Targeting macrophage-mediated tumor cell phagocytosis: An overview of phagocytosis checkpoints blockade, nanomedicine intervention, and engineered CAR-macrophage therapy
Authors: Davood Bashash
Susan Moradinasab
Atieh Pourbagheri-Sigaroodi
Seyed H Ghaffari
Journal: International Immunopharmacology (2022)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: CAR-macrophage; Immunotherapy; Nanomedicine; Phagocytosis Checkpoints Blockade; Tumor-associated Macrophage.
Affiliations: Iranian Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran., Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran., Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: .

Abstract:  Immunotherapy has been developing at an unprecedented speed with promising therapeutic outcomes in the wide spectrum of cancers. Up until now, most immunotherapies have focused on adaptive immunity; however, investigating the potential of macrophage phagocytosis and consequent adaptive immune cross-priming has led to a growing interest in exploiting macrophages in cancer therapy. In light of the positive evidence from preclinical studies and early clinical data, targeting macrophage phagocytosis has become a promising therapeutic strategy. Here, we review therapies based on harnessing and amplifying macrophage phagocytosis, such as blocking phagocytosis checkpoints and exploiting nanoparticles as efficient approaches in elevating macrophages-mediated phagocytosis. The present study introduces CAR-macrophage as the state-of-the-art modality serving as the bridge between the innate and adaptive immune system to mount a superior anti-tumor response in the treatment of cancer. We also take a look at the recent reports of therapies based on CAR-engineered macrophages with the hope of providing a future research direction for expanding the application of CAR-macrophage therapy. 

Retracted: No

PubPeer comments:
 This paper is very similar to a slightly older paper on the same topic by Siqi Chen et al.,  Harnessing and Enhancing Macrophage Phagocytosis for Cancer Therapy , published in Front. Immunol. (2021) 12:635173. doi: 10.3389 fimmu.2021.635173. Although the text is not a verbatim copy of the Chen 2021 paper, there are striking similarities throughout the paper, suggesting that part of the Chen text might have been used and rephrased. The Chen paper is cited as reference 109, but similarities start already at the beginning. Here are both abstracts compared: Abstract: * Chen 2021: Promising evidence from preclinical and clinical studies have established targeting macrophage phagocytosis as an effective therapeutic strategy, either alone or in combination with other therapeutic moieties. Here, we review the recent translational advances in harnessing macrophage phagocytosis as a pivotal therapeutic effort in cancer treatment. In addition, this review emphasizes phagocytosis checkpoint blockade and the use of nanoparticles as effective strategies to potentiate macrophages for phagocytosis. * Moradinasab 2022: In light of the positive evidence from pre-clinical studies and early clinical data, targeting macrophage phagocytosis has become a promising therapeutic strategy. Here, we review therapies based on harnessing and amplifying macrophage phagocytosis, such as blocking phagocytosis checkpoints and exploiting nanoparticles as efficient approaches in elevating macrophages-mediated phagocytosis. ![file] Introduction: * Chen 2021: Immunotherapy has had a long-standing history in the fight against cancer, with its early beginnings in the 19th century with Coleyu2019s toxin (1). Up until now, about 40 biologics have been approved by the U.S. Food and Drug Administration (FDA) for patient use, with approximately 4,000 being actively investigated in clinical trials globally (2, 3). * Moradinasab 2022: Cancer immunotherapy with a long-standing background began in 1893 with Coleyu2019s toxin [1]. And so far, immunotherapy with almost 40 FDA-approved biologics and several thousand agents being under investigation for clinical application has held promise in treating various types of cancers [2]. ![file] Introduction: * Chen 2021: Thus, understanding the mechanism behind phagocytosis regulation could provide a new avenue for the development of next- generation therapeutic modalities * Moradinasab 2022: Therefore, a deep understanding of the mechanism behind phagocytosis regulation opens a new door for developing next- generation anticancer approaches. * Chen 2021: In this review, we highlight recent advances made in enhancing macrophage by phagocytosis by targeting different stages of this process based on distinct principles. * Moradinasab 2022: In this review, we highlight the preset-day advancement in targeted therapies enhancing phagocytosis activity of macrophages for cancer treatment Main text: * Chen 2021: Despite the increasing interest in CAR-T cell therapies, there has been a struggle in reproducing its therapeutic efficacy observed in hematological malignancies in solid tumors (135u2013137) * Moradinasab 2022: Despite the successful exploit of CAR T cells in the hematological malignancies, reproducing their therapeutic efficacy in solid tumors has been less encouraging [150] * Chen 2021: Not only this, but macrophages have a unique quality in that they have a high degree of versatility and plasticity (147), and are thus able to adapt and change in response to external stimuli or the environment (148). * Moradinasab 2022: Beyond this, macrophagesu2019 plasticity makes them easily change in response to their environment [153]. * Chen 2021: The construction of CARs for macrophages requires similar components to that of T cells: a target binding extracellular domain adapted from an antibody, followed by a hinge sequence, a transmembrane domain connecting the extracellular domain and intracellular signaling domain (136). * Moradinasab 2022: Designing CAR constructs for macrophages is similar to those for T cells: an extracellular domain directing CAR specificity, a hinge sequence, and a transmembrane domain which is the connector of intracellular and extracellular domains [154]. ![file] * Chen 2021: CURRENT STUDIES OF CAR-MACROPHAGES. Up until now, the study of utilizing CAR-Ms, has been relatively limited. A recent study by Morrissey and colleagues was among the first to provide initial evidence that CAR-engineered macrophages can promote phagocytosis. * Moradinasab 2022: 4.1. Current studies. As of this writing, using CAR for macrophages is still in its infancy and limited studies are developing CAR-Ms. A recent study has shown that CAR-engineered macrophages can induce phagocytosis of targeted tumor cells ![file] Conclusion: * Chen 2021: Antibody-dependent cellular phagocytosis has long been extensively studied and applied in clinical settings for at least 20 years. For example, ritxuimab was the first-in class monoclonal antibody approved by the FDA in 1997. Since then, this list has expanded to include a plethora of novel antibodies of varying designs that are now approved or undergoing clinical trial evaluation. * Moradinasab 2022: The past several decades have witnessed that targeting macrophage phagocytosis has entered into the spotlight as the novel oncotherapy. It first began in 1997 with the initiation of ADCP via rituximab, an FDA- approved therapeutic monoclonal antibody. Since then, a wide spectrum of novel antibodies of various designs targeting ADPC was studied and underwent clinical trial evaluation. ![file] A SimTexter comparison show lots of short matches, with lots of words in common, but no verbatim copies. ![file] ,