As of this writing, there are fewer than 10 clinical trials using CAR-NK cells in the treatment of liquid tumors Table 1. CR: Complete Response. PR: Partial Response. OS: Overall Survival. QoL: Quality of Life. Liu et al. Although initial concerns were raised about the longevity of irradiated CDCAR-NK cells in vivo, the cells were detected one-week post-infusion, and there was a modest, although insignificant, treatment effect.
A major obstacle presented to CAR therapy is the lack of efficacy in solid tumors. This is due to poor perfusion to the tumor, TAA heterogeneity and the immunosuppressive tumor microenvironment TME that accompanies a solid tumor Figure 2. CAR-NK therapy attempts to remedy these issues with a limited number of clinical trials employing this technology in the treatment of solid malignancies, several of which will be reviewed here Table 2.
A Poor survival of adoptively transferred cells can be overcome in a variety of ways such as ER-retained cytokines, multiple infusions of CAR NKs, direct site injection and subcutaneous delivery of IL-2 to promote in vivo survival. Infiltrating T lymphocytes often express PD-1, and upon engagement with PD-L1 experience a significant decrease in effector function. Exciting preclinical data demonstrated PD-L1 specific efficacy of these cells against 15 tumor cell lines in vitro, and strong anti-tumor efficacy in vivo of triple negative breast cancer, bladder and lung tumors [ 88 ].
This trial is currently recruiting with no results posted. HER2 is overexpressed in several cancer types, such as breast cancer [ 89 ], gastric cancer [ 90 ], esophageal cancer [ 91 , 92 ], ovarian cancer [ 93 ] and endometrial cancer [ 94 ]. HER2-CAR-T therapy in glioblastoma has shown trafficking of these cells to the tumor, but the generation of high effector function T cells within the TME results in rapid selection of antigen-loss variants [ 97 , 98 ]. Due to the blood-brain barrier, CAR-NK cells were delivered through intracranial injection into the resection cavity wall to allow for a high density of effector cells that would otherwise be excluded from the tumor site Figure 2 , left panel.
In the subsequent expansion cohort, patients will be eligible to receive up to 12 weekly CAR-NK infusions administered into the resection cavity through a catheter and reservoir implanted during the initial relapse resection surgery.
Preclinical studies using NK cells transduced to express a CAR specific for EGFR have shown efficacy in tumor models of breast cancer brain metastasis [ ], glioblastoma models and patient derived glioblastoma stem cells [ , ].
MUC1 is a heavily glycosylated transmembrane glycoprotein expressed on ductal epithelial cells, with controversial evidence of its expression on human B and T cells [ , ] reviewed here: [ ]. MUC1 is overexpressed in several cancer types, including adenocarcinoma [ ], making it a suitable target for CAR-T therapy. To circumvent the immune suppression mediated by the TME, Li et al. These cells were shown to lyse MUC1 target cells in vitro and in vivo.
Of the initial 13 patients, three were withdrawn, nine had stable disease and one patient had progressive disease [ ]. A primary outcome measure was to determine the toxicity profile of Muc1-CAR-NK cells, and notably, there was no evidence of cytokine storm or bone marrow suppression in any patients on trial.
These results support the conclusion that the therapy is safe and mildly effective. In both hematologic malignancies and solid tumors there are several clinical trials that are recruiting, or active but not yet recruiting, that have not yet posted results. Although the trials are immature, they are noteworthy, and it is important to consider the diverse CAR-NK targets and treatment strategies under investigation when discussing the future of CAR-NK therapy in the clinic.
NKG2D ligands NKG2DL are expressed on most human tumor cells, such as ovarian, breast, prostate, colon and bladder cancer as well as leukemias and lymphomas [ ]. NKG2DL is also expressed on Tregs, myeloid derived suppressor cells MDSCs and epithelium promoting tumor survival and suppression of a robust anti-tumor immune response reviewed here: [ ].
The primary outcome is number of adverse events with secondary outcome evaluating anti-tumor response to CAR-NK infusions. Some patients enrolled will receive IL-2, delivered subcutaneously, to support in vivo growth of adoptively transferred NK cells. Additional studies are investigating PSMA, a protein that is highly expressed on epithelial cells of the prostate with very low or undetectable levels in epithelium of other tissues and organs.
The occurrence of treatment-related adverse events, defined as Grade 3 or greater, will be the primary endpoint. This trial is not yet recruiting and as such no results have been posted as of this writing.
Mesothelin is expressed in low levels in mesothelial cells of pericardium, pleura and peritoneum of healthy individuals, but is overexpressed in a variety of cancers, including but not limited to stomach, pancreatic, lung, breast and ovarian cancer [ ]. Primary outcomes will be occurrence of treatment-related adverse events. Several research groups are exploring different mechanisms of combating these concerns. Because this protein is not found on the cell surface, the CAR-T must be directed to the tumor through the use of a bispecific component, called a target module TM.
TMs that exist on this platform may be combined with additional TMs to target multiple TAAs simultaneously, inducing heterogeneity in the peptides the CARs are responding to without the risk of off-target effects Figure 2 , middle panel.
Mitwasi et al. GD2 is highly overexpressed in a variety of human tumors, and one of the only immunotherapy targets in neuroblastoma [ , ]. In fact, a mAb against GD2, dinutuximab, was approved for patients with high risk neuroblastoma [ ]. These data demonstrate proof of concept for further preclinical and clinical experimentation.
To avoid the immunosuppressive TME, Wang et al. Although the in vitro data look promising, in vivo, NKTN anti-tumor activity was moderate at best, with a minimal reduction of tumor weight at endpoint, and a slight, albeit significant increase in tumor infiltrating lymphocytes in animals treated with NKTN. Use of humanized mouse models and repeated injections may more closely mirror what is hoped to be observed in the clinic and include the effects these cells could have on the immune populations surrounding them.
Harnessing cells of the immune system to fight various malignancies has been widely explored, with the employment of immunotherapy revolutionizing cancer treatment. However, only a fraction of patients achieve durable clinical responses. Adoptive cell therapy with T cells has undergone extensive research and demonstrated clinical efficacy, and a growing body of evidence suggests that NK cells are also safe and efficacious.
While decades of research have demonstrated the difficulties surrounding adoptive cell transfer of allogeneic and autologous NK cells, the data have also found that NK cells represent a pool of innate immune cells poised for rapid tumor clearance.
The development of novel, immortalized NK cell lines for off-the-shelf therapy, as well as new gene-editing techniques to arm NK cells with additional mechanisms for targeting tumor cells CAR and increasing their cytotoxic potential endogenous cytokine production are pushing the field forward in exciting and important ways.
It is clear that NK cell transfer is a powerful weapon in the fight against cancer, and that NK cells will play a significant role in the future of immuno-oncology clinical strategies. The authors thank Debra Weingarten for her editorial assistance in the preparation of this manuscript.
All authors have read and agreed to the published version of the manuscript. National Center for Biotechnology Information , U. Journal List Cancers Basel v. Cancers Basel. Published online Jul Author information Article notes Copyright and License information Disclaimer. Received Jul 6; Accepted Jul This article has been cited by other articles in PMC. Abstract Cellular therapy has emerged as an attractive option for the treatment of cancer, and adoptive transfer of chimeric antigen receptor CAR expressing T cells has gained FDA approval in hematologic malignancy.
Introduction Harnessing the immune system for cancer treatment is one of the most exciting therapeutic possibilities in the history of cancer treatment, and one of the oldest.
NK Cell Cytotoxicity NK cells have two major cytotoxic mechanisms, granulocyte apoptosis mediated by perforin and granzyme and antibody-dependent cell-mediated cytotoxicity ADCC.
Inhibitory Receptor Blocking Similar to checkpoint blockade antibodies, therapeutic mAbs have been designed to block inhibitory receptors on NK cells. Cytokines to Activate Endogenous NK cells Treatment with exogenous cytokines is one of the most frequent immunotherapeutic strategies, with numerous agents being investigated for clinical use in multiple indications and combinations. Immunogenic Modulation It has been previously reported that certain standard-of-care therapies are capable of changing tumor cell phenotype to sensitize them to killing by cytotoxic immune cells including T cells and NK cells [ 22 , 23 ].
Adoptive Cell Transfer NK cells can be obtained from a variety of sources within a patient or healthy donor. Open in a separate window. Figure 1.
Autologous NK Cells While in vitro and in vivo studies have widely demonstrated the cytotoxicity of ex vivo expanded NK cell populations against tumor cell lines, clinical results have been less conclusive. Allogeneic NK Cells Allogeneic NK cell transfer for cancer treatment rose serendipitously from observations made when patients with leukemia were given allogeneic hematopoietic stem cell transplantation HSCT. Figure 2.
Early Phase I Trials In both hematologic malignancies and solid tumors there are several clinical trials that are recruiting, or active but not yet recruiting, that have not yet posted results. Conclusions Harnessing cells of the immune system to fight various malignancies has been widely explored, with the employment of immunotherapy revolutionizing cancer treatment.
Acknowledgments The authors thank Debra Weingarten for her editorial assistance in the preparation of this manuscript. Author Contributions S. Conflicts of Interest The authors declare no conflict of interest. References 1. Kalos M. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.
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Cancer Immunol. J Hematol Oncol. Published online May 1. Ying Gong , 1, 2 Roel G. Bos , 1, 2, 6 and Wilfred T. Germeraad 1, 2, 6. Roel G. Klein Wolterink. Gerard M. Wilfred T. Author information Article notes Copyright and License information Disclaimer. Germeraad, Email: ln. Corresponding author. Received Feb 10; Accepted Apr The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.
If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. This article has been cited by other articles in PMC. Associated Data Supplementary Materials Additional file 1. Additional file 2. Abstract Due to their efficient recognition and lysis of malignant cells, natural killer NK cells are considered as specialized immune cells that can be genetically modified to obtain capable effector cells for adoptive cellular treatment of cancer patients.
Supplementary Information The online version contains supplementary material available at Keywords: Cancer immunotherapy, Adoptive cell therapy, Chimeric antigen receptor, Natural killer cells, Genetic modification.
Introduction The human immune system has long been recognized as an important pillar of anticancer responses [ 1 , 2 ]. Open in a separate window. Vector backbone and promoter The vector backbone contains all elements needed for expression of the CAR such as the promoter, the polyadenine signal and transcriptional regulation fragments. Single-chain fragment variant scFv The single-chain fragment variant scFv , a fusion protein of the variable regions of the heavy and light chain of an antibody, is the tumor antigen-binding domain of the CAR.
Linkers The linker between the heavy and light chain contributes to the conformation of the scFv and therefore partly determines how well a CAR recognizes the target epitope. Synthetic biology: codon optimization and scFv humanization Codon optimization is a technique used to alter the use of nucleotides without changing the amino acid sequence. Lentiviruses Lentiviruses have been widely used in the gene therapy space for decades, as they are able to transduce cycling and non-cycling cells with high transduction efficiency.
Retroviruses Retroviruses have been used as gene therapy vectors for decades [ 95 ]. Sleeping beauty transposon Transposon-based systems can introduce CAR transgenes with higher efficiency and at predefined locations, which is an important advantage over conventional methods that do not possess an integrating element.
CAR-expression detection methods Following transduction of the chimeric antigen receptor, various techniques are available to assess CAR expression levels on the cell surface and to determine the efficacy of the developed CAR-NK cells. Flow cytometry Flow cytometry is widely used to detect CAR expression, since it is a fast and reliable detection method that provides quantitative data on protein expression at the single cell level.
Western blot Western blots that employ antibodies recognizing an antibody, as for flow cytometry, can also be used to detect CAR expression in a cell population [ ]. Confocal microscopy Fluorescent and electron microscopy can be used to visualize CAR molecules on the surface of effector cells.
Molecular imaging In addition to follow-up by flow cytometry and determination of gene copy numbers, various molecular imaging strategies are currently under investigation for experimental and clinical use. Approaches for enhancing NK cell virus-mediated transduction Lentiviruses and retroviruses are the most commonly used systems to induce stable expression of chimeric antigen receptors in NK cells.
Other small molecular compounds to enhance NK cell transduction In addition to statins, other compounds have been tested to enhance the viral transduction of NK cells. Alternative lentiviral pseudotypes for NK cell transduction VSV-G has long been used as the major glycoprotein for pseudotyping lentiviruses because of its broad tropism, facilitating the transduction of a wide range of cell types [ ]. Microfluidic mechanic devices The titer of the virus is a crucial parameter of the viral transduction.
Table 5 NK cell sources. NK cell lines: NK The aforementioned NK cell sources have one major disadvantage in common: Obtaining large numbers of NK cells is relatively cumbersome and time-consuming. Table 6 Approaches for NK cell expansion. Challenges Still many aspects on CAR constructs will have to be improved and many challenges lie ahead of the field. Supplementary Information Additional file 1. Acknowledgements The authors regret that it was not possible to include many interesting studies in the field due to limited space.
Authors' contributions All authors wrote and revised the initial draft, finalized the last version of the manuscript, and approved the final version. Funding Y. Declarations Ethics approval and consent to participate Not applicable. Competing interests G. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Food and Drug Administration or any other analogous regulatory authority. Celularity Inc. These therapeutic programs target indications in cancer, infectious and degenerative diseases. In addition, Celularity develops and manufactures innovative biomaterials also derived from the postpartum placenta.
If any of these risks materialize or underlying assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements.
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