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A DONOR-DEPENDENT SUBSET OF CYTOKINE-INDUCED KILLER (CIK) CELLS EXPRESS CD16 AND CAN BE RETARGETED TO EXERT A POTENT ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC)
Full text linkCancer adoptive cell therapy (ACT) relies on the infusion of immune cell populations mediating direct antitumor effects, such as cytotoxic CD8+ T lymphocytes (CTL), natural killer (NK) cells and Cytokine-Induced Killer (CIK) cells. In this study, we aimed at improving CIK cell potential for adoptive immunotherapy strategies. CIK cells are a heterogeneous population of ex vivo expanded lymphocytes, which share phenotypic and functional features with both NK and T cells. They exert a potent MHC-independent antitumor activity against both hematological and solid malignancies, but not normal tissues and hematopoietic precursors. Several clinical trials have demonstrated the feasibility and the therapeutic efficacy together with low toxicity of CIK cells infusion, supporting CIK cells as a very promising cell population for adoptive immunotherapy. In this work, CIK cells were obtained from PBMCs of healthy donors by the timed addition of IFN-γ, anti-CD3 antibody and IL-2. Analyzing their phenotype, we demonstrated for the first time a relevant expression of CD16 in a donor-dependent manner and, based on this observation, we proved the ability of CIK cells to kill tumors by an Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) mechanism. Indeed, the concurrent administration of clinically therapeutic mAbs, such as trastuzumab or cetuximab, led to a significant improvement of their antitumor activity in vitro against both ovarian and breast cancer cell lines. To formally prove that the CD16 receptor is functional and directly involved in the ADCC, an anti-CD16 blocking antibody was added to the assays. NK cell depletion from bulk cultures confirmed that the ADCC activity is accountable to the CIK CD16+ subpopulation. This novel function of CIK cells, never exploited before, was assessed for therapeutic efficacy in mouse models of human ovarian carcinoma xenografted in NOD/SCID common γ chain knockout (NSG) mice. Co-administration of CIK cells and mAbs significantly increased the survival of tumor-bearing mice, as compared to animals receiving CIK cells alone. CIK cell antitumor activity in vitro was also enhanced by the combination with bispecific antibodies and immunoligands, which are able to target both a tumor-associated antigen and activating receptors expressed by effector cells. Taken together, these data envisage new perspectives for adoptive immunotherapy where antigen-specific retargeting of T cells can be achieved by a combination therapy with clinical-grade monoclonal antibodies already widely used in cancer therapy, and CIK cell populations that are easily expandable in very large numbers, inexpensive, safe and do not require genetic manipulations. In conclusion, this new therapeutic strategy for the ACT treatment of different types of tumors could find wide implementation and application, and be expanded to the use of additional therapeutic antibodies.La terapia cellulare adottiva (Adoptive Cell Therapy, ACT) si basa sulla somministrazione di popolazioni di cellule immunitarie in grado di mediare un effetto antitumorale in modo diretto, ad esempio linfociti T CD8+ citotossici (CTL), cellule natural killer (NK) e cellule killer indotte da citochine (Cytokine-Induced Killer cells, CIK). Lo scopo di questo lavoro è stato quello di incrementare il potenziale delle cellule CIK nelle strategie di immunoterapia adottiva. Le cellule CIK sono una popolazione eterogenea di linfociti espansi ex vivo che condividono caratteristiche fenotipiche e funzionali sia con le cellule NK sia con le cellule T. Queste cellule esercitano una potente citotossicità MHC-indipendente nei confronti di tumori sia ematologici sia solidi, ma non di tessuti normali e precursori ematopoietici. Diversi trial clinici hanno dimostrato l’attuabilità, l’efficacia terapeutica e la bassa tossicità delle infusioni di cellule CIK, supportandole come popolazione cellulare molto promettente per l’immunoterapia adottiva. In questo lavoro, le cellule CIK sono state ottenute da cellule mononucleate del sangue periferico (Pheripheral Blood Mononuclear Cells, PBMCs) di donatori sani mediante l’aggiunta di interferone gamma (Interferon-γ, IFN-γ), anticorpi anti-CD3 e interleuchina 2 (Interleukin-2, IL-2). Analizzando il fenotipo, abbiamo dimostrato per la prima volta una rilevante espressione donatore-dipendente del recettore CD16 e, basandoci su questa osservazione, abbiamo analizzato la capacità delle cellule CIK di uccidere cellule tumorali mediante citotossicità cellulo-mediata anticorpo-dipendente (Antibody-Dependent Cell-mediated Cytotoxicity, ADCC). Infatti, abbiamo osservato che la simultanea somministrazione di anticorpi monoclonali terapeutici, come il trastuzumab e il cetuximab, portano ad un significativo incremento dell’attività antitumorale in vitro delle CIK nei confronti di linee cellulari di tumore ovarico e mammario. Per dimostrare che il CD16 è funzionale ed è direttamente coinvolto nell’ADCC, è stato aggiunto al saggio un anticorpo bloccante anti-CD16. La deplezione delle cellule NK ha confermato che l’ADCC è attribuibile alla sottopopolazione CD16+ delle cellule CIK. Questa nuova funzione delle cellule CIK, descritta qui per la prima volta, è stata valutata per la sua efficacia terapeutica in un modello murino di carcinoma ovarico umano trapiantato in topi NOD/SCID knockout per la catena comune γ (topi NSG). La co-somministrazione di cellule CIK e anticorpi monoclonali ha aumentato significativamente la sopravvivenza dei topi con tumore, in confronto ai topi trattati soltanto con le CIK. Inoltre, l’attività antitumorale in vitro delle cellule CIK è stata incrementata mediante la combinazione con anticorpi bispecifici e immunoligandi, in grado di legare contemporaneamente un antigene associato al tumore e un recettore attivatore espresso dalle cellule effettrici.
Complessivamente, questi dati prospettano nuove possibilità per l’immunoterapia adottiva, in cui il reindirizzamento antigene-specifico dei linfociti T può essere ottenuto mediante la combinazione di anticorpi monoclonali di utilizzo clinico, già ampiamente utilizzati per la terapia antitumorale, con popolazioni di cellule CIK, che sono facilmente espandibili, economiche, sicure e non richiedono manipolazioni genetiche. In conclusione, questa nuova strategia terapeutica per trattamento di diversi tipi di tumori mediante terapia cellulare adottiva potrà trovare ampie possibilità di implementazione e applicazione, e potrà essere estesa all’utilizzo di ulteriori anticorpi terapeutici
Cytokines for the induction of antitumor effectors: The paradigm of Cytokine-Induced Killer (CIK) cells
Full text linkCytokine-Induced killer (CIK) cells are raising growing interest in cellular antitumor therapy, as they can be easily expanded with a straightforward and inexpensive protocol, and are safe requiring only GMP-grade cytokines to obtain very high amounts of cytotoxic cells. CIK cells do not need antigen-specific stimuli to be activated and proliferate, as they recognize and destroy tumor cells in an HLA-independent fashion through the engagement of NKG2D. In several preclinical studies and clinical trials, CIK cells showed a reduced alloreactivity compared to conventional T cells, even when challenged across HLA-barriers; only in a few patients, a mild GVHD occurred after treatment with allogeneic CIK cells. Additionally, their antitumor activity can be redirected and further improved with chimeric antigen receptors, clinical-grade monoclonal antibodies or immune checkpoint inhibitors. The evidence obtained from a growing body of literature support CIK cells as a very promising cell population for adoptive immunotherapy. In this review, all these aspects will be addressed with a particular emphasis on the role of the cytokines involved in CIK cell generation, expansion and functionalization
Retargeting cytokine-induced killer cell activity by CD16 engagement with clinical-grade antibodies
Full text linkCytokine-induced Killer (CIK) cells are a heterogeneous population of ex vivo expanded T lymphocytes capable of MHC-unrestricted antitumor activity, which share phenotypic and functional features with both NK and T cells. Preclinical data and initial clinical studies demonstrated their high tolerability in vivo, supporting CIK cells as a promising cell population for adoptive cell immunotherapy. In this study, we report for the first time that CIK cells display a donor-dependent expression of CD16, which can be engaged by trastuzumab or cetuximab to exert a potent antibody-dependent cell-mediated cytotoxicity (ADCC) against ovarian and breast cancer cell lines, leading to an increased lytic activity in vitro, and an enhanced therapeutic efficacy in vivo. Thus, an efficient tumor antigen-specific retargeting can be achieved by a combination therapy with clinical-grade monoclonal antibodies already widely used in cancer therapy, and CIK cell populations that are easily expandable in very large numbers, inexpensive, safe and do not require genetic manipulations. Overall, these data provide a new therapeutic strategy for the treatment of Her2 and EGFR expressing tumors by adoptive cell therapy, which could find wide implementation and application, and could also be expanded to the use of additional therapeutic antibodies
Modulating Cytotoxic Effector Functions by Fc Engineering to Improve Cancer Therapy
Full text linkIn the last two decades, monoclonal antibodies have revolutionized the therapy of cancer patients. Although antibody therapy has continuously been improved, still a significant number of patients do not benefit from antibody therapy. Therefore, rational optimization of the antibody molecule by Fc engineering represents a major area of translational research to further improve this potent therapeutic option. Monoclonal antibodies are able to trigger a variety of effector mechanisms. Especially Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement- dependent cytotoxicity (CDC) are considered important in antibody therapy of cancer. Novel mechanistic insights into the action of monoclonal antibodies allowed the development of various Fc engineering approaches to modulate antibodies' effector functions. Strategies in modifying the Fc glycosylation profile (Fc glyco-engineering) or approaches in engineering the protein backbone (Fc protein engineering) have been intensively evaluated. In the current review, Fc engineering strategies resulting in improved ADCC, ADCP and CDC activity are summarized and discussed.</jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
How can Cytokine-induced killer cells overcome CAR-T cell limits
Full text linkThe successful treatment of patients affected by B-cell malignancies with Chimeric Antigen Receptor (CAR)-T cells represented a breakthrough in the field of adoptive cell therapy (ACT). However, CAR-T therapy is not an option for every patient, and several needs remain unmet. In particular, the production of CAR-T cells is expensive, labor-intensive and logistically challenging; additionally, the toxicities deriving from CAR-T cells infusion, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), have been documented extensively. Alternative cellular therapy products such as Cytokine-induced killer (CIK) cells have the potential to overcome some of these obstacles. CIK cells are a heterogeneous population of polyclonal CD3+CD56+ T cells with phenotypic and functional properties of NK cells. CIK cell cytotoxicity is exerted in a major histocompatibility complex (MHC)-unrestricted manner through the engagement of natural killer group 2 member D (NKG2D) molecules, against a wide range of hematological and solid tumors without the need for prior antigen exposure or priming. The foremost potential of CIK cells lies in the very limited ability to induce graft-versus-host disease (GvHD) reactions in the allogeneic setting. CIK cells are produced with a simple and extremely efficient expansion protocol, which leads to a massive expansion of effector cells and requires a lower financial commitment compared to CAR-T cells. Indeed, CAR-T manufacturing involves the engineering with expensive GMP-grade viral vectors in centralized manufacturing facilities, whereas CIK cell production is successfully performed in local academic GMP facilities, and CIK cell treatment is now licensed in many countries. Moreover, the toxicities observed for CAR-T cells are not present in CIK cell-treated patients, thus further reducing the costs associated with hospitalization and post-infusion monitoring of patients, and ultimately encouraging the delivery of cell therapies in the outpatient setting. This review aims to give an overview of the limitations of CAR-T cell therapy and outline how the use of CIK cells could overcome such drawbacks thanks to their unique features. We highlight the undeniable advantages of using CIK cells as a therapeutic product, underlying the opportunity for further research on the topic
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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