As a part of my series about “The Future of Healthcare” I had the pleasure of interviewing Dr. André Choulika, CEO and Chairman, Cellectis. Dr. André Choulika is the Chairman, CEO, and founder of Cellectis. Dr Choulika is a pioneer in the analysis and use of meganucleases to modify complex genomes. He is also an expert on gene editing and immunotherapies that are based on gene-edited CAR T-cells as well as the overall potential impact of gene editing to the healthcare and life sciences sectors through the development and therapeutic application of a new generation of cancer therapies. After receiving his PhD in molecular virology from the University of Paris VI (Pierre et Marie Curie), he 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.
Can you share the most interesting story that happened to you since you began your career?
Molecular genetics has been at the center of my life for over 35 years. It’s a fascinating science that requires hard work to get results, which can often seem dry to many people. Over time, I became accustomed to analyzing and integrating our progress with a lot of detachment and coldness. However, when our first therapeutic product candidate, UCART19, was first given to a patient in 2015 under a companionate protocol, I kept my scientific mindset worrying about series of things — especially the safety of the patient. I was satisfied when we learned everything went well and that the patient was cancer free one month later. Six months after, the story broke in the press, and I was at home watching the news on TV. Watching the segment, I had the chance to see the face of this young patient who had been treated with UCART19, smiling and playing happily. This raised a deep emotion in me that never happened before, sparking a passion to help more patients in the same way. At that moment, I understood the purpose I’ve been working towards my whole life.
Can you tell us about your “Big Idea That Might Change the World”?
The expression “it’s in my DNA” is commonly used to indicate the deepest inscription of who we are — but that’s about to change. The cells that make us who we are, our DNA, is no longer our genetic destiny. The ability to edit DNA in our cells not only frees us of a defined fate, but also opens the gate to an unknown world. As someone who helped to pioneer gene editing over 30 years ago, gene editing is the next transformative step of medicine and has the potential to completely reshape it in the very near future. In the 21st Century, humans are going to be able to erase unhealthy DNA mutations in their DNA, and this could be the end of some genetic diseases and potentially the beginning of a new page in the history of human kind.
Gene editing is entering our lives through game changing applications. The first application that has already changed lives is coming from gene editing to fight cancer. While it’s clear that T-cell therapies are coming to the forefront of cancer treatment in today’s society with the recent FDA approval of Novartis’ Kymriah and Kite’s Yescarta, both of these autologous products focus on leveraging a patient’s own T-cells to create cancer treatments. This has serious constraints, including high pricing and limited market access, highlighting the need to personalize medicine on a larger scale. Cellectis introduced the transgressive idea of editing the genes of healthy T-cells to make then “off-the-shelf”. In this way, patients don’t need to provide their own T-cells to generate the product. “Off-the-shelf” T-cells, also named allogeneic, can be manufactured on an industrial scale, getting to patients faster, even for those that are lacking healthy — or any — T-cells within their bodies, and in a more cost-effective way. The ability to edit genes has the potential to free us of using patient derived cells and would allow us to grab a treatment for cancer right out of the freezer whenever a patient is in need.
Furthermore, allogeneic products can be available for all patients globally, including those who are unable to produce autologous CARs in countries where the technology is not yet available. There are also lower logistical complexities and associated costs, as allogeneic products can potentially be shipped within a day worldwide and have the potential to reduce the final cost. Re-dosing is even possible with this approach, which contributes to a patient’s overall survival.
How do you think this will change the world?
The ability to edit genes has opened the potential to fix any genetic defect in cells. It provides the possibility to treat people by curing the roots of diseases, instead of merely treating the symptoms, potentially changing how we treat diseases moving forward. However, if initial spectacular results have been obtained with gene-edited CART therapies, access to other genetic inborn diseases will still have challenges ahead that I’m sure will be overcome in the next decades. The promise of “off-the-shelf”, universal CAR T-cell therapies is enormous, especially for people living with certain forms of blood cancers. Additionally, since patients would be immediately dosed with allogeneic products, these treatments would be more accessible than the autologous treatments currently on the market.
Cellectis has already seen very promising results with UCART19 having dosed patients in compassionate care cases in the U.K. in November 2015 and May 2016. They were the first patients helped by gene editing and show what gene editing can mean for the future of medicine — for patients, doctors and the cancer treatment landscape at large. Now this product candidate is in clinical trials under Servier and Allogene through a licensing agreement. Recently, data was presented at ASH 2018 (a premier industry conference) which showed the continued progress of UCART19 in Phase 1 clinical trials, for both pediatric and adult ALL patients. We are pleased to see continued progress for UCART19 under the management of our partners.
Was there a “tipping point” that led you to this idea? Can you tell us that story?
The true tipping point that changed my life and made me focus all my energy on the concept of gene editing happed in the early 90’s. At that time, I was doing research at Institut Pasteur, playing with the first gene editing tool, which was called Omega back then (now named I-Scel and are meganucleases). Omega was naturally occurring DNA scissors discovered by Professor Bernard Dujon, who was my teacher at the University.
I’m a virologist by training and I was working on a mouse leukemia retrovirus, the Moloney Murin Leukemia Virus. Of course, I decided to introduce the target DNA sequence of Omega into this virus that was recombined. After I infected mice cells with this recombinant virus that, like HIV, integrates into the host genome, I introduced the infected cells. What I saw left me flabbergasted. I observed that the virus popped out of some of the host cells from their DNA, which was an incredible outcome that could have a huge impact on a number of diseases.
We immediately met with the patent department of Institut Pasteur. In 1992, we filed for the first patent on nuclease-based gene editing and included our vision on how this discovery could change the world (which can now be seen in the patent database of the USPTO website). Since then, I’ve remained dedicated to my life’s mission of using gene editing towards a cure. Three decades later, and we have good insight on how to potentially cure some forms of leukemia. I will probably need a second life to see my dreams of the early 90’s fulfilled, but it has been a fantastic journey.
What do you need to lead this idea to widespread adoption?
The first complete remission we had in leukemia in 2015 has already shown the industry the awesome power of gene editing in cell and gene therapy. Nevertheless, Cellectis is currently conducting a series of clinical trials with the first gene-edited, “off-the-shelf” CAR T-cell product candidates to be developed in the U.S. These trials include: UCART123 for patients with acute myeloid leukemia (AML), UCART22 for patients with B-cell acute lymphoblastic leukemia (B-ALL), and in 2019, UCARTCS1 in multiple myeloma (MM). We expect more trials, and data, within the coming years.
In order to do this, we need to move these products through the clinical trial process successfully and into the manufacturing stage, whereby they then become available to patients. Patients with these diseases are in dire need of effective, affordable and easily accessible treatments, and “off-the-shelf” product candidates aim to do just that. We are a patient driven company, and we’re committed to finding a cure for patients with incurable diseases. Having a social impact and helping people live their lives is the best momentum driver for leading widespread adoption.
Thank you so much for joining us. This was very inspirational.