Human Chimeric Antigen Receptor Macrophages for Cancer Immunotherapy

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Summary

Though chimeric antigen receptor-modified T cell therapy has shown exciting outcomes in hematologic malignancies treatment, its response to solid tumors is limited and needs more exploration. Macrophages, with the advantage of phagocytosis and migrating to tumor inches, are engineered to express car to kill tumor cells and refine inhibitory tumor microenvironments. Adenoviral vectors are functional to deliver CARs to native human macrophages and maintain a pro-inflammatory characteristic. The generated CAR-MA showed significant target-specific cytotoxicity and improved survival in preclinical in vitro assay and in vivo mouse models.

CAR-macrophages Development and Evaluation

Though chimeric antigen receptor (CAR) modified T cells have shown exciting outcomes in hematologic malignancies treatment, their response to solid tumors is limited and needs more exploration. Macrophages are differentiated from bone myeloid-derived monocyte cells and are recruited to tumor tissues. Macrophages have the capability of phagocytosis and present antigens to T cells to induce adaptive immune responses. Consequently, macrophages are promising adaptive immune cells and are modified to express CARs to kill tumor cells and refine inhibitory tumor microenvironments.

Fig.1 The first-generation CAR-modified macrophages performed antigen-specific phagocytosis and cytotoxicity.¹

Adenoviral vector is verified to be a suitable choice to deliver CAR molecular, consisting of antigen-specific scFv and CD3ζ intracellular domain, to freshly isolated human macrophages and showed high transduction efficiency. The generated anti-HER2 CAR-MA displayed significant phagocytosis and killing toward HER2+ tumor cells in vitro. After in vivo injection of CAR-MA into tumor-loaded mouse models, the macrophages could migrate to tumor tissue and eradicate tumor cells, and prolonged mice survival time.

Fig.2 Anti-HER2 CAR-MA reduced tumor burden in mice and prolonged survival time.¹

Pro-inflammatory (M1) macrophage could invert to M2 phenotype in an inhibitory tumor microenvironment. In this article, scientists have validated that adenovirus transduction led to M1 phenotype activation in CAR-MA cells and helped maintain an M1-related IFN-expressing phenotype for several months. Furthermore, the M1 CAR-MA induces the M2 macrophage transfer to the M1 phenotype, promising to discharge the inhibitory tumor microenvironment. The established CAR-MA also presents intracellular antigen processing and cross-presentation function and induces non-specific T cell response to enhance anti-tumor activity.

Fig.3 Adenoviral vector endowed CAR-MA cell M1 phenotype and remodeled TME to improve therapeutic results.¹

CAR-MA Therapy Development Service at Creative Biolabs

As lead biotech in offering advanced cell and gene therapies for global clients, Creative Biolabs has developed cutting-edge technologies and validated platforms for tumor biology study and immunotherapy development, including CAR-T, CAR-NK, and CAR-MA.

One-Stop CAR-MA Development Service

Our one-stop CAR-MA development service contains the whole process from antigen identification to clinical tests. The workflow includes target identification and selection, high-affinity antibody generation, CAR design and construction, CAR-MA cell preparation, macrophage activation and expansion, and CAR-MA assessment.

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CAR Design & Construction

Creative Biolabs offers custom car design services to find the most suitable car structure for phagocytosis and killing function. We provide first-, second-, and third-generation CARs containing mono- or dual-specific antigen receptor as well as different intracellular signal domains.

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Macrophages Activation and Expansion Service

The phenotype of macrophage is invertible according to extracellular signals. Creative Biolabs provides many methods to produce proinflammatory macrophage cells using various stimuli. The unique biomarkers are used to test cell phenotype and subsets.

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CAR-MA Preparation Service

CAR-MA can be established using various strategies. Creative Biolabs provides customized preparation pathways, including iPSC-derived, monocyte-derived, and primary macrophage-derived CAR-MA. We also provide alternative viral vectors, such as lentiviral and adenovirus.

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CAR-MA Functional Assays

The generated CAR-MA cells are completely analyzed using multiple assays to characterize features and functions using various in vitro and in vivo assays. Our capabilities include CAR expression tests, CAR-MA specificity tests, phagocytosis tests, phenotyping, and antigen-presentation tests.

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Related Products at Creative Biolabs

Creative Biolabs provides immunotherapy-related products and kits covering T, NK cells, and macrophages (MA). Our products contain the reagents necessary for the whole process of cell therapy development for various targets of cancers, such as primary human & mouse immune cells, CAR vectors, CAR viral particles, mAb for flow cytometry analysis, and so on. Please refer to our website of products to get more information.

HER2-Targeted Product Category

Reference

Klichinsky, M.; et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nature biotechnology. 2020, 38(8): 947–953.