With proactive government support and an increasingly specialised workforce, China has become one of the leading nations in the development of Chimeric Antigen Receptor T-cell (CAR-T) therapies, along with the US. More than 200 CAR-T therapies are being developed in China, and the number of ongoing clinical trials continues to increase. Here, we highlight three Chinese biotech firms working in this exciting new area.
In his latest stop in a long career as a biotech investor and entrepreneur, William Wei Cao became the founder, chairman and CEO of Gracell: a fast-growing CAR-T biotech in Shanghai dedicated to developing first-in-class CAR-T therapies to serve patient needs.
Despite the burgeoning industry, CAR-T technology is still in fact in its infancy. Motivated by the hope of refining the many imperfections of CAR-T technology, Wei Cao founded Gracell – named after a portmanteau of the words ‘Grace’ and ‘Cell’.
According to Wei Cao, there are four main obstacles to the development of CAR-T therapies: first, their significant cost; second, the lengthy ‘vein to vein’ process (the time from when cells are extracted to when they are infused back into the patient); third, patient relapse (after six to 12 months, up to 50 percent of patients will relapse); fourth, the low efficacy of CAR-T in solid tumours. Gracell aspires to tackle these four core problems with four corresponding platforms.
The FAST-CAR platform aims to deal with both the cost and the length of manufacturing process. With this platform, Gracell has reduced the average time for production from two weeks to overnight – the shortest within the industry so far. To top it off, in terms of potency, FAST-CAR is 30 to 50 times more potent than conventional CAR-T.
The second is ‘off-the-shelf’ CAR-T. The concept is straightforward: to make CAR-T therapies from healthy donor cells and manufacture hundreds of thousands of doses that can be stored for use when needed. Unlike other CAR-T therapies that use toxic immune-suppressive drugs, Gracell aims to use CAR-T cells themselves to attack the host immune cells.
With regards to patient relapse, Gracell packs two GPS systems into the T-cell to target two different tumour antigens – because it is very unlikely that both will disappear at the same time – as well as, including a suicide switch to kill the T-cell if needed.
Of lower priority, they have a fourth platform aimed at targeting solid tumours.
Solid tumours are arguably one of the hardest areas for CAR-T therapy. In general, CAR-T cells recognize and attack cancer antigens present on the extracellular surface of tumours. Nonetheless, solid tumours are difficult to target because its cancer antigens are primarily expressed intracellularly by peptide-MHC complexes. Developing drugs that target these antigens is extremely difficult and hence, they are often termed ‘undruggable’.
Despite the difficulties, Dr Zhang Yu decided to rise to the challenge by founding Aeon Therapeutics – a joint venture between a Chinese cell and gene therapy engineering company, VcanBio, and a San Francisco-based cell and gene therapy biotech, Eureka Therapeutics.
Eureka is set to developing a pipeline of novel cancer therapeutics targeting intracellular and cell-surface targets with two of its proprietary platforms: ARTEMIS™ platform and E-ALPHA® antibody discovery platform. Aeon Therapeutics focuses on commercializing Eureka’s assets for solid tumours in China.
ARTEMIS™ platform mimics the natural biology of T-cells to fight cancer, with the intention of creating safer and potentially more effective T-cell therapies. E-ALPHA® antibody discovery platform comprises a highly diverse human-derived antibody phage library of over 100 billion clones with unique antibody sequences that is designed to enable the development of highly specific antibodies against target antigens, including peptide-MHC complexes and cell surface proteins.
With these ground-breaking platforms, Aeon Therapeutics has entered a largely untapped market in China: liver cancer. Globally, over 50 percent of new liver cancer cases, as well as deaths, come from China. Dr Zhang’s team has become a pioneer in the development of an anti-AFP (α-fetoprotein) CAR-T therapy for hepatocellular carcinoma (HCC).
This anti-AFP CAR-T therapy received US IND approval in January 2019, with the first patient being enrolled last month. So far, it has demonstrated a favourable safety profile with no observed cytokine release syndrome or drug-related neurotoxicity.
Dr Zonghai Li has achieved a lot in his distinguished career. He is the inventor of countless cancer-focused technologies: (1) Hpd3cell, a new phage display technology; (2) FR806, a new safety switch for T cell therapy; and (3) Run-CAR technology, used to increase the antitumour activities of CAR-T cells. He was also the first to identify GE11, a peptide ligand of EGFR that is now the most widely used unnatural peptide in antitumour studies.
Among his various accomplishments, Li stands out for founding CARsgen Therapeutics: an innovative biotech committed to delivering cures to cancer patients worldwide. In only five years, since the company was founded, Li’s team has launched several first-in-class CAR-T clinical trials for the treatment of relapsed/refractory tumours.
Most recently, CARsgen Therapeutics made headlines as its multiple myeloma CAR-T cell therapy CT053 was granted orphan drug status by the US FDA. CT053 is composed of fully human anti-BCMA (B Cell Maturation Antigen) autologous chimeric antigen receptor T cells. BCMA is a protein found on the surface of myeloma cells and is considered a primary target for cell therapy.
According to Li, “19 of 24 patients with relapsed and refractory multiple myeloma showed complete response… and importantly, no event of [side effect] grade 3 or higher cytokine release syndrome (CRS) was observed,” in Phase I trials.
By the end of 2019, CARsgen intends to submit 5 INDs to the NMPA (National Medical Products Administration in China) and 2 INDs to the FDA in 2019.