J Immunother Cancer
Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
Published: December 2023
Background: Macrophages have recently become attractive therapeutics in cancer immunotherapy. The potential of macrophages to infiltrate and influence solid malignancies makes them promising targets for the chimeric antigen receptor (CAR) technology to redirect their stage of polarization, thus enhancing their anticancer capacities. Given the emerging interest for CAR-macrophages, generation of such cells so far mainly depends on peripheral blood monocytes, which are isolated from the respective donor prior to genetic manipulation. This procedure is time-intensive and cost-intensive, while, in some cases, insufficient monocyte amounts can be recovered from the donor, thus hampering the broad applicability of this technology. Hence, we demonstrate the generation and effectiveness of CAR-macrophages from various stem cell sources using also modern upscaling technologies for next generation immune cell farming.
Methods: Primary human hematopoietic stem and progenitor cells and induced pluripotent stem cells were used to derive anti-CD19 CAR-macrophages. Anticancer activity of the cells was demonstrated in co-culture systems, including primary material from patients with leukemia. Generation of CAR-macrophages was facilitated by bioreactor technologies and single-cell RNA (scRNA) sequencing was used to characterize in-depth response and behavior of CAR-macrophages.
Results: Irrespective of the stem-cell source, CAR-macrophages exhibited enhanced and antigen-dependent phagocytosis of CD19 target cancer cells with increased pro-inflammatory responses. Phagocytic capacity of CAR-macrophages was dependent on target cell CD19 expression levels with superior function of CAR-macrophages against CD19 cancer cell lines and patient-derived acute lymphocytic leukemia cancer cells. scRNA sequencing revealed CAR-macrophages to be distinct from eGFP control cells after co-culture with target cells, which includes the activation of pro-inflammatory pathways and upregulation of chemokines and cytokines associated with adaptive immune cell recruitment, favoring the repolarization of CAR-macrophages to a pro-inflammatory state. Taken together, the data highlight the unique features of CAR-macrophages in combination with the successful upscaling of the production pipeline using a three-dimensional differentiation protocol and intermediate scale bioreactors.
Conclusion: In summary, our work provides insights into the seminal use and behavior of CAR-macrophages which are derived from various sources of stem cells, while introducing a unique technology for CAR-macrophage manufacturing, all dedicated to the clinical translation of CAR-macrophages within the field of anticancer immunotherapies.
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http://dx.doi.org/10.1136/jitc-2023-007705 | DOI Listing |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10749073 | PMC |
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Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China. Electronic address:
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Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China. Electronic address:
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Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
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Cancer therapy has been revolutionized by immunotherapeutic agents exploiting adaptive antitumor immunity in the past two decades. However, the overall response rate of these immunotherapies is limited, and patients also develop resistance upon treatment, promoting a rapidly growing exploration of anti-tumor innate immunity for effective cancer therapy. Among these, macrophage immunotherapy through harnessing macrophage phagocytosis has been thrust into the spotlight due to its potential for simultaneously inducing cancer cell killing effect and mobilizing adaptive antitumor responses.
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Department of Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital; Jinan 250014, China; School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
Chimeric antigen receptor (CAR) cell immunotherapies, including CAR-T, CAR-Macrophages, CAR-Natural Killer, CAR-γδ T, etc., have demonstrated significant advancements in the treatment of both hematologic malignancies and solid tumors. Despite the notable successes of traditional CAR cell manufacturing, its application remains constrained by the complicated production process and expensive costs.
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