affordable and effective.
Artificial thymic organoids
Earlier this year Onco’Zine reported on a study by University of California scientists demonstrating a technique for coaxing pluripotent stem cells — which can give rise to every cell type in the body and which can be grown indefinitely in the lab — into becoming mature T cells capable of killing tumor cells. The technique UCLA researchers developed uses structures called artificial thymic organoids. They work by mimicking the environment of the thymus, the organ in which T cells develop from blood stem cells. Kite Pharma, a subsidiary of Gilead Sciences, holds a license to this method for cancer therapy, which is patented by the Regents of the University of California. The method is not yet available in clinical trials and has not been approved by the FDA for use in humans. 
Now, in contrast to technologies used by Novartis and Kite, scientist at Cellectis have designed a next generation, gene-edited, CAR-T immunotherapy using the company’s gene editing technology. This technology allows scientists to create allogeneic or off-the-shelf CAR T-cells, meaning they are derived from healthy donors rather than the patients themselves.
Gene editing is a type of genetic engineering in which DNA is inserted, deleted, repaired or replaced from a precise location in the genome. The most fundamental challenge of gene editing is the need to specifically and efficiently target a precise DNA sequence within a gene.
Cellectis uses a proprietary nuclease-based gene editing technology which makes it possible to edit any gene with highly precise insertion, deletion, repair and replacement of DNA sequences. The company’s nucleases act like DNA scissors to edit genes at precise target sites and allow us to design allogeneic CAR T-cells.
Earlier this year scientists at Cellectis published a study in BMC Biotechnology, a Springer Nature journal, describing and evaluating the development of the SWIFF-CAR, a CAR construct with an embedded on/off-switch, which enables tight control of the CAR surface presentation and subsequent cytolytic functions using a small molecule drug. 
The reversible control of these engineered T-cells represents a promising approach to further mitigate the potential toxicities that are associated with CAR T-cell administration in clinical settings and to improve the process of CAR T-cell production for specific target antigens.
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