Human chimeric antigen receptor macrophages for cancer immunotherapy

Klichinsky, Michael; Ruella, Marco; Shestova, Olga; Lu, Xueqing Maggie; Best, Andrew; Zeeman, Martha E.; Schmierer, Maggie; Gabrusiewicz, Konrad; Anderson, Nicholas; Petty, Nicholas E.; Cummins, Katherine D.; Shen, Feng; Shan, Xinhe; Veliz, Kimberly; Blouch, Kristin; Yashiro–Ohtani, Yumi; Kenderian, Saad S.; Kim, Miriam; O’Connor, Roddy S.; Wallace, Stephen R.; Kozlowski, Miroslaw; Marchione, Dylan M.; Shestov, Maksim; García, Benjamin A.; June, Carl H.; Gill, Saar

doi:10.1038/s41587-020-0462-y

Cited by 785 publications

(726 citation statements)

References 37 publications

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“…To program engulfment based on recognition of the SARS-CoV-2 spike protein, we used a CAR design for the synthetic receptor strategy in our study. The synthetic receptors were constructed to contain an scFv derived from an antibody recognizing the virus spike protein, CR3022, which has been reported to bind with the receptor-binding domain of the SARS-CoV-2 S glycoprotein with high affinity, and the CD8 transmembrane domain present in the αCD19 CAR for T cells 9 . For the cytoplasmic domains, we used the and CD3ζ (CARζ) in our study (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A CAR construct includes antigen-recognition domains in the form of a single-chain variable fragment (scFv) or a binding receptor/ligand in the extracellular domains, a transmembrane domain providing the scaffold and signaling transduction, and intracellular domains from the T cell receptor (TCR) and costimulatory molecules that trigger T cell activation 7 . Based on the longstanding interest in harnessing macrophages to combat tumor growth 8,9 , human macrophages engineered with CARs have been developed and characterized for their antitumor potential. Macrophages, critical effectors of the innate immune system, are responsible for sensing and responding to microbial threats and promoting tissue repair.…”

Section: ~ 3 ~mentioning

confidence: 99%

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CAR Macrophages for SARS-CoV-2 Immunotherapy

Lei

Qian

et al. 2020

Preprint

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Targeted therapeutics for the treatment of coronavirus disease 2019 (COVID-19), especially severe cases, are currently lacking. As macrophages have unique effector functions as a first-line defense against invading pathogens, we genetically armed human macrophages with chimeric antigen receptors (CARs) to reprogram their phagocytic activity against SARS-CoV-2. After investigation of CAR constructs with different intracellular receptor domains, we found that although cytosolic domains from MERTK (CARMERTK) did not trigger antigen-specific cellular phagocytosis or killing effects, unlike those from MEGF10, FcRγ and CD3ζ did, these CARs all mediated similar SARS-CoV-2 clearance in vitro. Notably, we showed that CARMERTK macrophages notably reduced the virion load without upregulation of proinflammatory cytokine expression. These results suggest that CARMERTK drives an ‘immunologically silent’ scavenger effect in macrophages and pave the way for further investigation of CARs for the treatment of individuals with COVID-19, particularly those with severe cases at a high risk of hyperinflammation.

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Section: Resultsmentioning

confidence: 99%

Section: ~ 3 ~mentioning

confidence: 99%

CAR Macrophages for SARS-CoV-2 Immunotherapy

Lei

Qian

et al. 2020

Preprint

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“…While our paper is being reviewed, Klichinsky et. al reported PBMC-derived macrophage transduced with a CAR through adenovirus showed strong in vivo anti-tumor effect, and one key reason is the adenoviral vector Ad5f35 used imparted a sustained pro-inflammatory M1 phenotype 37 .…”

Section: Discussionmentioning

confidence: 99%

Induced Pluripotent Stem Cell-derived CAR-Macrophage Cells with Antigen-dependent Anti-Cancer Cell Functions for Liquid and Solid Tumors

Zhang

Tian

Dai

et al. 2020

Preprint

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One sentence summary:We developed CAR-expressing iPSC-induced macrophage cells that have antigen-dependent phagocytosis and pro-inflammatory functions and anti-cancer cell activity for both liquid and solid tumor cells. Abstract:The Chimera antigen receptor (CAR)-T cell therapy has gained great success in the clinic. However, there are still major challenges for its wider applications in a variety of cancer 2 types including lack of effectiveness due to the highly complex tumor microenvironment, and the forbiddingly high cost due to personalized manufacturing procedures. In order to overcome these hurdles, numerous efforts have been spent focusing on optimizing Chimera Antigen Receptors, engineering and improving T cell capacity, exploiting features of subsets of T cell or NK cells, or making off-the-shelf universal T cells. Here, we developed induced pluripotent stem cells (iPSCs)-derived, CAR-expressing macrophage cells (CAR-iMac). These cells showed antigen-dependent macrophage functions such as expression and secretion of cytokines, polarization toward the pro-inflammatory/anti-tumor state, and phagocytosis of tumor cells, as well as some in vivo anti-cancer cell activity for both liquid and solid tumors. This technology platform for the first time provides an unlimited source of iPSC-derived engineered CARmacrophage cells which could be utilized to eliminate cancer cells or modulate the tumor microenvironment in liquid and solid tumor immunotherapy.

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“…Currently, ACT can be classified according to its mechanism of action: namely ACT with tumour-infiltrating lymphocytes (TILs); ACT using T-cell receptor (TCR) gene therapy; and ACT with chimeric antigen receptor (CAR) modified T-cells [ 319 ]. Most cancer cell therapies have employed transfusion of autologous T-cells into patients, including CD8+ CTLs alone or combined with CD4+ helper (Th) cells, although NK or cytokine-induced killer cells and macrophages have also been used [ 320 , 321 ].…”

Section: Agents and Strategies For Cancer Immunotherapymentioning

confidence: 99%

“…injected human ovarian cancer cells have shown that polymeric nanoparticles incorporating platinum accumulate in TAMs, then deliver their payload to neighbouring tumour cells and inflict DNA damage [ 361 ]. In addition, human macrophages have been genetically engineered with CARs to boost antigen-specific phagocytosis and tumour reduction in pre-clinical models [ 321 ].…”

Section: Agents and Strategies For Cancer Immunotherapymentioning

confidence: 99%

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

Macpherson

Barry

Ricciardelli

et al. 2020

JCM

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Recent advances in the understanding of immune function and the interactions with tumour cells have led to the development of various cancer immunotherapies and strategies for specific cancer types. However, despite some stunning successes with some malignancies such as melanomas and lung cancer, most patients receive little or no benefit from immunotherapy, which has been attributed to the tumour microenvironment and immune evasion. Although the US Food and Drug Administration have approved immunotherapies for some cancers, to date, only the anti-angiogenic antibody bevacizumab is approved for the treatment of epithelial ovarian cancer. Immunotherapeutic strategies for ovarian cancer are still under development and being tested in numerous clinical trials. A detailed understanding of the interactions between cancer and the immune system is vital for optimisation of immunotherapies either alone or when combined with chemotherapy and other therapies. This article, in two main parts, provides an overview of: (1) components of the normal immune system and current knowledge regarding tumour immunology, biology and their interactions; (2) strategies, and targets, together with challenges and potential innovative approaches for cancer immunotherapy, with attention given to epithelial ovarian cancer.

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Human chimeric antigen receptor macrophages for cancer immunotherapy

Cited by 785 publications

References 37 publications

CAR Macrophages for SARS-CoV-2 Immunotherapy

CAR Macrophages for SARS-CoV-2 Immunotherapy

Induced Pluripotent Stem Cell-derived CAR-Macrophage Cells with Antigen-dependent Anti-Cancer Cell Functions for Liquid and Solid Tumors

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

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