SUZHOU, China – Chinese CAR T therapy developers from early to IPO-ready-stage are confident that they can create a strong presence in the global scene with their innovations, and they are also making strategies that will work best for their home market. One of the companies receiving a lot of attention at the EBC conference is Legend Biotech Corp. With a Nasdaq IPO coming soon, Legend Biotech has been in the spotlight at home and abroad, and it has a BCMA-targeting CAR T candidate for treating multiple myeloma nearing the NDA stage, in co-development with Janssen Biotech Inc.
Legend was one of the first Chinese biotech firms to partner with a multinational company to help take its innovation abroad.
Frank Fan, chief scientific officer of Legend Biotech, said he believes success comes from identifying the right target. BCMA is now a well-validated target with a slew of candidates – CAR T therapies, bispecific antibodies and antibody-drug conjugates – undergoing development.
“When the target is well-validated and your product is well-designed, you will see astonishing results,” he said. According to data from a phase Ib trial, LCAR-B38M achieved a 100% overall response rate (ORR), while competitors’ ORR ranged from 80% to 91%. Last December, the FDA granted breakthrough designation to Legend’s LCAR-B38M.
While Legend Biotech has set an encouraging example for Chinese cell therapy developers, the competitive landscape in China has been dominated by CD19- and BCMA-directed CAR T products, raising concerns about how undifferentiated the current landscape is.
At the EBC conference, some players shared how they plan to stand out in the space in different ways. They are looking at new targets, new approaches and strategies that may help guarantee success.
Persongen Biotherapeutics (Suzhou) Co. Ltd. intends to stand out from the competition by becoming the first company to market a CD7-directed CAR T therapy in the world. It is aiming to achieve that in 2022 or 2023.
Its CD7-CAR T is being developed to treat patients with relapsed/refractory T-lymphoblastic lymphoma (LBL) and acute lymphocytic leukemia (ALL). The biotech said three patients achieved 100% ORR, with two seeing complete response and one partial response. Persongen is set to unveil more clinical data at the European Hematology Association meeting in Germany next month.
“CD7 is the most promising therapeutic target for T-ALL,” said Lin Yang, CEO of Persongen. He explained that all T-ALL subtypes, including early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), a high-risk subset of T-ALL, strongly express CD7.
Though CD5 and CD1a also show promise for that indication, Yang said since CD5 expression on T cells is about 10 times than what appears on B cells, a low-affinity, high-avidity CAR targeting CD5 may steer clear of CD5-positive B cells while selectively killing T cells. Meanwhile, CD1a-CAR T does not include CAR T-cell fratricide and bypasses the need for sophisticated genome editing-based disruption of target antigens in T cells.
Persongen conducted a single-arm, open-label, first-in-human phase I pilot study to investigate the autologous CD7-CAR T cell manufacturing feasibility without contamination of malignant T cells. CAR T cells for seven patients have been manufactured with a success rate of 100%, without abnormal T-cell contamination.
The biotech infused six patients and evaluated five. The therapy candidate yielded 100% ORR. Four patients had grade 1 cytokine release syndrome (CRS), and only one case has grade 2 CRS. No neurotoxicity was observed.
“The manufacturing of autologous CD7-CAR T cells was confirmed feasible. The CRS grade is generally low. The CD7-CAR T cells showed therapeutic effect,” said Yang. “The CD7-CAR T therapy, with demonstrated manageable toxicity, is effective in the treatment of r/r T-ALL/LBL.”
Established in late 2019, Grit Therapeutics made its debut at the conference. Grit CEO Yarong Liu said the startup centers its work on tumor infiltrating lymphocytes (TIL).
“We want to find a TIL therapy candidate that is clinically proven to be effective in a few indications, so to understand better why cell therapy works in some indications but not some others. Then we can find out the role of TIL in immuno-oncology to better design next-generation products,” she explained.
An important task for the startup, Liu said, is to establish a unique manufacturing process to produce tumor-specific T cells in vitro.
Leveraging China’s clinical resources
For Shanghai Genbase Biotechnology Co. Ltd., a key advantage of developing cell therapies in China is to leverage the country’s large patient pool, so as to stand a chance of competing with the Western competition.
That is one of the strategies that Genbase CEO Jijun Yuan has set to achieve success. He said the biotech has been working closely with clinical physicians, especially oncologists, for a decade to gain access to a lot of clinical samples and data in China.
“The development of cell therapy needs to involve clinical physicians to a large extent. We were used to developing small-molecule drugs and antibodies in the laboratory, but cell therapy is a very different game,” he said.
Yuan said the biotech is working on TCRT programs with the help of the resources it has gained from the physicians.
As the company is China-focused, eventually it will need to launch a product that is affordable for many in the country. Yuan said Genbase is working hard to reduce manufacturing costs.
“CAR T manufacturing requires a closed system. We want to build a closed system, but one that is semi-automatic so we can lower the costs. We’re doing a lot of work in this regard and hope to lower the cost to a level that is affordable for Chinese patients while not compromising quality,” Yuan said.
Combination is future trend
Both Liu and Yuan said they believe that cell therapy is one of the many ways to treat solid tumors, and it could yield better results when combined with other therapies.
“Cell therapy itself cannot eliminate tumors completely,” Liu said. “We need to address relapsed solid tumors, thus developing combination therapies with cell therapy can be a approach.”
Yuan agreed. He further suggested that cell therapy be combined with bispecific antibodies, chemotherapy and even surgery to inhibit tumor growth.