Expanding the horizon of CAR T cell therapy: from cancer treatment to autoimmune diseases and beyond

Abstract

Chimeric antigen receptor (CAR)-T-cell therapy has garnered significant attention for its transformative impact on the treatment of hematologic malignancies such as leukemia and lymphoma. Despite its remarkable success, challenges such as resistance, limited efficacy in solid tumors, and adverse side effects remain prominent. This review consolidates recent advancements in CAR-T-cell therapy and explores innovative engineering techniques and strategies to overcome the immunosuppressive tumor microenvironment (TME). We also discuss emerging applications beyond cancer, including autoimmune diseases and chronic infections. Future perspectives highlight the development of more potent CAR-T cells with increased specificity and persistence and reduced toxicity, providing a roadmap for next-generation immunotherapies.

Keywords: CAR-T cells; adoptive immunotherapy; autoimmune diseases; solid tumors; tumor microenvironment.

Figure 1

Manufacturing process of CAR-T-cell therapy. The first step in the generation of CAR-T cells is the collection of blood samples from the patient. Subsequently, peripheral blood mononuclear cells (PBMCs) are isolated from the collected blood samples. Immunomagnetic beads are utilized to isolate T cells, which are activated simultaneously. Next, the gene encoding the chimeric antigen receptor (CAR) is introduced into the T cells via viral infection. Finally, the CAR-T cells are expanded in vitro and then reinfused into the patient’s body to eradicate tumors.

Figure 2

History of CAR-T-cell development. First-generation CAR-T cells are built upon the CD3-ζ chain. While they possess the ability to activate T cells, their antitumor efficacy is relatively limited. Second-generation CARs include a costimulatory molecule, such as CD28 or 4-1BB, which enhances the activation and functionality of CAR-T cells. Third-generation CARs further enhance the intracellular signaling domain by including a second costimulatory molecule. When a single-chain variable fragment (scFv) binds to tumor-associated antigens (TAAs), it activates the first signal through CD3ϵ and the second signal via two costimulatory signals, thereby strengthening the T-cell response. Fourth-generation CAR-T cells, also referred to as “cytokine-mediated killers at the cosmic level,” are engineered to release modified genes into tumor tissue upon the binding of the CAR to targeted antigens. This unique design aims to increase antitumor activity in a more targeted and potent manner. Fifth-generation CAR-T cells are designed by adding a cytoplasmic IL-2R β-chain domain and a STAT3/5 binding site to the second-generation design. This modification is expected to further optimize the activation, proliferation, and antitumor capabilities of CAR-T cells.

Figure 3

CAR-T cells for the treatment of noncancerous diseases. CAR-T cells are emerging in the field of noncancer disease treatment. CAR-T-cell therapy is not limited to cancer treatment. It has demonstrated significant potential in multiple areas, including autoimmune diseases, chronic infectious diseases, and diseases associated with aging. In autoimmune diseases, targeting CD19 can be used to treat SLE, and targeting Dsg3 can be used to treat PV, while CAR-Tregs can be used to treat type 1 diabetes. In infectious diseases such as AIDS, CAR-T-cell therapy is a potential way to clear host cells. With respect to senescence-associated diseases, CAR-T cells promote longevity by removing aging cells.

Figure 4

Challenges faced by CAR-T-cell therapy. CAR-T-cell therapy is constrained primarily by issues related to effectiveness and toxicity. CAR-T cells may become exhausted, resulting in short-lived resistance. This can lead to antigen escape in tumors, causing tumor recurrence. The heterogeneity of tumors also limits the efficacy of CAR-T-cell therapy. In the tumor microenvironment, various environmental changes occur. For example, it is often challenging for T cells to infiltrate solid tumors. In addition, immunosuppressive cells are recruited, inhibitory molecules are expressed, and metabolic reprogramming takes place. These factors collectively make it difficult to achieve a favorable prognosis when treating solid tumors. Moreover, CAR-T-cell therapy can sometimes produce excessive toxicity to the human body, inducing CRS or other on-target off-tumor toxicities and damaging normal cells in the body.

Figure 5

Harnessing multiple strategies to increase CAR-T-cell efficacy. The efficacy of CAR-T-cell therapy can be increased by employing various strategies.(1)The cost of CAR-T cells can be reduced by inducing CAR-T cells from iPSCs and cell lines or through in situ engineering approaches. (2)Virus-free engineering of CAR-T cells with LNPs or exosomes is an effective means to decrease genotoxicity.(3-4)The discovery of novel gene editing methods and the exploration of new targets have the potential to increase CAR-T-cell efficacy and overcome tumor resistance to CAR-T-cell therapy.(5)It is essential to control excessive toxicity by constructing new types of CAR-T cells.(6-7)Remodeling the TME or leveraging natural mutations can also contribute to the enhancement of CAR-T-cell efficacy. Collectively, these approaches can be utilized to improve CAR-T-cell therapies, offering promising avenues for the advancement of this field in the treatment of various malignancies.