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Release date:2023/9/27 15:55:59

CAR-T (Chimeric Antigen Receptor T-Cell) Immunotherapy is an innovative treatment that utilizes the body's immune system to combat cancer. The current CAR T-cell therapies are individually tailored for each patient. This process involves collecting T cells from the patient and then reengineering them in the laboratory to create surface proteins called CARs. These CARs recognize and bind to specific proteins, or antigens, on the surface of cancer cells.

Since 2017, the Food and Drug Administration (FDA) has granted approval to six CAR T-cell therapies. All are approved for the treatment of blood cancers, including lymphomas, some forms of leukemia, and, most recently, multiple myeloma.

FDA Approved CAR-T Cell Therapies
Trade Name Drug Name Target Company Approval Date Indications
Kymriah Tisagenlecleucel CD19 Novartis Aug 2017 Acute Lymphoblastic Leukemia, B-Cell Lymphoma, Follicular Lymphoma
Yescarte Axicabtagene ciloleucel CD19 Kite Oct 2017 Large B-Cell Lymphoma; Follicular Lymphoma
Tecartus Brexucabtagene autoleucel CD19 Kite Jul 2020 Mantle Cell Lymphoma, Acute Lymphoblastic Leukemia
Breyanzi Lisocabtagene maraleucel CD19 BMS Feb 2021 Diffuse Large B-Cell Lymphoma
Abecma Idecabtagene vicleucel BCMA BMS Mar 2021 Relapsed or Refractory Multiple Myeloma
Carvykti Ciltacabtagene autoleucel BCMA Janssen Feb 2022 Relapsed or Refractory Multiple Myeloma

Table. FDA Approved CAR-T therapies

However, CAR-T cell therapy also sometimes causes severe or even life-threatening side effects, such as Cytokine Release Syndrome (CRS) and neurotoxicity.

Recently, the University of Pennsylvania published a study in which they successfully developed an in-situ PEGylated CAR-T cell, providing a safer alternative for CAR-T cell therapy[1]. This research has found a solution that could help CAR-T therapies reach their full potential while minimizing CRS and neurotoxicity.

Macrophages/monocytes might be the major source of the core cytokine in CRS

Severe CRS typically occurs within one day after CAR-T cell infusion, with symptoms including high fever, vomiting, cardiovascular and respiratory dysfunction. Without treatment, this can lead to multi-organ failure or patient death. CRS is also accompanied by neurotoxicity. However, neurotoxicity typically occurs several weeks after the resolution of CRS-related symptoms and may result in patient mortality.

Previous studies have shown that monocytes/macrophages play an important role in the adverse effects of CAR-T cell therapy. In humanized mouse experiments, increased monocyte counts were associated with severe CRS. At the same time, the overactivation of monocytes/macrophages is a source of toxic cytokines that trigger CRS and neurotoxicity. Thus, macrophages play a crucial role in CAR-T cell therapy.

Therefore, reducing monocyte overactivation by controlling CAR T cell-monocyte interactions could provide a potential solution for CRS and neurotoxicity.

PEGylated CAR-T cells

The research team engineered CAR-T cells with azido groups, which can recognize and target tumors just like regular CAR-T cells. Once the CAR-T cells triggered mild macrophage activation and led to the initial symptoms of a cytokine storm, the research team accomplished in-situ PEGylated CAR-T cells by intravenously injecting long-chain polyethylene glycol modified with DBCO (DBCO-PEG) and covalently linking it to the azide-modified CAR-T cell surface. This polymer serves as a physical spacer that blocks the interaction between CAR-T cells, macrophages and tumor cells, thereby reducing the over-activation of macrophages and extensive secretion of toxic cytokines.

PEGylated-car-t-cell

Figure 1. PEGylated CAR-T cells [1]

The research team also observed that the expansion of CAR-T cells led to a reduction in the surface density of PEG over time. Since tumor cells and CAR-T cells are smaller in size compared to macrophages, CAR-T cells will interact with tumor cells first rather than macrophages as the PEG density gradually decreases. This ensures that CAR-T cells kill tumor cells without causing over-activation of macrophages, thus expanding the safe therapeutic window of CAR-T therapy.

Figure 2. CAR-T cells and PEG [1]

In addition, in situ PEGylated CAR-T cells are less neurotoxic compared to the therapeutic antibody tocilizumab (IL-6 receptor antibody). This is because the strategy of in situ PEGylated CAR-T cells inhibits macrophage activation and reduces the production of neurotoxicity-triggering cytokines (e.g., IL-1). Thus, in situ PEGylated CAR-T cells provide a new strategy for safer material-based cellular immunotherapy.

While the use of PEG may potentially trigger the production of anti-PEG antibodies, the research team has indicated that future work will assess different polymers or nanoparticles as alternatives to manage CRS and neurotoxicity in CAR-T cell therapy. Furthermore, as cell interactions are involved in many crucial physiological and pathological processes, future research will also explore the use of in-situ biomaterial conjugation strategies for treating other diseases.

Conclusion

In recent years, the regulation of gene, protein, metabolism, and epigenetic levels has become the primary focus in the field of drug development. However, the results of this latest research indicate that the independent use of materials to modulate cell interactions is also an effective approach to disease treatment. In-situ PEGylation of CAR-T cells offers a novel solution to the safety concerns in CAR-T cell therapy, presenting significant promise for the future of cell-based immunotherapy.

Biopharma PEG, as a leading PEG derivatives supplier, can provide high-purity DBCO-PEG and other PEG for your in-situ PEGylation request. 

References:
[1] Gong, N., Han, X., Xue, L. et al. In situ PEGylation of CAR T cells alleviates cytokine release syndrome and neurotoxicity. Nat. Mater. (2023). https://doi.org/10.1038/s41563-023-01646-6

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