John Maher, Leucid Bio, tells Megan Thomas about his work and offers valuable advice to others in this field.
MT: Where do you work, and can you tell us what you’re working on at the moment?
JM: I am Chief Scientific Officer of a CAR T-cell spin-out company called Leucid Bio. I am also a Clinician Scientist at King’s College London and a Consultant Immunologist at Eastbourne Hospital. The primary focus of my work is CAR T-cell immunotherapy of cancer, with a focus on solid tumours, which traditionally have proven much harder to treat using this approach. At Leucid, we are developing a next generation lateral CAR platform which we believe delivers optimised signalling to CAR T-cells. When compared with existing linear CAR designs, our lateral CAR architectures significantly improve anti-tumour activity in a range of solid tumour model systems owing to greater functional persistence of the cells.
MT: What’s been the highlight of your career so far?
JM: While a visiting fellow in the lab of the CAR pioneer, Michel Sadelain, I was the first to design and test second generation (2G) CARs in human T-cells, assembling this from first generation (1G) and co-stimulatory CAR systems that Sadelain had developed. Immediately prior to my fellowship, 2G CAR technology was invented by Helene Finney in the UK, but had only been tested in immortalised models. I was so impressed by the functionality of 2G CARs in human T-cells that I devoted my career to this technology. There are now seven approved CAR-T products worldwide, all of which are 2G designs.
MT: What drug discovery breakthrough has been most impactful to your research?
JM: At a personal level, the development of high throughput gene synthesis approaches has really accelerated the rate at which we can generate new CARs. This allows us to produce hundreds of these molecules with similar target specificity, enabling rapid functional comparison using in vitro model systems. Leucid Bio routinely uses this approach in its CAR discovery platform.
MT: What has been the best piece of career advice you have received?
JM: In the early days of CAR research, I was advised by many that, by working in this area, I was creating a graveyard for my career. CAR T-cell immunotherapy was seen as a niche activity that would never impact meaningfully on patient care or undergo commercialisation. I’m glad that I listened instead to the pioneers in this field such as Michel Sadelain and Malcolm Brenner and stuck with it, rather than going against my instinct at the time.
MT: What advice would you offer someone looking to follow in your footsteps?
JM: I think that there are several elements required for success in any field. While natural talent in an area is of clear importance, there are several other attributes that are equally valuable. You need to be dogged, determined, make smart decisions, be collaborative, open to advice and engage with mentors who will support you in your career and choices. Do not be discouraged by failure. Follow your instincts and keep on trying to achieve what you believe in.
MT: If you could make everyone read one book, article or academic paper, what would it be and why?
JM: There is no contest here. It is Finney et al (1998) ‘Chimeric receptors providing both primary and costimulatory signalling in T cells from a single gene product’, J Immunol. 161(6):2791-7. The simple 2G CAR solution described in this unassuming paper was an enormous inspiration to me in the design of better CARs at the beginning of my career. When the Nobel Assembly at the Karolinska Institute deliberate over whether the development of CAR technology merits the award for Medicine or Physics, I do hope they will remember the inventor of the first enabled CAR technology, Dr Finney.
DDW Volume 24 – Issue 2, Spring 2023