scholarly journals 671 Biological impacts of standard of care chemotherapies on immune effector cells from AML patients

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A699-A699
Author(s):  
Dmitry Zhigarev ◽  
Alexander MacFarlane ◽  
Christina Drenberg ◽  
Reza Nejati ◽  
Asya Varshavsky ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Phenotype ◽  
Second Line ◽  
Color Flow ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
And Function

BackgroundAcute myeloid leukemia (AML) is a heterogeneous group of malignant bone marrow diseases, characterized by massive and uncontrolled proliferation of myeloid precursor cells, which alters normal blood cell ratios. This disease is common to older adults and collectively displays one of the lowest 5-year overall survival rates (<25%) among all cancers, currently representing the deadliest form of leukemia. Improved treatments are clearly needed, and immunotherapies are attractive candidate therapies to explore.There are currently several standard chemotherapeutic treatment schemes for AML, which could be divided into two major groups: (1) cytotoxic chemotherapy (“7+3” or daunorubicin-cytarabine) and (2) hypomethylating agents (HMAs). HMAs include both 5-azacytidine and decitabine, which are cytidine analogs that inhibit DNA methyltransferase, resulting in the hypomethylation of DNA and inducing expression of silenced gene loci. Currently, HMAs are routinely delivered in combination with the Bcl-2 inhibitor venetoclax.The goals of this study are to determine how these standard first line therapies can affect the frequency and functional integrity of effector immune cells in patients' blood and establish when the phenotype and function of immune cells are restored to identify time windows when second line immunotherapies could be most effective.MethodsMore than 100 blood samples were obtained from 33 previously untreated AML patients. More than 50 measurable biomarkers were analyzed using 14-color flow cytometry to assess immune phenotypes of T and NK cells in peripheral blood of AML patients prior to treatment and at up to four timepoints after initiation of treatment with HMA or chemotherapy.ResultsWe found several significant changes in immune cell phenotype and function that occur in response to these therapies. Treatment with HMAs was strikingly less impactful on immune cells in patients compared to previously published in vitro studies. Nevertheless, HMA treatment increased perforin levels in T and NK cells, inhibited IFN-gamma secretion by CD8+ T cells, and changed expression of several checkpoint molecules. While chemotherapy caused fewer phenotypic changes it dramatically decreased the total number of immune cells. We also determined viable, functional and phenotypical recovery periods for immune effector cells after the treatments.ConclusionsOur results are important for introducing new second line immunotherapies to these chemotherapeutic regimens for treating AML and to improve overall understanding of immune cell behavior under conditions of anti-tumor treatment.AcknowledgementsSupported by grants from Janssen and the U.S./Israel Binational Science Foundation.Ethics ApprovalThe study was approved by the Fox Chase Cancer Center Institutional Review Board, approval number 17-8010, and all patients provided informed consent before taking part in the study.

scholarly journals To cure or not to cure: consequences of immunological interactions in CML treatment

2018 ◽  
Author(s):  
Artur César Fassoni ◽  
Ingo Roeder ◽  
Ingmar Glauche
Keyword(s):  
Immune Cell ◽  
Cell Number ◽  
Leukemic Cells ◽  
Critical Parameters ◽  
Treatment Cessation ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Tki Treatment ◽  
And Function

AbstractRecent clinical findings in Chronic Myeloid Leukemia (CML) patients suggest that the number and function of immune effector cells are modulated by Tyrosine Kinase Inhibitors (TKI) treatment. There is further evidence that the success or failure of treatment cessation at least partly depends on the patient’s immunological constitution. Here, we propose a general ODE model to functionally describe the interactions between immune effector cells with leukemic cells during the TKI treatment of CML. In total, we consider 20 different sub-models, which assume different functional interactions between immune effector and leukemic cells. We show that quantitative criteria, which are purely based on the quality of model fitting, are not able to identify optimal models. On the other hand, the application of qualitative criteria based on a dynamical system framework allowed us to identify nine of those models as more suitable than the others to describe clinically observed patterns and, thereby, to derive conclusion about the underlying mechanisms. Additionally, including aspects of early CML onset, we can demonstrate that certain critical parameters, such as the strength of immune response or leukemia proliferation rate, need to change during CML growth prior to diagnosis, leading to bifurcations that alter the attractor landscape. Finally, we show that the crucial parameters determining the outcome of treatment cessation are not identifiable with tumor load data only, thereby highlighting the need to measure immune cell number and function to properly derive mathematical models with predictive power.MSC Classification: 92B05, 37N25, 34C60, 37G35

scholarly journals The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3542
Author(s):  
Joanna Domagala ◽  
Mieszko Lachota ◽  
Marta Klopotowska ◽  
Agnieszka Graczyk-Jarzynka ◽  
Antoni Domagala ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Nk Cell ◽  
Metabolic Changes ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Almost All

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.

Quality Controls of Immune Regulatory Properties of Ex-Vivo, GMP-Grade Expanded Mesenchymal Stromal Cells for Clinical Use (European multicenter study CASCADE),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4049-4049
Author(s):  
Mauro Krampera ◽  
Cedric Mènard ◽  
Luciano Pacelli ◽  
Giulio Bassi ◽  
Joelle Dulong ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nk Cells ◽  
Stromal Cells ◽  
Culture Conditions ◽  
Clinical Use ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Immunomodulatory Properties ◽  
Set Up

Abstract Abstract 4049 Aim of the European Consortium CASCADE is to standardize GMP-grade production and clinical use of Mesenchymal Stromal Cells (MSC) to treat skin and corneal wounds. MSC possess immunogenicity and immunomodulatory properties that must be carefully addressed before clinical use. CASCADE Immunological Unit is aimed to set up and validate a wide panel of functional assays to fully characterize in a standardized and reproducible manner the immunomodulatory properties of MSC obtained inside CASCADE Units from bone marrow, adipose tissue, cord blood, and amniotic membrane (BM, AT, CB, AM) through different GMP-grade expansion protocols including platelet lysate- and fetal calf serum-based culture conditions. Immune cells were isolated using indirect immunomagnetic depletion; samples with less than 96% of purity were discarded. For the experiments, MSC were expanded in the same medium used for production and harvested at 70% confluence. Primed MSC were obtained by 48h-treatment with 10 ng/ml of rh-INFγ and 15 ng/ml of rh-TNFα. Cocultures were set up by plating primed or unprimed MSC in 96 or 48 flat bottomed – well plates; CFSE-stained T, B, NK cells were seeded at different effector cell:MSC ratios. Cells were harvested after 4 or 6 days of coculture for proliferation evaluation by FACS analysis. T cells were stimulated with mitogenic αCD3 plus αCD28 antibodies at 0.5 μg/ml each; B cells were activated with CD40L at 50 ng/ml, its enhancer at 5 g/ml, IL-2 20 UI/ml, CpG 2006 2.5 μg/mL, and F(ab')2 anti-IgM/IgA/IgG 2 μg/mL; NK cells were activated with 100 U/ml rh-IL2. To identify the molecular mechanisms involved in immunomodulatory properties of MSC, coculture of immune effector cells and MSC were performed in the presence of specific inhibitors, after identifying their non-toxic and effective concentrations: 1 mM for L-1MT (IDO inhibitor), 2 μM for snPP (HO-1 inhibitor), 5 μM for NS-398 (COX2 inhibitor), 1 mM for L-NMMA (iNOS inhibitor) and 10 μg/ml for anti-IFNγ neutralizing antibody. We also studied the capacity of resting and primed MSC to sustain the survival of unstimulated T, B, and NK cells through the evaluation of the percentage of caspase-3negCD45pos viable immune cells after 4 to 6 days in culture with or without MSC. For MSC immunogenicity assay, the proliferation of allogeneic T was evaluated at day 5 of culture by incorporation of 3H-Thymidine; in addition, NK cells were activated for 2 days with 100 U/ml of rh-IL2 whereas resting or primed MSC were loaded with non radioactive fluorophore (BaTDA) or with Cr51 and used as target cells. Inflammatory milieu significantly upregulated MHC class I and II, CD54, CD106, CD40, CD274, CD112, CD155 expression, and downregulated NKG2D ligands (ULBP 1–3, MICA/B) and mesenchymal markers (CD73, CD90, CD105). AT-derived MSC expressed less MHC class II, CD200 and CD106 molecules than BM-MSC. MSC coculture inhibited T and NK cell proliferation without inducing apoptosis, and this effect was greater in presence of primed MSC. On the contrary, only primed MSC were capable of suppressing B cell proliferation. In addition, MSC inhibited apoptosis of resting T, B, and NK cells, while inflammatory priming increased their pro-survival activity. T cell/MSC coculture showed that activation of IDO and HO-1 was the main mechanism involved in MSC immune modulation, as the addition of specific inhibitors (L-1-MT and snPP) significantly reverted the phenomenon. MSC never promoted allogeneic T cell proliferation; by contrast, IL-2-activated NK cells could efficiently recognize and kill allogenic unprimed MSC. However, MSC became insensitive to NK cells once primed with inflammatory cytokines. Some differences were observed depending on the origin and culture conditions of clinical-grade MSC. All the experimental protocols to assess MSC inhibitory effects on immune effector cells have been standardized and will be applied for the release of GMP-grade MSC produced inside the CASCADE Consortium. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

2021 ◽  
Vol 12 ◽  
Author(s):  
Yijia Li ◽  
Yangzhe Wu ◽  
Yi Hu
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Immune Cells ◽  
Expression Patterns ◽  
Immune Effector ◽  
Effector Cells ◽  
Cell Functions ◽  
Metabolic Plasticity ◽  
Signal Transduction Networks ◽  
Immune Effector Cells

Cellular metabolism of both cancer and immune cells in the acidic, hypoxic, and nutrient-depleted tumor microenvironment (TME) has attracted increasing attention in recent years. Accumulating evidence has shown that cancer cells in TME could outcompete immune cells for nutrients and at the same time, producing inhibitory products that suppress immune effector cell functions. Recent progress revealed that metabolites in the TME could dysregulate gene expression patterns in the differentiation, proliferation, and activation of immune effector cells by interfering with the epigenetic programs and signal transduction networks. Nevertheless, encouraging studies indicated that metabolic plasticity and heterogeneity between cancer and immune effector cells could provide us the opportunity to discover and target the metabolic vulnerabilities of cancer cells while potentiating the anti-tumor functions of immune effector cells. In this review, we will discuss the metabolic impacts on the immune effector cells in TME and explore the therapeutic opportunities for metabolically enhanced immunotherapy.

scholarly journals CXCL12 Inhibition By Nox-A12 (Olaptesed Pegol) Synergizes with the ADCC Activity of CD20 Antibodies By Increasing NK Cell Infiltration in a 3D Lymphoma Model

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3021-3021 ◽  
Author(s):  
Dirk Zboralski ◽  
Anna Kruschinski ◽  
Axel Vater
Keyword(s):  
Nk Cells ◽  
Peripheral Blood ◽  
Hematological Malignancies ◽  
Nk Cell ◽  
Cell Infiltration ◽  
Malignant Cells ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Anti Cd20

Abstract Hematological malignancies are characterized by the expansion of malignant cells in the peripheral blood and in stroma-rich niches such as the bone marrow or lymphoid tissues. Anti-CD20 monoclonal antibodies (mAbs) are highly effective in eliminating malignant cells in the peripheral blood with the help of immune effector cells, e.g. NK cells mediating antibody-dependent cellular cytotoxicity (ADCC). However, residual malignant cells often continue to persist in protective stromal niches. These compartments have similarities to the solid tumor microenvironment (TME) where mAb therapy is restricted by poor tissue penetration and low effector cell infiltration. The CXCL12-neutralizing L-RNA aptamer NOX-A12 (olaptesed pegol) has been shown to mobilize malignant cells from the bone marrow into the peripheral blood, thereby sensitizing them to the action of standard therapy such as the anti-CD20 mAb rituximab (Blood. 2014;124(21):1996). In addition to malignant cells, CXCR4 expressing immune cells are effectively mobilized by NOX-A12 (Clin Pharmacol Ther. 2013;94(1):150-157). Recently we have shown that NOX-A12 increases lymphocyte infiltration into solid tumor-stroma spheroids, thereby synergizing with anti-PD-1 checkpoint blockade (Cancer Res 2016;76(14 Suppl): 1473). Here we established 3D lymphoid spheroidal microtissues mimicking the stroma-rich and CXCL12-abundant TME of lymphoid malignancies. We investigated the effect of NOX-A12 on NK effector cell infiltration into lymphoma spheroids and tested the combination with anti-CD20 mAbs. Spheroids were generated by co-culturing of CXCL12-expressing murine stromal MS-5 cells and CD20-expressing lymphoma cells in ultra-low attachment plates for 24 hours. Primary human NK cells, isolated from healthy donors, were added to the spheroids in the presence of various concentrations of NOX-A12 and an anti-CD20 mAb, either rituximab or obinutuzumab. The next day, spheroids were washed and dissociated for NK cell quantification and lymphoma cell viability determination by flow cytometry. We found that the ADCC efficacy of anti-CD20 mAbs is lower in 3D spheroids compared to conventional 2D assays due to low NK cell infiltration into the microtissues. Interestingly, NOX-A12 increased the amount of NK cells in the lymphoma-stroma spheroids up to 8-fold in a dose-dependent manner (Figure A), likely by forming de novo CXCL12 gradients into the dense microtissue due to the particular penetration characteristic of L-RNA aptamers. Of note, the NOX-A12-mediated increase of NK cells in the spheroids synergized with both anti-CD20 mAbs tested in terms of NK cell-mediated killing of lymphoma cells (Figure B). The present work complements the mechanism of action data of NOX-A12 by adding enhancement of NK cell infiltration into stroma-rich tumor compartments to the already established effects of mobilizing malignant and immune effector cells into the peripheral blood. These data as well as the good toxicity profile and the promising data in phase 2a clinical trials in patients with CLL and MM justify further clinical trials in patients with hematological malignancies to verify the greater efficacy of combination treatment using ADCC-inducing mAbs and NOX-A12. Figure Figure. Disclosures Zboralski: NOXXON Pharma AG: Employment. Kruschinski:NOXXON Pharma AG: Employment. Vater:NOXXON Pharma AG: Employment.

scholarly journals Immune Cell Profiling of Peripheral Blood as Signature for Response During Checkpoint Inhibition Across Cancer Types

2021 ◽  
Vol 11 ◽  
Author(s):  
Vinicius Araujo B. de Lima ◽  
Morten Hansen ◽  
Iben Spanggaard ◽  
Kristoffer Rohrberg ◽  
Sine Reker Hadrup ◽  
...  
Keyword(s):  
Immune Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Large Fraction ◽  
Response To Treatment ◽  
Cell Phenotype ◽  
Checkpoint Inhibition ◽  
Color Flow ◽  
Immune Profile

Despite encouraging results with immune checkpoint inhibition (ICI), a large fraction of cancer patients still does not achieve clinical benefit. Finding predictive markers in the complexity of the tumor microenvironment is a challenging task and often requires invasive procedures. In our study, we looked for putative variables related to treatment benefit among immune cells in peripheral blood across different tumor types treated with ICIs. For that, we included 33 patients with different solid tumors referred to our clinical unit for ICI. Peripheral blood mononuclear cells were isolated at baseline, 6 and 20 weeks after treatment start. Characterization of immune cells was carried out by multi-color flow cytometry. Response to treatment was assessed radiologically by RECIST 1.1. Clinical outcome correlated with a shift towards an effector-like T cell phenotype, PD-1 expression by CD8+T cells, low levels of myeloid-derived suppressor cells and classical monocytes. Dendritic cells seemed also to play a role in terms of survival. From these findings, we hypothesized that patients responding to ICI had already at baseline an immune profile, here called ‘favorable immune periphery’, providing a higher chance of benefitting from ICI. We elaborated an index comprising cell types mentioned above. This signature correlated positively with the likelihood of benefiting from the treatment and ultimately with longer survival. Our study illustrates that patients responding to ICI seem to have a pre-existing immune profile in peripheral blood that favors good outcome. Exploring this signature can help to identify patients likely to achieve benefit from ICI.

scholarly journals Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1353
Author(s):  
Andrea Díaz-Tejedor ◽  
Mauro Lorenzo-Mohamed ◽  
Noemí Puig ◽  
Ramón García-Sanz ◽  
María-Victoria Mateos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Cytotoxic Effects ◽  
Disease Evolution ◽  
Immune Effector ◽  
Effector Cells ◽  
Surface Molecules ◽  
Immune Effector Cells

Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterations in the expression of surface molecules are also responsible for immunosuppression. In this scenario, immunotherapy, as is the case of immunotherapeutic monoclonal antibodies (mAbs), aims to boost the immune system against tumor cells. In fact, mAbs exert part of their cytotoxic effects through different cellular and soluble immune components and, therefore, patients’ immunosuppressive status could reduce their efficacy. Here, we will expose the alterations observed in symptomatic MM, as compared to its precursor stages and healthy subjects, in the main immune populations, especially the inhibition of effector cells and the activation of immunosuppressive populations. Additionally, we will revise the mechanisms responsible for all these alterations, including the interplay between MM cells and immune cells and the interactions among immune cells themselves. We will also summarize the main mechanisms of action of the four mAbs approved so far for the treatment of MM. Finally, we will discuss the potential immune-stimulating effects of non-immunotherapeutic drugs, which could enhance the efficacy of immunotherapeutic treatments.

Adoptive Immune Cell Therapy for the Control of Fungal Infections in Hematopoietic Stem Cell Transplant Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4358-4358
Author(s):  
Lung-Ji Chang ◽  
Yin Liang ◽  
Lily Lien ◽  
Chun- Rong Tong ◽  
Lu-Jia Dong ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Fungal Infections ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Immune Effector ◽  
Effector Cells ◽  
Transplant Patients ◽  
Fungal Antigens ◽  
Anti Fungal

Abstract Similar to virus infections, fungal infections are commonly seen in immunosuppressed transplant patients and can be life-threatening. Invasive Aspergillosis and Candidiasis are principal fungal infections among hematopoietic stem cell transplant (HSCT) patients, but Aspergillosis and other molds are the leading cause of deaths by fungal infections in immunocompromised allogeneic HSCT patients. The most effective treatment for fungal infections is preemptive and empirical anti-fungal therapies using agents such as fluconazole and amphotericin B deoxycholate (AmB-D). However, the success rate of antifungal therapy is generally low (in the 30–40% range) and associated with high toxicity. Both diagnosis and treatment for fungal infections are expensive and often ineffective. While improved formulations of AmB-D, second-generation triazoles, and echinocandins may be tolerable, newer generations of anti-fungal agents are very expensive. In animal studies, it has been shown that Aspergillosis can be successfully treated using Aspergillus-specific cytotoxic T cells (CTLs). Therefore, it is conceivable that CTLs specific to fungal antigens are effective in controlling fungal infections in allogeneic HSCT patients. To explore anti-fungal immune cell therapy, we used two different approaches to generate fungus-specific immune cells: Trichoderma and Rhizopus fungal lysates as antigen source to pulse dendritic cells (DCs), and pooled antigenic peptides to pulse DCs. The antigen-primed DCs were then co-cultured with lymphocytes to generate antigen-specific immune effector cells. The ex vivo generated anti-fungal immune cells displayed antigen-specific effector functions as illustrated by intracellular IFN-γ and CD107a staining. Interestingly, the fungus-specific immune effector cells are mostly CD4 T cells for all three species of fungal antigens. In a pilot clinical study, patients were selected when diagnosed with invasive aspergillosis based on galactomannan and beta-glucan assays, radiographs, CT scans, and/or blood cultures, or after an extended unsuccessful anti-fungal treatment with non-tolerable organ toxicity. Early indications suggest that the infusion of anti-fungal immune cells is safe, with therapeutic efficacy based on objective clinical evidence and importantly, is cost-effective. Nevertheless, more effective diagnosis and surveillance tools are needed to document the effectiveness of our anti-fungal immune cell treatment.

scholarly journals Anti-Tumorigenic Activities of IL-33: A Mechanistic Insight

2020 ◽  
Vol 11 ◽  
Author(s):  
Sara Andreone ◽  
Adriana Rosa Gambardella ◽  
Jacopo Mancini ◽  
Stefania Loffredo ◽  
Simone Marcella ◽  
...  
Keyword(s):  
Immune Cell ◽  
Allergic Diseases ◽  
Lymphoid Cells ◽  
Parasitic Infections ◽  
Immune Effector ◽  
Effector Cells ◽  
Interleukin 33 ◽  
Cancer Immunity ◽  
Immune Effector Cells

Interleukin-33 (IL-33) is an epithelial-derived cytokine that can be released upon tissue damage, stress, or infection, acting as an alarmin for the immune system. IL-33 has long been studied in the context of Th2-related immunopathologies, such as allergic diseases and parasitic infections. However, its capacity to stimulate also Th1-type of immune responses is now well established. IL-33 binds to its specific receptor ST2 expressed by most immune cell populations, modulating a variety of responses. In cancer immunity, IL-33 can display both pro-tumoral and anti-tumoral functions, depending on the specific microenvironment. Recent findings indicate that IL-33 can effectively stimulate immune effector cells (NK and CD8+ T cells), eosinophils, basophils and type 2 innate lymphoid cells (ILC2) promoting direct and indirect anti-tumoral activities. In this review, we summarize the most recent advances on anti-tumor immune mechanisms operated by IL-33, including the modulation of immune checkpoint molecules, with the aim to understand its potential as a therapeutic target in cancer.

scholarly journals Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Faroogh Marofi ◽  
Heshu Sulaiman Rahman ◽  
Lakshmi Thangavelu ◽  
Aleksey Dorofeev ◽  
Favian Bayas-Morejón ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Tumor Cells ◽  
Immune Effector ◽  
Effector Cells ◽  
Car T Cells ◽  
Cell Immunotherapy ◽  
Car T ◽  
Immune Effector Cells ◽  
T Cell Immunotherapy

AbstractIn recent decades, a new method of cellular immunotherapy was introduced based on engineering and empowering the immune effector cells. In this type of immunotherapy, the immune effector cells are equipped with chimeric antigen receptor (CAR) to specifically target cancer cells. In much of the trials and experiments, CAR-modified T cell immunotherapy has achieved very promising therapeutic results in the treatment of some types of cancers and infectious diseases. However, there are also some considerable drawbacks in the clinical application of CAR-T cells although much effort is in progress to rectify the issues. In some conditions, CAR-T cells initiate over-activated and strong immune responses, therefore, causing unexpected side-effects such as systemic cytokine toxicity (i.e., cytokine release syndrome), neurotoxicity, on-target, off-tumor toxicity, and graft-versus-host disease (GvHD). To overcome these limitations in CAR-T cell immunotherapy, NK cells as an alternative source of immune effector cells have been utilized for CAR-engineering. Natural killer cells are key players of the innate immune system that can destroy virus-infected cells, tumor cells, or other aberrant cells with their efficient recognizing capability. Compared to T cells, CAR-transduced NK cells (CAR-NK) have several advantages, such as safety in clinical use, non-MHC-restricted recognition of tumor cells, and renewable and easy cell sources for their preparation. In this review, we will discuss the recent preclinical and clinical studies, different sources of NK cells, transduction methods, possible limitations and challenges, and clinical considerations.

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