Cellectis is a clinical-stage biopharmaceutical company focused on developing a new generation of cancer immunotherapies based on gene-edited T-cells (UCART). Based in New York City and Paris, the company is capitalizing on its 17 years of expertise in gene editing. Built on its flagship TALEN® technology and pioneering electroporation system PulseAgile, Cellectis uses the power of the immune system to target and eradicate cancer cells. Armed with its pioneering genome engineering technologies, Cellectis’ goal is to create innovative products in multiple fields and with various target markets.
Leading Cellectis is Dr. André Choulika, Chairman, CEO, and founder of the company. Choulika has a Ph.D. in molecular virology from the University of Paris VI (Pierre et Marie Curie), and completed a research fellowship in the Harvard Medical School Department of Genetics. Later, while working in the Division of Molecular Medicine at Boston Children’s Hospital, he developed the first approaches to meganuclease-based human gene therapy. He is one of the inventors of nuclease-based genome editing technologies and a pioneer in the analysis and use of meganucleases to modify complex genomes.
WuXi AppTec Communications, as part of a new industry series on gene editing, spoke with Choulika about the future path forward of this cutting-edge technology and where it is headed.
WuXi: What at kind of gene editing is your company using and how are you applying it?
André Choulika: Cellectis is totally agnostic in regard to gene editing technologies. We are willing to try every available technology and use the most adapted approaches for specific applications. We started in 1999 with homing endonucleases, named meganucleases, that were at that time the only existing gene editing technology. We benchmarked meganucleases with the other available technology in the early 2000’s, Zinc Finger Nucleases, with balanced pros and cons on both sides. We remained very focused on meganucleases until 2010 when we learned about TAL effector nucleases, TALEN®. In fall 2010, we tested TALEN with great success in terms of ease to design, precision and efficiency. Very rapidly, we acquired an exclusive license from the University of Minnesota over this technology. From the TALEN technology, we developed new versions with Compact TALEN, BurrH (a different backbone then TALs) and MegaTAL together with Precision Genome Engineering, Inc. In early 2013, we got very excited about Crispr-Cas9 and launched a series of experiments to benchmark the technology with our existing portfolio of gene editing technologies. CRISPR revealed it was very accessible to design. Even a high school kid could design a CRISPR. However, the precision and the efficiency were far less than that achieved with TALEN and our expectations; and the induced cytotoxicity resulting from CRISPR made us leave this technology essentially for functional genomics experiments only.
We apply gene editing to engineer T-cells such as for the manufacturing of off-the-shelf CAR T-cells to provide these CAR T-cells with new attributes such as resistance to certain drugs, overcoming checkpoint inhibition, or suppressing cross-T-cell reactions. In addition, we invest in developing our gene editing technologies to design a new generation of antiviral approaches through viral DNA clipping or generating immune cells resistant to infection. Finally, for the longer term, we are developing some gene editing approaches to treat genetic diseases and metabolic disorders. The real challenge for these new applications come from vector technologies as sometimes it is necessary to bring into the cells several molecular components such as DNA and RNA or DNA and proteins that cannot be vectorized the same way.
WuXi: How does your company’s approach differ from other companies in the gene editing field?
André Choulika: The big difference between Cellectis and other companies is our long term experience in the gene editing field. We have been in this space for more than 17 years and have a deep understanding of DNA recombination processes as well as a strong and seasoned team of long time gene editing experts. Also, we are not a one technology company, which I believe is a flawed strategy, as technologies are meant to be obsolete one day. What we do have is a systematic approach and we use any gene editing technologies that is an appropriate application for our purpose. Today, it is obvious that TALEN is by far the superior technology for therapeutic use. In fact, the first patients have been treated with TALEN engineered products with a clear patient benefit. These patients, who were treated in 2015, are today still in complete remission. Since then, all of the clinical potential has been expressed in the clinic by TALEN based products. This is what makes us different –we are patient centric.
WuXi: What diseases are best treated with therapeutic gene editing? Do you see any limitations?
André Choulika: Leukemias are diseases that are being addressed today in clinical trials by therapeutic gene editing with TALEN-edited CAR T-cells. Therefore, cancer and, especially liquid tumors, are today best treated with therapeutic gene editing.
The real challenge we are all facing with gene editing today is to bring enough gene editing tools into the right cells. The second challenge is to not harm these cells through off target effects and make them sicker than they were, or worse than this, make them cancerous. Doing the DNA repair, gene targeting or knockout with a high efficiency is not the big challenge anymore. Therefore, the best treated diseases are the ones where you can operate on the cells ex-vivo, check the integrity of the cells after gene editing, for the health of the patient, QC the cells, and then place the cells back into the patient. Gene edited CAR T-cells for oncology are the most accessible, followed by blood diseases, but it requires the ability to manipulate bone marrow stem cells, and immune deficiencies. The eye is also an accessible organ for gene editing, but it requires a good mastery of the potential off-target effects of the gene editing tool. Finally, the liver is an organ that could be targeted in-vivo more easily than others and would open the gate to treat a series of metabolic diseases.
I do not see any limitation to gene editing once the vector technologies are developed. Gene editing is a revolution in the way modern molecular medicine is foreseen. Doctors will have to adapt.
WuXi: Do you need a different business model for commercializing gene editing technology? If so, how is the business model structured?
André Choulika: Largely, gene editing allows for the creation of three kinds of things: research, building new species, and treating patients. Commercializing gene editing as research tools is already a business. CRISPR was a huge revolution in this space. I only see some business potential in guide RNA libraries similar to siRNA libraries to make fictional genomic, pharmacogenomics, or validate genomic targets. It is so accessible and cheap to make a CRISPR that I do not see a strong interest in making it a business service to research.
Generating new species makes sense in the agricultural biotechnology field. All the big players are investing in this space but the real challengers are small players. The future challenger in this space may be a small player such as Calyxt, Inc. based in the Twin Cities in Minnesota. There are also players such as Recombinetics, Inc., which are editing cattle. Today, a very select number of consumers have encountered gene edited products, food or fibers. My bet is that in the coming decade, billions of people will be consuming gene edited products on a daily basis.
Finally, in the therapeutic field, you can see two business models :products or services. An off-the-shelf product such as UCART123 to treat AML fits perfectly in the current business model of any biotech or pharmaceutical company. An autologous CART treatment is more a personalized medicine type of approach and is more similar to a bone marrow transplant kind of business. This could be translated to the entire gene editing space and is the way business models are going to evolve in the future. The only way to keep viable margins in the current regulatory space is the for the product business model to support a capital intensive R&D process with a high attrition rate. With the progress of gene editing and the ability to address the roots of diseases at the genomic level and not treating only symptoms will drive biotechnology more and more toward the personalized type of medicine approach. For each group of individuals with a genotypic mutation, there will need to be a specific medicine. This will require the regulatory authorities to undergo a drastic evolution, a revolution, to make this economically viable for the payers and the biotech companies. Unless the only ones to find their way into this new medicine may be hospitals. Like surgery, gene editing might become a genome surgery type of treatment and the business model that comes with it.
WuXi: What are the major challenges you face in bringing gene editing therapies to patients?
André Choulika: As of today, the main challenge we are facing with UCART is CMC. We associate several levels of challenges, a cell therapy based on primary cells, gene editing and gene therapy, and the requirements of CMC robustness, quality and yields. Patients have the right to receive a therapy that is safe, certified and consistent. We have undergone several manufacturing campaigns so far and the products are now in the clinic. And it is very exciting to see the hurdles being solved one after the other. We have been at the forefront of bringing gene editing to help patients with unmet medical needs and we believe that spectacular progress has been made in the past five years. However, in the future, new gates will be opened and there will be wider patient access.
WuXi: What kinds of collaborations are essential for your company? Are you pursuing global partnerships?
André Choulika: Cellectis has two strategic collaborations, one with Servier and one with Pfizer, on CAR T-cells in oncology. These two collaborations are essential for us, as Pfizer and Servier are developing a significant part of our CART product portfolio and the products they are developing are very valuable and represent a significant part of our assets. Any progress on their side is an important step for us and we are collaborating in the development of these products and closely observing the progress of the trials. Nevertheless, Cellectis is not a CAR T-only company and our strong gene editing capabilities open a huge space of new opportunities. Some of these opportunities are developed by us on a standalone basis, similar to our CART portfolio, UCART123, UCARTCS1 and UCART22, which are self-owned. We also do envision pursuing new partnership opportunities outside the CAR T space using gene editing either for antiviral applications or to treat some metabolic diseases.
WuXi: How will gene editing technology evolve over the next five years?
André Choulika: With gene editing, I can predict the future quite well on a long term basis, but on a mid-term range, it is much more difficult. Technologies always evolve faster than what we forecast, but on the other side, we are always more optimistic about patient access to these technological evolutions. That being said, vector technologies are where we will see most of the progress in gene editing for the next five years because this is where the current problems are. On the other side, off-target effects of gene editing technologies will harnessed by better genome wide analysis. The reduction of off-targets will be addressed by nucleases with a DNA protein interaction which will not involve an RNA guide. With 20 amino-acids against 4 bases spread on a 32 base-pairs site, the array of solutions is infinite. This is where the solution will come from. Finally, the real paradigm shift will be within large DNA synthesis and synthetic biology. Today, building full human chromosomes projects are launched. We see this as a huge project, similar to the launch of the sequencing of the human genome in 1990. In five years, we will be able to synthesize DNA per the gigabase with speed and accuracy. This is where gene editing will evolve, from editing to composing DNA.
WuXi: Do you foresee any challenges in the public acceptance of gene editing therapies?
André Choulika: Of course, the debate will have to be addressed. When you start intervening in the real human nature of genes and editing them, it triggers questions from the public. There is no debate over the fact that there will be large public acceptance of a therapy based on gene editing which can help a patient who is suffering from a debilitating disease. The question is more about what happens in the long run, and we need to know exactly where we are heading. The current discussions are not so much on gene editing based therapies but about editing the human germ line or embryos. However, if you move the cursor to 50 years from now and start doing essentially therapeutic somatic gene editing, fixing all mutations causing diseases in all patients; at a time, there will be a disconnect between what is encoded in human somatic cells and the germ line of people. So, no, I do not see any issues in public acceptance on somatic gene editing, but these are serious matters for a debate in the long run.
Wuxi: Where would you rank gene editing technology in the history of biotech advances?
André Choulika: I would rank gene editing in the history of human kind as a major paradigm shift in the history of Earth, far deeper than anything since the rise of Homo sapiens. Human fate is now within our hands.