SHANGHAI – Gracell Biotechnologies Co. Ltd., of Suzhou and Shanghai, has received an $85 million endorsement from topflight venture investors active in China's biotech scene led by Singapore's Temasek with Lilly Asia Ventures, and joined by Kington Capital, King Star Capital and Chengdu Miaoji. This is the second round of financing for Gracell; the startup received $10 million from 6 Dimensions Capital in 2017.

William Cao, Gracell's founder, chairman, lead shareholder and CEO, previously helmed the Nasdaq-listed Cellular Biomedicine Group. There he was responsible for that company's push to develop affordable stem cell and other cellular treatments for a range of conditions.

Cellular therapies often require adapting the patient's own cells, making them difficult to scale, time-consuming to manufacture and prohibitively expensive. Cao has made it his mission to tackle those issues by focusing on low-cost manufacturing and off-the-shelf solutions for what he calls next-generation cellular therapy drugs, always with an eye for what makes sense for the Chinese market.

"In my opinion, even a price tag [of] ¥1 million (US$150,000) is unbearable for Chinese cancer patients. When approved CAR T therapies can cost as much as $500,000 in the U.S., we have to find a better solution," Cao told BioWorld.

Faster, better and cheaper?

The company is pursuing four platforms: dual CAR, universal CAR, Fast CAR (a proprietary name) and one for solid tumors. The biotech expects to file INDs for three products by the end of the year.

One platform has the potential to confer some first-in-class credibility. The Fast CAR technology shortens the time it takes to modify a patient's T cells, from the standard nine days to 14 days for approved CAR T therapies, to merely overnight.

In patients with advanced cancer, cutting out the additional wait time can make all the difference. In the two to three weeks it takes to modify the cells and reinsert them, the patient's body may be so riddled with tumors that there are no viable T cells left. But Cao said that is only one of the advantages of Fast CAR.

"This is a dramatic time-saving to get the drug to the patient's bedside faster, but the real highlight is that the cells manufactured by Fast CAR appear younger and more potent based on our phenotype analysis, and the cost is lower. We have shrunk the manufacturing process to overnight and it does not compromise on quality or efficacy of the cell; rather, it improves it significantly," explained Cao.

The effective dose for cells using the Fast CAR method is between 1/20th and 1/30th or 20 to 30 times more potent than conventionally manufactured CAR T.

The process relies on combining virus and cell culture technology and has already seen positive results in humans, said Cao. The plan is to release data this summer at an international conference.

Gracell is approaching its next nearest competitor, CAR T pioneer Carl June, of the University of Pennsylvania, who is also processing CAR T treatments in a matter of days.

Cao said he expects Fast CAR's application of the technology will be unlimited, and can be applied to lymphoma, multiple myeloma and solid tumors as well.

A universal, off-the-shelf solution

Not to be outdone, Gracell is going for an even more speedy and scalable solution: an off-the-shelf product that can be administered immediately; an allogeneic rather than autologous cell treatment.

"We are developing a CAR T drug that will be universal without the need to be individualized. If it is premade, it can be given to the patient without delay for a much lower cost," said Cao.

The aim is to develop a best-in-class solution by using CRISPR to edit the cells to top the already established Cellectis SA allogeneic offering that makes use of transcription activator-like effector nuclease (Talen) genome editing technology.

CRISPR is used to edit the genes to sidestep graft-vs.-host disease (GVHD) – the body's rejection of cells that do not match its own. In animal models editing genes ex vivo, researchers have been able to eliminate the Cas9 proteins.

"In our universal CAR T idea, we simply delete the molecules that cause the GVHD so the patient body can tolerate the allogeneic T cells," said Cao.

The plan is to use that treatment on patients in the hospital setting, using China's institutional review board (IRB) pathway within the next six months. Given the high valuations of Cellectis, Cao said that program has garnered significant investor interest.

Dual CAR T

Much like bispecific antibodies, Gracell is also developing double-header CAR Ts that attack two targets at once.

The firm has two dual CAR T products: a CD19/CD22 CAR and a CD19/CD20 CAR. But the number of products is beside the point, said Cao, who is looking to ascertain if the dual CAR T process is workable.

"The number of products is not the question; just like other companies, we use CD19 to prove the principle. It is a golden benchmark to see how we compare," Cao said.

For multiple myeloma, the company has an additional dual CAR T, targeting BCMA and an undisclosed antigen X. Cao maintained that dual CARs have a higher chance of reducing the chances for a relapse caused by antigen escape that prolongs the efficacy period of the drug.

For example, in B-cell leukemia, a CD19 CAR T treatment will experience antigen escape, said Cao. When the CD19 antigen disappears, the leukemia cell returns, having avoided the CAR T cells' surveillance. But the leukemia cell has other antigens, providing an opportunity to design a second CAR T on the same T cell that will recognize additional molecules.

In that aspect, Gracell is looking to be best in class. The Seattle Children's Hospital has already tested its autologous CD19/CD22 dual CAR on patients.

The China advantage and drawback

Cao credits the 2016 changes in the regulatory regime to allow clinical experiments in a single hospital setting via the IRB path (similar to the investigator-initiated trial in the U.S.) as a huge boon to the development of cellular treatments in China.

That early leap into human studies allows companies to quickly obtain feedback and data before seeking approval for a multiregional trial with the drug regulators. The early human data are especially important when analyzing living immune cell therapies, which are less than effective in mouse models.

The IRB path only requires a hospital's ethical and scientific board approval. Although the scandalous CRISPR experiment conducted by Jiankui He to edit human embryos also used that pathway, Cao said the window to keep using IRB remains open with the majority of practitioners respecting the guidelines.

Early access to patients has put Gracell ahead of some competitors that have been slower to collect data in humans.

On the other hand, Gracell may hit speed bumps in the more prosaic world of procurement. The firm will need to license certain technologies and equipment from the U.S., which may become more difficult in the current geopolitical climate of U.S.-China tensions. In many instances, there are no local substitutes.

Although there may be a tide of rising conservatism toward working with Chinese partners, Cao is optimistic about partnering with a big pharma, most of which have a large presence in China already.

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