The Emergence of Fifth Generation CAR-T: A Boon for Late-Stage Cancer Patients or a Major Breakthrough in Solid Tumor Treatment?

The fifth-generation CAR-T is designed as a universal type of CAR-T. Is this risk-free CAR-T capable of achieving significant breakthroughs in solid tumor treatment, or is it effectively reducing costs to enable scalable production and treatment?

After nearly three decades of development, CAR (Chimeric Antigen Receptor) technology has undergone continuous innovation. Currently, CAR has evolved to its fifth generation. Its aim is to enhance the safety of treatments by reducing toxicity and non-specific antigen recognition. This is achieved by stimulating proliferation, activation, and the generation of memory phenotypes within CAR-T cells to improve efficiency and provide immune regulation for the optimal function of CAR-T cells.

Generation CAR-T

The Evolution of Different Generations of CAR-T

First Generation CAR:

The first-generation CAR comprises an extracellular single-chain variable fragment (scFv) as the antigen recognition binding domain and an intracellular CD3ζ as the cellular activation signaling domain. Despite initiating cytotoxic anti-tumor responses within transplanted T cells, first-generation CAR-T cells exhibit lower levels of cytotoxicity and proliferation due to the CAR structure lacking co-stimulatory domains, which results in inadequate interleukin (IL)-2 production.

Second Generation CAR:

Building upon the CD3ζ signal transduction domain, the second-generation CAR includes an additional co-stimulatory signaling domain that activates T cells, significantly enhancing T cell proliferation and survival. For instance, CD28 can deliver robust activation signals, enabling T cells to achieve high levels of cytotoxic activity in a shorter duration, while 4-1BB provides prolonged activation signals, sustaining T cell-mediated killing of tumor cells. However, limitations arise in second-generation CAR-T cells utilizing retroviruses as viral vectors, restricting the length of transgene fragments they can carry. As a result, it becomes necessary to choose between incorporating CD28 and 4-1BB into T lymphocytes.

Third Generation CAR:

Third-generation CAR-T cells utilize larger DNA-carrying lentiviruses as viral vectors, allowing simultaneous incorporation of DNA fragments for both CD28 and 4-1BB into T cells. Consequently, the third-generation CAR structure encompasses two co-stimulatory domains, theoretically addressing the need for higher activation intensity and sustained survival of CAR-T cells. However, the safety concerns associated with prolonged and high-level persistence of CAR-T cells, including potential attacks on the host’s immune system, remain unresolved despite these advancements.

Fourth Generation CAR:

The design concept behind the fourth-generation CAR revolves around the precise treatment of cancerous diseases. For instance, solid tumors generate a microenvironment (TME) during their chronic progression, preventing CAR-T cells from penetrating the tumor interior. As a result, CAR-T therapy demonstrates limited efficacy in treating solid tumors. TRUCK CAR-T involves incorporating cytokines (such as IL-12) or chemokines into the CAR structure. This facilitates increased infiltration of T cells into tumor tissues while recruiting other immune cells within the body to eliminate tumor cells. In some studies, a suicide gene or certain drug-sensitive genes are attached to the CAR structure to ensure the clearance of CAR-T cells from the body post-treatment, preventing inadvertent harm to normal cells and enhancing the safety and controllability of CAR-T therapy.

Fifth Generation CAR:

The fifth-generation CAR-T, known as universal CAR-T, achieves T-cell receptor α (TCR-α) and β (TCR-β) chain deletion by knocking out the TRAC gene. This implies the removal of the T-cell receptor (TCR) from the surface of T cells, thereby avoiding the occurrence of graft-versus-host disease (GVHD) in transplantation reactions.

Since the FDA’s approval of the CD19 CAR-T product, Novartis’s Kymriah, in 2017, CAR-T cell therapy has entered a stage of rapid development. However, the currently approved and marketed products are all second-generation CAR-T therapies. There is still a long way to go for CAR-T to become widespread in the market.

Safety concerns constitute the primary challenge for CAR-T, such as off-target effects, cytokine release syndrome (CRS), and neurotoxicity (NTX). Currently available CAR-T products primarily focus on treating hematologic malignancies, with no major breakthroughs achieved yet in treating solid tumors.

In 2021, China’s NMPA approved three CAR-T products for marketing: FOSUNKITE’s Axicabtagene Ciloleucel injection, JW Therapeutics’s Relmacabtagene Autoleucel Injection, and the recently approved JUVENTAS’s Inaticabtagene Autoleucel Injection, all targeting CD19. Additionally, earlier this year, IASO Bio obtained approval for Equecabtagene Autoleucel Injection, targeting BCMA. While CAR-T targeting CD19 has shown effectiveness, its scope remains limited to B-cell-related hematologic malignancies. BCMA-targeted CAR-T is restricted to treating multiple myeloma. To address solid tumor treatment, the development of more specific and potent targets is necessary.

Among the recently released domestically developed JUVENTAS’s Inaticabtagene Autoleucel Injection, its competitive advantage lies in its price, which has decreased to below one million RMB(Approximately $140,000 US).

With the continuous advancement of molecular biology technologies, more breakthroughs are expected in CAR molecule design. This progression anticipates the development of safer and more efficient universal CAR-T therapies in the future, benefiting a broader spectrum of cancer patients.

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