With hundreds of on-going clinical trials and 5 FDA-approved drugs to date, CAR-T cell therapy is one of the most attractive immunotherapies that have got the most attention and advanced the furthest in clinical development.
Nevertheless, despite remarkable success in the treatment of hematological malignancies, many obstacles remain to be surmounted by researchers to improve efficacy of CAR-T cells and further broaden the scope of its application in the field of cancer therapeutics.
Explore Resistance Mechanism to CAR-T Cell Therapy in Blood Cancer
Disease recurrences following CAR-T cell therapy are frequently observed in clinical trails of blood cancers such as acute lymphoblastic leukemia and multiple myeloma. However, the mechanisms of resistance is still unclear.
In a recent issue of Nature Communications, Mehmet et al demonstrate that biallelic loss of B-cell maturation antigen (BCMA) following initial CAR-T cell infusion leads to acquired resistance to retreatment in a patient with multiple myeloma (Mehmet et al. 2021).
As wrote by the authors, this finding means that myeloma cells may be able to acquire alternative growth mechanisms to survive without BCMA expression and related signaling intermediates.
Another study shows that CAR-T treatment failure is also associated with immune dysregulation (Michael et al. 2021). In this study, immune dysregulation is observed higher in patients with high tumor burden as those patients have increased serum inflammatory markers and tumor expression of interferon signaling.
Overcome Challenges of CAR-T Therapy for Solid Tumor
In solid tumor therapeutics, traditional CAR-T cells are often exhausted and inactive due to highly immunosuppressive tumor microenvironments, components of which conspire to blunt the immune response (Andrew et al. 2021). Besides, high antigen heterogeneity in solid tumors provides them with an effective mechanism of escape from CAR-T cells.
To overcome those obstacles posed by solid tumors, a new type of immune cells called synthetic notch (synNotch)-CAR T cells is recently designed and used to treat mesothelioma, ovarian cancer, and glioblastoma (Joseph et al and Axel et al. 2021). The researchers report that synNotch-CAR T cells have better performance in treating solid tumors than traditional CAR-T cells in mouse models, with long-lived memory of T cells and little toxicity or damage to healthy tissue.
Other novel treatment strategies for solid tumors include inducing metabolic intervention to CAR-T cell therapy (Anthos et al. 2021), using drugs to temporarily suppress T cell activity (Evan et al. 2021) and discovering new potential targets for systemic agents in tumor tissues (Adam. 2021).
Most tumor antigens reside inside tumor cells, out of the reach of CARs, making most efforts unsuccessful to identify unique antigens on the surface of solid tumors. However, a research team from Thomas Jefferson University has now reported that an intestinal epithelial protein, named guanylyl cyclase C (GUVY2C), can be a desired target for treating upper-gastrointestinal (GI) cancers. The investigators established patient-derived xenograft (PDX) models in mice and found GUCY2C-directed CAR-T cells restricted GI cancer PDX growth and even led to complete tumor elimination.
Choe, Joseph H., et al. "SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma." Science Translational Medicine 13.591 (2021).
Christofides, Anthos, Natalia M. Tijaro-Ovalle, and Vassiliki A. Boussiotis. "Commentary on: Combination of Metabolic Intervention and T Cell Therapy Enhances Solid Tumor Immunotherapy." Immunometabolism 3.2 (2021).
Hou, Andrew J., Laurence C. Chen, and Yvonne Y. Chen. "Navigating CAR-T cells through the solid-tumour microenvironment." Nature Reviews Drug Discovery (2021): 1-20.
Hyrenius-Wittsten, Axel, et al. "SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models." Science Translational Medicine 13.591 (2021).
Jain, Michael D., et al. "Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma." Blood, The Journal of the American Society of Hematology 137.19 (2021): 2621-2633.
Samur, Mehmet Kemal, et al. "Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma." Nature communications 12.1 (2021): 1-7.
Snook, Adam. "GUCY2C‐Directed CAR‐T Cell Therapy for Upper‐GI Cancers." The FASEB Journal 35 (2021).
Weber, Evan W., et al. "Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling." Science 372.6537 (2021).
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Q1: Who is the first patient cured by CAR-T cell therapy?
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Q2: CAR-T cell therapies against multiple myeloma include which of the following targets?
Q3: Which of the following is the first FDA-approved CAR-T cell therapy?
Q4: Which of the following challenges is posed by solid tumor?
Q5: Which of the following is a side effect of CAR-T cell therapy?
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