Universal CAR-T, Transaction +1

CAR-T therapy (chimeric antigen receptor t-cell immunotherapy) has been a favorite of the innovative drug market in recent years. However, up to now, the CAR-T therapies approved for marketing in the world are autologous products, which means after extracting cells from patients, T cells are activated by using gene engineering technology, with chimeric antigen receptors (CAR) targeting cancer antigens expressed on their surfaces, and then the proliferated cells are infused back into the patient's body. Subsequently, CAR-T cells use CAR as a targeting mechanism to specifically recognize tumor cells in the body and release a large number of effector molecules through immune action to kill the tumor cells.

Despite the impressive therapeutic effects of this type of therapy, its high pricing, restricted by the uniqueness of its manufacturing process, with marketed products priced over USD 1 million, significantly limits patient access. Furthermore, autologous CAR-T products involve steps such as gene modification, activation, culture, expansion, and modification, resulting in a relatively long preparation period (typically 2-3 weeks). Due to these limitations, universal CAR-T (UCAR-T), also known as off-the-shelf CAR-T or allogeneic CAR-T, has emerged and gained significant industry attention.

Since November, several transactions have occurred in the UCAR-T field among MNCs (multinational pharmaceutical companies). Notably, Roche acquired Poseida Therapeutics, a biopharmaceutical company focused on developing the UCAR-T therapy, on November 26 for a total value of USD 1.5 billion.

What are the advantages and limitations of UCAR-T? What is the current status of its development?

The Cost-Effective UCAR-T Attracts MNCs to Compete

Unlike autologousCAR-T therapy, UCAR-T is a type of CAR-T therapy prepared from allogeneic T cells collected from healthy donors. These T cells are genetically engineered and expanded on a large scale in vitro to produce off-the-shelf cell drugs. Since they are derived from healthy donors, they are not affected by the number and quality of the patient's T cells, resulting in a high preparation success rate. A single batch can meet the needs of hundreds of patients, offering absolute advantages in time and price.

Currently, UCAR-T cell therapy has sparked a R&D boom. Recently, Roche announced that it will acquire Poseida, a clinical-stage biopharmaceutical company, for a total value of approximately USD 1.5 billion. Poseida leverages a proprietary gene engineering platform technology to gradually transition from autologous to allogeneic CAR-T therapy.

In fact, Roche's collaboration with Poseida began in August 2022, with a focus on developing the UCAR-T therapy for hematologic tumors. The collaboration covers the R&D of multiple UCAR-T therapies targeting multiple myeloma, B-cell lymphoma, and other hematological indications.

With this significant acquisition of Poseida, Roche has gained access to Poseida's proprietary platform, the non-viral piggyBac DNA delivery system. This platform uses gene editing technology to deliver CAR molecules to T cells, with the advantage of generating CAR-T products with highly active stem cell memory T cells (TSCM cells). These cells exhibit more durable high-activity responses and lower toxicity. Additionally, non-viral vectors have low manufacturing costs, short production times, and low risks of mutagenesis and tumorigenesis.

Poseida's products under development also aim to address the limitations of CAR-T therapy, including issues such as duration of response and safety. Taking P-MUC1C-ALLO1, the pipeline under development, as an example, it is designed to be fully allogeneic, utilizing gene editing to eliminate or reduce reactions between the host and the graft, holding potential for the treatment of multiple solid tumors. In preclinical models, P-MUC1C-ALLO1 has been shown to eliminate triple negative breast cancer and ovarian cancer tumor cells to undetectable levels.

In summary, Poseida's unique transfection, editing, and delivery platforms have the potential to bring about the UCAR-T therapy with lower costs and shorter production times, addressing current bottlenecks in the field.

At present, UCAR-T has become a R&D boom in the field of cellular therapy. Besides Roche, several other MNCs, such as Novartis and Takeda, have also entered this field in recent days. On November 20, Novartis announced a collaboration with Vyriad to discover and develop the In Vivo CAR-T therapy, a novel type of universal cell therapy that has garnered significant attention due to its potential to "reduce costs and increase efficiency". Under the terms of the agreement, Novartis will focus on advancing Vyriad's identified and developed In Vivo CAR-T cell therapy into clinical trials, while Vyriad will receive upfront payments, milestone payments, and tiered royalties for the selected projects.

Also on November 20, Takeda announced a cooperation agreement with Alloy Therapeutics, which will develop Takeda's proprietary induced pluripotent stem cell (iPSC)-derived CAR-T cell platform (iCAR-T) and iPSC-derived CAR-NK platform (iCAR-NK). The aim is to accelerate the development of key therapies for the treatment of solid and hematological malignant tumors.

iCAR-T has the potential to develop the universal cell therapy, providing top performance and improved potency. Compared with autologous cell therapies, the manufacturing costs are significantly reduced.

The fact that two MNCs officially announced collaborations in the field of UCAR-T on the same day underscores the popularity of this field. Despite its popularity, the UCAR-T therapy, which is still in the early stages of exploration, has several challenges that need to be addressed.

Rising R&D Trends Both in China and Abroad: Unresolved Bottlenecks for UCAR-T

Due to the fact that UCAR-T is derived from healthy donors and is not affected by the quantity and quality of patients' T cells, it boasts a high preparation success rate and a single batch can meet the needs of hundreds of patients, offering absolute advantages in time and price. Therefore, numerous pharmaceutical companies in China and abroad have joined the race.

According to public information, over 20 UCAR-T products from more than ten companies, such as Cellectis, Allogene Therapeutics, Celyad, Caribou Bioscienses, and CRISPER Therapeutics, have already entered the clinical stage. Last July, Pfizer invested USD 25 million in stock equity in Caribou Biosciences to promote the company's exploration of allogeneic CAR-T therapy for multiple myeloma.

In China, there are also more than ten pharmaceutical companies, including Bioheng, BRL Medicine, LEGN.US, Innovent, Overland Pharma, CARsgen, and Gracell Bio, that have entered the UCAR-T race.

Despite the large number of entrants, the development of universal CAR-T has been limited by the immune rejection that allogeneic T cells may cause upon transplantation, and product development still faces many challenges. For example, allogeneic cells infused into patients may attack the host, leading to graft versus-host disease (GVHD), which can be life-threatening to patients. Secondly, due to the autoimmune limitations of the human body, allogeneic cells may be quickly recognized and eliminated by the host's immune cells, limiting their antitumor activity.

Additionally, issues such as the cell source and quality control of allogeneic CAR-T cell infusions, as well as related ethical concerns, cannot be overlooked.

Most importantly, from the perspective of efficacy, there seems to be a certain gap between the efficacy of UCAR-T and autologous CAR-T. Research data indicates that clinical trials of UCAR-T have shown an overall response rate of 67% among patients, with a median duration of response of 4.1 months. In comparison, the mainstream autologous CAR-T cell therapy boasts an initial overall response rate of approximately 90% and a 5-year initial remission rate of 58%, demonstrating superior efficacy.

Even with many uncertainties, UCAR-T therapy is undoubtedly the ultimate solution for CAR-T therapy, and bottlenecks will eventually be overcome amidst the continuous updates and iterations in biotechnology.

Primary references:

1、Roche enters into a definitive agreement to acquire Poseida Therapeutics, including cell therapy candidates and related platform technologies.

2、https://www.prnewswire.com/news-releases/vyriad-announces-strategic-collaboration-with-novartis-to-develop-in-vivo-car-t-cell-therapies-302310717.html.

3、https://vyriad.com/science/in-vivo-platforms/.

About  the Author    

Xiaobin

Xiaobin holds a Master's degree in Pharmacy and currently work as a public health control staff. Navigating through the intricate and complex data each day and feeling a sense of insignificance of herself. While being happy to witness the golden time of the development of Chinese bio-pharmaceutical industry. Hope to learn and improve together with everyone.