180 results
Search Results
152. Stable and transient periodic oscillations in a mathematical model for CTL response to HTLV-I infection.
- Author
-
Lang, John and Li, Michael
- Subjects
- *
OSCILLATIONS , *CYTOTOXIC T cells , *HTLV-I , *POSTURAL balance , *HOPF bifurcations , *MATHEMATICAL models - Abstract
The cytotoxic T lymphocyte (CTL) response to the infection of CD4 T cells by human T cell leukemia virus type I (HTLV-I) has previously been modelled using standard response functions, with relatively simple dynamical outcomes. In this paper, we investigate the consequences of a more general CTL response and show that a sigmoidal response function gives rise to complex behaviours previously unobserved. Multiple equilibria are shown to exist and none of the equilibria is a global attractor during the chronic infection phase. Coexistence of local attractors with their own basin of attractions is the norm. In addition, both stable and unstable periodic oscillations can be created through Hopf bifurcations. We show that transient periodic oscillations occur when a saddle-type periodic solution exists. As a consequence, transient periodic oscillations can be robust and observable. Implications of our findings to the dynamics of CTL response to HTLV-I infections in vivo and pathogenesis of HAM/TSP are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
153. Induction of contact-dependent CD8+ regulatory T cells through stimulation with staphylococcal and streptococcal superantigens.
- Author
-
Taylor, Amanda L., Cross, Elizabeth L. A., and Llewelyn, Martin J.
- Subjects
- *
STAPHYLOCOCCAL disease treatment , *CYTOTOXIC T cells , *GENETIC regulation , *SUPERANTIGENS , *TOXIC shock syndrome , *CELL proliferation , *BIOMARKERS - Abstract
Summary The bacterial superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes are potent stimulators of polyclonal T-cell proliferation. They are the causes of toxic shock syndrome but also induce CD25+ FOXP3+ regulatory cells in the CD4 compartment. Several studies have recently described different forms of antigen-induced regulatory CD8+ T cells in the context of inflammatory diseases and chronic viral infections. In this paper we show that bacterial superantigens are potent inducers of human regulatory CD8+ T cells. We used four prototypic superantigens of S. aureus (toxic shock syndrome toxin-1 and staphylococcal enterotoxin A) and Str. pyogenes (streptococcal pyrogenic exotoxins A and K/L). At concentrations below 1 ng/ml each toxin triggers concentration-dependent T-cell receptor Vβ-specific expression of CD25 and FOXP3 on CD8+ T cells. This effect is independent of CD4+ T-cell help but requires antigen-presenting cells for maximum effect. The cells also express the activation/regulatory markers cytotoxic T-lymphocyte antigen-4 and glucocorticoid-induced tumour necrosis factor receptor-related protein and skin homing adhesins CD103 and cutaneous lymphocyte-associated antigen. Superantigen-induced CD25+ FOXP3+ CD8+ T cells were as potent as freshly prepared naturally occurring CD4+ regulatory T cells in suppressing proliferation of CD4+ CD25− T cells in response to anti-CD3 stimulation. Although superantigen-induced CD8+ CD25+ FOXP3+ express interleukin-10 and interferon-γ their suppressive function is cell contact dependent. Our findings indicate that regulatory CD8+ T cells may be a feature of acute bacterial infections contributing to immune evasion by the microbe and disease pathogenesis. The presence and magnitude of regulatory CD8+ T-cell responses may represent a novel biomarker in such infections. Superantigen-induced regulatory CD8+ T cells also have therapeutic potential. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
154. Interplay of Polarity Proteins and GTPases in T-Lymphocyte Function.
- Author
-
Fung, Ivan, Russell, SarahM., and Oliaro, Jane
- Subjects
- *
POLARITY (Chemistry) , *CYTOTOXIC T cells , *CELL physiology , *IMMUNE response , *GENETIC mutation , *CELLS , *ANTIGEN presentation - Abstract
Polarity refers to the asymmetric distribution of different cellular components within a cell and is central to many cell functions. In T-cells, polarity regulates the activation, migration, and effector function of cytotoxic T-cells (CTLs) during an immune response. The regulation of asymmetric cell division by polarity proteins may also dictate CTL effector and memory differentiation following antigen presentation. Small GTPases, along with their associated polarity and adaptor proteins, are critical for mediating the polarity changes necessary for T-cell activation and function, and in turn, are regulated by guanine exchange factors (GEFS) and GTPase activating proteins (GAPS). For example, a novel GEF, dedicator of cytokinesis 8 (DOCK8) was recently identified as a regulator of immune cell function and mutations in DOCK8 have been detected in patients with severe combined immunodeficiency. Both B and T-cells from DOCK8 mutant mice form defective immunological synapses and have abnormal functions, in addition to impaired immune memory development. This paper will discuss the interplay between polarity proteins and GTPases, and their role in T-cell function [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
155. A Peptide Filtering Relation Quantifies MHC Class I Peptide Optimization.
- Author
-
Dalchau, Neil, Phillips, Andrew, Goldstein, Leonard D., Howarth, Mark, Cardelli, Luca, Emmott, Cardelli, Elliott, Tim, and Werner, Joern M.
- Subjects
- *
MAJOR histocompatibility complex , *PEPTIDES , *CYTOTOXIC T cells , *CANCER cells , *DISEASE progression , *CARRIER proteins , *VIRUS diseases , *IMMUNE response - Abstract
Major Histocompatibility Complex (MHC) class I molecules enable cytotoxic T lymphocytes to destroy virus-infected or cancerous cells, thereby preventing disease progression. MHC class I molecules provide a snapshot of the contents of a cell by binding to protein fragments arising from intracellular protein turnover and presenting these fragments at the cell surface. Competing fragments (peptides) are selected for cell-surface presentation on the basis of their ability to form a stable complex with MHC class I, by a process known as peptide optimization. A better understanding of the optimization process is important for our understanding of immunodominance, the predominance of some T lymphocyte specificities over others, which can determine the efficacy of an immune response, the danger of immune evasion, and the success of vaccination strategies. In this paper we present a dynamical systems model of peptide optimization by MHC class I. We incorporate the chaperone molecule tapasin, which has been shown to enhance peptide optimization to different extents for different MHC class I alleles. Using a combination of published and novel experimental data to parameterize the model, we arrive at a relation of peptide filtering, which quantifies peptide optimization as a function of peptide supply and peptide unbinding rates. From this relation, we find that tapasin enhances peptide unbinding to improve peptide optimization without significantly delaying the transit of MHC to the cell surface, and differences in peptide optimization across MHC class I alleles can be explained by allele-specific differences in peptide binding. Importantly, our filtering relation may be used to dynamically predict the cell surface abundance of any number of competing peptides by MHC class I alleles, providing a quantitative basis to investigate viral infection or disease at the cellular level. We exemplify this by simulating optimization of the distribution of peptides derived from Human Immunodeficiency Virus Gag-Pol polyprotein. INSET: Author Summary. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
156. The interactions between major immune effector cells and Hepatocellular Carcinoma: A systematic review.
- Author
-
Schoenberg, Markus Bo, Li, Xiaokang, Li, Xinyu, Han, Yongsheng, Börner, Nikolaus, Koch, Dominik, Guba, Markus Otto, Werner, Jens, and Bazhin, Alexandr V.
- Subjects
- *
T cells , *KILLER cells , *HEPATOCELLULAR carcinoma , *TUMOR-infiltrating immune cells , *CYTOTOXIC T cells , *CELL communication , *LIVER tumors - Abstract
• Major immune effector cells like CD8+ T lymphocytes and natural killer cells are able to kill or inhibit Hepatocellular carcinoma (HCC) cells and their cytotoxic ability can be enhanced or down-regulated by certain cytokines or drugs. • HCC cells can impair the function of major immune effector cells through a variety of mechanisms. • Organoids or direct contact cell co-culture especially with primary HCC cells and tumor infiltrating lymphocytes provide better understanding of cell–cell interactions between major immune effector cells and HCC cells. • Immunotherapy like checkpoint inhibitors and adoptive cell transfer showed notable effectiveness and safety in preventing HCC recurrence as adjuvant therapy. Hepatocellular carcinoma (HCC) is the most common liver neoplasm with high morbidity and mortality. Tumor immunotherapy might be promising adjuvant therapy for HCC after surgery. To better develop HCC immunotherapy, comprehensive understanding of cell–cell interactions between immune effector cells and HCC cells remains crucial. To review the existing studies to summarize the cell–cell interactions between major immune effector cells and HCC cells providing new data for HCC immunotherapy. A systematic review was conducted by searching PubMed database covering all papers published in recent five years up to January 2020. The guidelines of the preferred reporting items for systematic reviews were firmly followed. There are 9 studies researching the interactions between CD8+ T lymphocytes and HCC cells and 22 studies researching that between natural killer (NK) cells and HCC cells. Among the 9 studies, 6 studies reported that CD8+ T lymphocytes showed cytotoxicity towards HCC cells while 3 studies found CD8+ T lymphocytes were impaired by HCC cells. Among the 22 studies, 20 studies presented that NK cells could inhibit HCC cells. Two studies were found to report NK cell dysfunction in HCC. Based on the systematic analysis, we concluded that CD8+ T lymphocytes and NK cells can inhibit HCC cells. While in turn, HCC cells can also result in the dysfunction of those effector cells through various mechanisms. Organoids and direct contact cell co-culture with primary HCC cells and TILs should be the most innovative way to investigate the interactions and develop novel immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
157. Dynamics of a reaction-diffusion fractional-order model for M1 oncolytic virotherapy with CTL immune response.
- Author
-
Younoussi, Majda El, Hajhouji, Zakaria, Hattaf, Khalid, and Yousfi, Noura
- Subjects
- *
CYTOTOXIC T cells , *ONCOLYTIC virotherapy , *IMMUNE response , *T cells , *PARTIAL differential equations , *FRACTIONAL differential equations - Abstract
• A reaction-diffusion fractional-order model for M1 oncolytic virotherapy with CTL immune response is presented. • Threshold parameters and equilibria are determined. • Stability analysis are rigorously established. • Numerical simulations are given to illustrate the analytical results. Despite many years of research, cancer continues to be a major worldwide concern. Several researchers proposed their mathematical models to understand and describe the dynamics of tumor cells under some cancer treatments. In this paper, we present a fractional partial differential equation system to describe the dynamics in space and time of the concentration of normal cells, tumor cells, nutrient, M1 virus, and cytotoxic T lymphocytes (CTL) cells, as well as the interaction between them. We study and analyze the equilibrium points of the presented system. The global stability of these equilibrium points is proved by constructing adequate Lyapunov functional for each equilibrium point. Furthermore, we give some numerical simulations to illustrate our results. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
158. A model for type I diabetes in an HIV-infected patient under highly active antiretroviral therapy.
- Author
-
Chávez, Joseph Páez, Wijaya, Karunia Putra, Pinto, Carla M.A., and Burgos-Simón, Clara
- Subjects
- *
HIGHLY active antiretroviral therapy , *HIV , *TYPE 1 diabetes , *CYTOTOXIC T cells , *HYPERGLYCEMIA , *PEOPLE with diabetes , *DIABETES in children - Abstract
Type 1 diabetes (T1D), previously known as juvenile diabetes or insulin-dependent diabetes, is an autoimmune disease characterized by the insufficient (or lack of) production of insulin by the pancreas. Insulin is crucial to maintain blood sugar at healthy levels. High blood sugar damages the body and causes a variety of symptoms, ranging from severe thirst, fatigue, to urinary infections. The cells responsible for the production of insulin are the β -cells. In T1D, these are killed by an abnormal response of the immune system. Specific clones of cytotoxic T-cells invade the pancreatic islets of Langerhans, and eliminate them. T1D diabetes may develop in human immunodeficiency virus (HIV)-infected patients, though in rare situations. In this paper, we propose a cell model for the development of T1D in these patients, after immune restoration, during highly active antiretroviral therapy (HAART). The study includes the derivation of the qualitative properties of the model, and its comprehensive investigation via path-following methods, using the continuation platform COCO. In this way, the main theoretical predictions are verified in detail. Furthermore, this numerical part establishes accurate parameter thresholds to ensure an effective disease treatment in HIV-infected persons to prevent the development of T1D. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
159. Analysis of a within-host HIV/HTLV-I co-infection model with immunity.
- Author
-
Elaiw, A.M. and AlShamrani, N.H.
- Subjects
- *
HIV , *HTLV-I , *RETROVIRUSES , *MIXED infections , *CYTOTOXIC T cells , *ADULT T-cell leukemia , *GLOBAL asymptotic stability - Abstract
• A new HIV/HTLV-I co-infection model with latency and Cytotoxic T lymphocytes (CTLs) immune response is developed and rigorously analyzed. • Both silent and active infected cells have been considered. • Well-possedness of the model and existence of equilibria are established. • Global stability of the equilibria are established by means of Lyapunov functions. • We have presented numerical simulations to illustrate the effectiveness of our main results. Human immunodeficiency virus (HIV) and human T-lymphotropic virus type I (HTLV-I) are two retroviruses that attack the immune cells and impair their functions. Both HIV and HTLV-I can be transmitted between individuals through direct contact with certain body fluids from infected individuals. Therefore, a person can be co-infected with both viruses. HIV causes acquired immunodeficiency syndrome, while HTLV-I is the causative agent for adult T-cell leukemia and HTLV-I-associated myelopathy/tropical spastic paraparesis. Several mathematical models have been developed in the literature to describe the within-host dynamics of HIV and HTLV-I mono-infections. However, modeling a within-host dynamics of HIV/HTLV-I co-infection has not been involved. In the present paper, we are concerned to formulate and analyze a new HIV/HTLV co-infection model under the effect of Cytotoxic T lymphocytes (CTLs) immune response. The model describes the interaction between susceptible CD4+T cells, silent HIV-infected cells, active HIV-infected cells, silent HTLV-infected cells, Tax-expressing HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. The HIV can spread by two routes of transmission, virus-to-cell and cell-to-cell. On the other side, HTLV-I has two modes of transmission, (i) horizontal transmission via direct cell-to-cell contact, and (ii) vertical transmission through mitotic division of Tax-expressing HTLV-infected cells. The well-posedness of the model is established by showing that the solutions of the model are nonnegative and bounded. We define a set of threshold parameters which govern the existence and stability of all equilibria of the model. We explore the global asymptotic stability of all equilibria by utilizing Lyapunov function and LaSalle's invariance principle. We have presented numerical simulations to justify the applicability and effectiveness of the theoretical results. In addition, we evaluate the effect of HTLV-I infection on the HIV dynamics and vice versa. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
160. Predicting TCR-Epitope Binding Specificity Using Deep Metric Learning and Multimodal Learning.
- Author
-
Luu, Alan M., Leistico, Jacob R., Miller, Tim, Kim, Somang, and Song, Jun S.
- Subjects
- *
DEEP learning , *ARTIFICIAL neural networks , *CYTOTOXIC T cells , *CONVOLUTIONAL neural networks , *AMINO acid sequence - Abstract
Understanding the recognition of specific epitopes by cytotoxic T cells is a central problem in immunology. Although predicting binding between peptides and the class I Major Histocompatibility Complex (MHC) has had success, predicting interactions between T cell receptors (TCRs) and MHC class I-peptide complexes (pMHC) remains elusive. This paper utilizes a convolutional neural network model employing deep metric learning and multimodal learning to perform two critical tasks in TCR-epitope binding prediction: identifying the TCRs that bind a given epitope from a TCR repertoire, and identifying the binding epitope of a given TCR from a list of candidate epitopes. Our model can perform both tasks simultaneously and reveals that inconsistent preprocessing of TCR sequences can confound binding prediction. Applying a neural network interpretation method identifies key amino acid sequence patterns and positions within the TCR, important for binding specificity. Contrary to common assumption, known crystal structures of TCR-pMHC complexes show that the predicted salient amino acid positions are not necessarily the closest to the epitopes, implying that physical proximity may not be a good proxy for importance in determining TCR-epitope specificity. Our work thus provides an insight into the learned predictive features of TCR-epitope binding specificity and advances the associated classification tasks. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
161. In Situ Crosslinked Hydrogel Depot for Sustained Antibody Release Improves Immune Checkpoint Blockade Cancer Immunotherapy.
- Author
-
Kim, Jihoon, Francis, David M., Thomas, Susan N., and Blanco-Prieto, Maria J.
- Subjects
- *
CYTOTOXIC T cells , *PROGRAMMED cell death 1 receptors , *DRUG side effects , *TREATMENT effectiveness , *IMMUNOTHERAPY , *IMMUNOGLOBULINS , *CELLULAR immunity - Abstract
The therapeutic inhibition of immune checkpoints, including cytotoxic T lymphocyte-associated protein (CTLA)-4 and programmed cell death 1 (PD-1), through the use of function blocking antibodies can confer improved clinical outcomes by invigorating CD8+ T cell-mediated anticancer immunity. However, low rates of patient responses and the high rate of immune-related adverse events remain significant challenges to broadening the benefit of this therapeutic class, termed immune checkpoint blockade (ICB). To overcome these significant limitations, controlled delivery and release strategies offer unique advantages relevant to this therapeutic class, which is typically administered systemically (e.g., intravenously), but more recently, has been shown to be highly efficacious using locoregional routes of administration. As such, in this paper, we describe an in situ crosslinked hydrogel for the sustained release of antibodies blocking CTLA-4 and PD-1 signaling from a locoregional injection proximal to the tumor site. This formulation results in efficient and durable anticancer effects with a reduced systemic toxicity compared to the bolus delivery of free antibody using an equivalent injection route. This formulation and strategy thus represent an approach for achieving the efficient and safe delivery of antibodies for ICB cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
162. HTLV/HIV Dual Infection: Modeling and Analysis.
- Author
-
Elaiw, Ahmed M. and H. AlShamrani, Noura
- Subjects
- *
HIV infections , *HTLV-I , *HTLV , *RETROVIRUSES , *HIV , *CYTOTOXIC T cells , *GLOBAL asymptotic stability - Abstract
Human T-lymphotropic virus type I (HTLV-I) and human immunodeficiency virus (HIV) are two famous retroviruses that share similarities in their genomic organization, and differ in their life cycle as well. It is known that HTLV-I and HIV have in common a way of transmission via direct contact with certain body fluids related to infected patients. Thus, it is not surprising that a single-infected person with one of these viruses can be dually infected with the other virus. In the literature, many researchers have devoted significant efforts for modeling and analysis of HTLV or HIV single infection. However, the dynamics of HTLV/HIV dual infection has not been formulated. In the present paper, we formulate an HTLV/HIV dual infection model. The model includes the impact of the Cytotoxic T lymphocyte (CTLs) immune response, which is important to control the dual infection. The model describes the interaction between uninfected CD 4 + T cells, HIV-infected cells, HTLV-infected cells, free HIV particles, HIV-specific CTLs, and HTLV-specific CTLs. We establish that the solutions of the model are non-negative and bounded. We calculate all steady states of the model and deduce the threshold parameters which determine the existence and stability of the steady states. We prove the global asymptotic stability of all steady states by utilizing the Lyapunov function and Lyapunov–LaSalle asymptotic stability theorem. We solve the system numerically to illustrate the our main results. In addition, we compared between the dynamics of single and dual infections. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
163. What are the immune responses during the growth of Ehrlich's tumor in ascitic and solid form?
- Author
-
Feitosa, Ivan Brito, Mori, Bruno, Teles, Carolina Bioni Garcia, and Costa, Alysson Guimarães da
- Subjects
- *
IMMUNE response , *TUMOR growth , *ASCITIC fluids , *INTERLEUKIN-6 , *SCIENTIFIC literature , *CYTOTOXIC T cells - Abstract
Traditionally, Ehrlich's tumor is used in experimental oncology to investigate the therapeutic capacity of different synthetic chemotherapeutic agents or to evaluate the antitumoral activity of different substances of natural origin. However, the understanding of immune mechanisms during Ehrlich carcinogenesis is still limited. In this review, we seek to describe the immune response during Ehrlich's tumor growth, and natural response without the influence of pharmacological administration, immunotherapies or concomitant challenges. The study followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A systematic review was carried out that included experimental trials with mice challenged with Ehrlich's tumor. The research was carried out in three databases including MEDLINE/PubMed, Scopus, Latin American and Caribbean Literature in Health Sciences (LILACS). The searches resulted in 913 papers being found, of which 55 articles were considered eligible, and of these 55, 29 were selected for analysis. Findings indicate that there is an increase in the expression of M2 and T Helper (TH2) macrophages and of the cytokines IL-17, IL-1B, IL-6 and PGE in the ascitic form of Ehrlich. These phenotypic expressions are also found in ascitic neoplasms in humans. Ehrlich's solid tumor was characterized by increased expression of CD4, CD8, neutrophils and TNF-a, Foxp3 + and Qa-2 +, and these characteristics are analogous to human breasts cancers. It is our understanding that further studies are needed to assess the immune mechanisms in Ehrlich's tumor, since these findings can be used to improve cancer treatments that are analogous to Ehrlich's tumor. Unlabelled Image [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
164. Stability of a general adaptive immunity HIV infection model with silent infected cell-to-cell spread.
- Author
-
AlShamrani, N.H.
- Subjects
- *
CYTOTOXIC T cells , *HIV infections , *GLOBAL asymptotic stability , *T cells , *HIV infection transmission , *IMMUNITY , *DYNAMICAL systems - Abstract
This paper proposes and analyzes an adaptive immunity HIV infection model. The model describes the interaction between healthy CD 4 + T cells, silent (latent) infected cells, active infected cells, free HIV particles, Cytotoxic T lymphocytes (CTLs) and antibodies. The healthy CD 4 + T cells can be infected when they are contacted by one of the following: (i) free HIV particles, and this is known as virus-to-cell (VTC) transmission (ii) silent infected cells, and we call this mode of infection as silent HIV-infected cell-to-cell (CTC) transmission, and (iii) active infected cells, and we call this mechanism active HIV-infected CTC transmission. The incidence rates of the healthy CD 4 + T cells with free HIV particles, silent infected cells, and active infected cells are given by general functions. Moreover, the production/proliferation and removal/death rates of all compartments are represented by general functions. The model is an improvement of the existing HIV infection models which have neglected the incidence between the silent infected cells and healthy CD 4 + T cells. We first show that the model is well-posed. Then, we show that the model has five equilibria and their existence are governed by five threshold parameters. Under a set of conditions on the general functions and the threshold parameters, we have proven the global asymptotic stability of all equilibria by using Lyapunov's method. We have illustrated the theoretical results via numerical simulations. We have studied the effect of CTC transmission on the dynamical behavior of the system. We have shown that inclusion of CTC transmission decreases the concentration of the healthy CD4 + T cells and increases the concentrations of the infected cells and free HIV particles. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
165. Toxoplasma gondii ROP38 protein: Bioinformatics analysis for vaccine design improvement against toxoplasmosis.
- Author
-
Nosrati, MohammadReza Chaechi, Ghasemi, Ezatollah, Shams, Morteza, Shamsinia, Sadegh, Yousefi, Ali, Nourmohammadi, Hassan, Javanmardi, Erfan, Kordi, Bahareh, Majidiani, Hamidreza, Ghaffari, Ali Dalir, and Shakarami, Farzaneh
- Subjects
- *
TOXOPLASMA gondii , *PROTEIN analysis , *CYTOTOXIC T cells , *TOXOPLASMOSIS , *AMINO acid residues - Abstract
Rhoptry proteins (ROPs) play a significant role in various stages of Toxoplasma gondii (T. gondii) life cycle, being critical for both invasion and intracellular survival. ROP38 is a key manipulator of host gene expression and has a function in tachyzoite to bradyzoite conversion. In this study, we've employed various bioinformatics online tools for immunogenicity prediction of ROP38 protein, comprising physico-chemical, antigenic and allergenic profiles, transmembrane domain, subcellular localization, post-translational modification (PTM) sites, secondary and 3D structure, B-cell, MHC-binding and cytotoxic T-lymphocyte (CTL) epitopes. The findings showed 54 PTM sites without a transmembrane domain. Also, ROP38 was proved a non-allergenic and antigenic protein. The protein had Sec signal peptide (Sec/SPI) with 0.8762 likelihood. The secondary structure included 52.68% random coil, 29.57% alpha helix and 17.74% extended strand. Based on Ramachandran plot output for refined model, 95.3%, 3.4%, and 1.4% of amino acid residues were incorporated in the favored, allowed, and outlier regions, respectively. B-cell epitopes TFPGDDIQTSS (67–72) and KAKNKWGRTRYTLQG (207–221) as well as T-cell epitope LSPVGFFTAL (6–15) possessed the highest antigenic index in the protein sequence. This paper is a premise for further researches, and provides insights for the development of a suitable vaccine against toxoplasmosis. More empirical studies are required using the ROP38 alone or in combination with other antigens/epitopes in the future. Image 1 • This is the first in silico analysis of Toxoplasma gondii ROP38 protein. • Potential B-cell, CTL and MHC-binding epitopes were determined in this study. • Bioinformatics revealed several interesting aspects of the protein as a vaccine candidate. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
166. Study of dose-dependent combination immunotherapy using engineered T cells and IL-2 in cervical cancer.
- Author
-
Cho, Heyrim, Wang, Zuping, and Levy, Doron
- Subjects
- *
T cells , *CERVICAL cancer , *T cell receptors , *CYTOTOXIC T cells , *CELL populations , *CANCER cells - Abstract
• A mathematical model for combination therapy using engineered T cells and IL-2. • The results provide a TCR T cell dose window for a successful therapy. • Combination therapy does not always provide a better outcome. Adoptive T cell based immunotherapy is gaining significant traction in cancer treatment. Despite its limited efficacy so far in treating solid tumors compared to hematologic cancers, recent advances in T cell engineering render this treatment increasingly more successful in solid tumors, demonstrating its broader therapeutic potential. In this paper we develop a mathematical model to study the efficacy of engineered T cell receptor (TCR) T cell therapy targeting the E7 antigen in cervical cancer cell lines. We consider a dynamical system that follows the population of cancer cells, TCR T cells, and IL-2 treatment concentration. We demonstrate that there exists a TCR T cell dosage window for a successful cancer elimination that can be expressed in terms of the initial tumor size. We obtain the TCR T cell dose for two cervical cancer cell lines: 4050 and CaSki. Finally, a combination therapy of TCR T cell and IL-2 treatment is studied. We show that certain treatment protocols can improve therapy responses in the 4050 cell line, but not in the CaSki cell line. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
167. Anti-angiogenesis: Opening a new window for immunotherapy.
- Author
-
Guo, Feifei and Cui, Jiuwei
- Subjects
- *
IMMUNOTHERAPY , *TUMOR microenvironment , *CANCER treatment , *CANCER research , *CYTOTOXIC T cells - Abstract
The tumor microenvironment (TME) provides a guarantee for the survival and development of solid tumors. In recent years, treatment strategies for TME have set off a great upsurge in the field of cancer research. Tumor angiogenesis and tumor immune microenvironment are two important research branches of TME, and antiangiogenic therapy and immunotherapy have gradually become one important focus of cancer treatment research. More interestingly, increasing number of studies have indicated that there are complex regulatory interactions between the two treatment strategies, with multiple regulatory mechanisms involved. Based on these findings, clinical studies on the combination of immunotherapy and antiangiogenic therapy have also been carried out gradually. This combination strategy has shown good results in many types of tumors, but it also faces many challenges. The paper analysed the potential mechanism of the immunotherapy and antiangiogenic therapy combination, discussed the latest significant clinical trial progress and the existing challenges and problems, aiming to offer some available insights on the effective clinical application of this combination pattern. Unlabelled Image [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
168. CAR T cells for T-cell leukemias: Insights from mathematical models.
- Author
-
Pérez-García, Víctor M., León-Triana, Odelaisy, Rosa, María, and Pérez-Martínez, Antonio
- Subjects
- *
LEUKEMIA , *MATHEMATICAL models , *ANTIGEN receptors , *AUTOMOBILES , *TUMOR growth , *CYTOTOXIC T cells - Abstract
• A mathematical model of CAR-T cell treatment for T-cell leukaemias is developed. • CAR-T cell treatment can control, but not eradicate, T-cell leukaemias. • The model describes the dynamics observed in vitro. Immunotherapy has the potential to change the way all cancer types are treated and cured. Cancer immunotherapies use elements of the patient immune system to attack tumor cells. One of the most successful types of immunotherapy is CAR-T cells. This treatment works by extracting patient's T-cells and adding to them an antigen receptor allowing tumor cells to be recognized and targeted. These new cells are called CAR-T cells and are re-infused back into the patient after expansion in-vitro. This approach has been successfully used to treat B-cell malignancies (B-cell leukemias and lymphomas). However, its application to the treatment of T-cell leukemias faces several problems. One of these is fratricide, since the CAR-T cells target both tumor and other CAR-T cells. This leads to nonlinear dynamical phenomena amenable to mathematical modeling. In this paper we construct a mathematical model describing the competition of CAR-T, tumor and normal T-cells and studied some basic properties of the model and its practical implications. Specifically, we found that the model reproduced the observed difficulties for in-vitro expansion of the therapeutic cells found in the laboratory. The mathematical model predicted that CAR-T cell expansion in the patient would be possible due to the initial presence of a large number of targets. We also show that, in the context of our mathematical approach, CAR-T cells could control tumor growth but not eradicate the disease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
169. Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials.
- Author
-
Kooshkaki, Omid, Derakhshani, Afshin, Hosseinkhani, Negar, Torabi, Mitra, Safaei, Sahar, Brunetti, Oronzo, Racanelli, Vito, Silvestris, Nicola, and Baradaran, Behzad
- Subjects
- *
PROGRAMMED cell death 1 receptors , *IMMUNE checkpoint inhibitors , *CLINICAL trials , *TARGETED drug delivery , *PROGRAMMED death-ligand 1 , *CYTOTOXIC T cells , *CANCER , *T cells - Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells' responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
170. Early Epigenetic Immune Quantification Following Alpha/Beta T-Cell/CD19 B-Cell Depleted Haploidentical Stem Cell Transplant Correlates with CD4+ T Cell Recovery at Day +100.
- Author
-
Mavers, Melissa, Schulze, Janika, Barbarito, Giulia, Lakshmanan, Uma, Parkman, Robertson, Weinberg, Kenneth I., Chu, Julia, Agarwal, Rajni, Roncarolo, Maria Grazia, Sachsenmaier, Christoph, Bacchetta, Rosa, and Bertaina, Alice
- Subjects
- *
STEM cell transplantation , *T cells , *HEMATOPOIETIC stem cell transplantation , *CYTOTOXIC T cells , *EPIGENETICS , *LYMPHOCYTE count - Abstract
Patients who fail to adequately reconstitute the donor-derived immune system after allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for infections and leukemia relapse. In the past, pan T-cell depleted haploidentical grafts were associated with delayed immune reconstitution (IR). Recently, the majority of patients receiving αβ T-cell/B-cell depleted haploidentical HSCT (αβhaplo-HSCT) reach a threshold of 200 CD3+ T cells/mcl by 100 days after HSCT (Bertaina A et al. Blood 2014 Jul 31;124(5):822-6). However, a proportion of patients experience a slower IR with consequent higher morbidity and mortality. Early prediction of delayed IR may permit prompt clinical intervention such as infusion of donor lymphocytes or of virus-specific cytotoxic T cells. Flow cytometry, the most widely applied approach for IR analysis, suffers from intrinsic limitations, such as high lymphocyte number requirement, degradation of samples, and insufficient standardization due to technical and operator variability. To overcome these limitations, we used a DNA methylation-based quantitative PCR that detects the epigenetic signature of different peripheral blood immune cell subsets (epigenetic quantification). This technique provides relative and absolute immune cell counts applicable to fresh, frozen, or paper-spotted dried blood. Epigenetic measurements are based on a per cell DNA copy number and provide a clear positive or negative signal rather than arbitrarily defined thresholds for "positivity" as in flow cytometry. We hypothesize that epigenetic quantification at day 15 after αβhaplo-HSCT could predict flow-based IR at day 100. Patients were consented at Lucile Packard Children's Hospital (Stanford, CA). Blood was collected between days 10-17 for epigenetic quantification and days 82-124 for flow cytometry. Bisulfite treated DNA underwent qPCR quantification of cell type-specific DNA regions of de-methylation (Baron U et al. Sci Transl Med 2018 Aug 1;10(452):eaan3508). Flow cytometry was performed using directly conjugated antibodies. Absolute cell counts were determined, plotted, and then analyzed using a linear regression model. In the first 5 αβhaplo-HSCT patients evaluated, we found a direct correlation between the epigenetic quantification at day 15 and flow cytometry at day 100 for CD4+ T cells (P=0.01), while the early epigenetic quantification of CD3+ and CD8+ T cells was not informative (Fig. 1). Preliminary data suggest that the use of epigenetic quantification early after αβhaplo-HSCT can predict the IR of CD4+ T cells at day 100 in αβhaplo-HSCT recipients. Ongoing analysis on a larger cohort of both αβhaplo-HSCT and unmanipulated HSCT recipients, will confirm if epigenetic quantification results obtained early post-HSCT can be used as a clinical biomarker of delayed IR and guide physicians in the use of post-HSCT adoptive immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
171. DPP8 is a novel therapeutic target for multiple myeloma.
- Author
-
Sato, Tsutomu, Tatekoshi, Ayumi, Takada, Kohichi, Iyama, Satoshi, Kamihara, Yusuke, Jawaid, Paras, Rehman, Mati Ur, Noguchi, Kyo, Kondo, Takashi, Kajikawa, Sayaka, Arita, Kotaro, Wada, Akinori, Murakami, Jun, Arai, Miho, Yasuda, Ichiro, Dang, Nam H., Hatano, Ryo, Iwao, Noriaki, Ohnuma, Kei, and Morimoto, Chikao
- Subjects
- *
MYELOMA proteins , *PEPTIDASE , *PROTEOLYTIC enzymes , *CYTOTOXIC T cells , *CELL lines - Abstract
Dipeptidyl peptidases (DPPs) are proteolytic enzymes that are ideal therapeutic targets in human diseases. Indeed, DPP4 inhibitors are widely used in clinical practice as anti-diabetic agents. In this paper, we show that DPP4 inhibitors also induced cell death in multiple human myeloma cells. Among five DPP4 inhibitors, only two of them, vildagliptin and saxagliptin, exhibited apparent cytotoxic effects on myeloma cell lines, without any difference in suppression of DPP4 activity. As these two DPP4 inhibitors are known to have off-target effects against DPP8/9, we employed the specific DPP8/9 inhibitor 1G244. 1G244 demonstrated anti-myeloma effects on several cell lines and CD138+ cells from patients as well as in murine xenograft model. Through siRNA silencing approach, we further confirmed that DPP8 but not DPP9 is a key molecule in inducing cell death induced by DPP8/9 inhibition. In fact, the expression of DPP8 in CD38+ cells from myeloma patients was higher than that of healthy volunteers. DPP8/9 inhibition induced apoptosis, as evidenced by activated form of PARP, caspases-3 and was suppressed by the pan-caspase inhibitor Z-VAD-FMK. Taken together, these results indicate that DPP8 is a novel therapeutic target for myeloma treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
172. The Role of Nanovaccine in Cross-Presentation of Antigen-Presenting Cells for the Activation of CD8+ T Cell Responses.
- Author
-
Kim, Cheol Gyun, Kye, Yoon-Chul, and Yun, Cheol-Heui
- Subjects
- *
T cells , *ANTIGEN presenting cells , *MAJOR histocompatibility complex , *CYTOTOXIC T cells , *MEMBRANE fusion , *MATERIALS science - Abstract
Explosive growth in nanotechnology has merged with vaccine development in the battle against diseases caused by bacterial or viral infections and malignant tumors. Due to physicochemical characteristics including size, viscosity, density and electrostatic properties, nanomaterials have been applied to various vaccination strategies. Nanovaccines, as they are called, have been the subject of many studies, including review papers from a material science point of view, although a mode of action based on a biological and immunological understanding has yet to emerge. In this review, we discuss nanovaccines in terms of CD8+ T cell responses, which are essential for antiviral and anticancer therapies. We focus mainly on the role and mechanism, with particular attention to the functional aspects, of nanovaccines in inducing cross-presentation, an unconventional type of antigen-presentation that activates CD8+ T cells upon administration of exogenous antigens, in dendritic cells followed by activation of antigen-specific CD8+ T cell responses. Two major intracellular mechanisms that nanovaccines harness for cross-presentation are described; one is endosomal swelling and rupture, and the other is membrane fusion. Both processes eventually allow exogenous vaccine antigens to be exported from phagosomes to the cytosol followed by loading on major histocompatibility complex class I, triggering clonal expansion of CD8+ T cells. Advancement of nanotechnology with an enhanced understanding of how nanovaccines work will contribute to the design of more effective and safer nanovaccines. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
173. A fractional numerical study on a chronic hepatitis C virus infection model with immune response.
- Author
-
Saad, Khaled M., Gómez-Aguilar, J.F., and Almadiy, Abdulrhman A.
- Subjects
- *
CHRONIC hepatitis C , *HEPATITIS C virus , *VIRUS diseases , *CYTOTOXIC T cells , *IMMUNE response , *HEPATITIS B - Abstract
• We propose a new model of fractional-order for the hepatitis C virus (HCV) infection. • The results obtained in this paper are a kind of the power-law and the exponential-law kernel. • The numerical solutions based upon the fundamental theorem of fractional calculus as well as the Lagrange polynomial interpolation. • We investigate the effect of the variation of the fractional-order. • We obtain chaotic behaviors for (HCV) infection. Our main aim in this article is to introduce and investigate a new model of fractional-order model for hepatitis C virus (HCV) infection with immune response, in which the effect of dendritic cells (DC) and cytotoxic T lymphocytes (CTL) on HCV infection is considered. In the first stage, the HCV model was extended to Liouville-Caputo (LC) fractional derivative and Caputo-Fabrizio fractional derivative in the Caputo sense (CFC). In particular, we evaluate the approximate solutions of this model by means of the power law and the exponential law kernel. The approximate solutions are based upon the fundamental theorem of fractional calculus as well as the Lagrange polynomial interpolation. We study the effect of the variation the fractional-order on the behavior of the solutions due to the presence of definitions of new fractional-calculus operators. We observe that the chaotic behavior and illustrate the chaotic of a chronic HCV infection model with immune response by plotting the solutions in the plane. Finally, some numerical simulations using with the aid of Mathematica were done for different values of fractional order. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
174. Implicit Riesz wavelets based-method for solving singular fractional integro-differential equations with applications to hematopoietic stem cell modeling.
- Author
-
Mohammad, Mutaz and Trounev, Alexander
- Subjects
- *
INTEGRO-differential equations , *HEMATOPOIETIC stem cells , *CYTOTOXIC T cells , *NUMERICAL analysis , *FRACTIONAL differential equations - Abstract
Riesz wavelets in L 2 (R) have been proven as a useful tool in the context of both pure and numerical analysis in many applications, due to their well prevailing and recognized theory and its natural properties such as sparsity and stability which lead to a well-conditioned scheme. In this paper, an effective and accurate technique based on Riesz wavelets is presented for solving weakly singular type of fractional order integro-differential equations with applications to solve system of fractional order model that describe the dynamics of uninfected, infected and free virus carried out by cytotoxic T lymphocytes (CTL). The Riesz wavelet in this work is constructed via the smoothed pseudo-splines refinable functions. The advantage of using such wavelets, in the context of fractional and integro-differential equations, lies on the simple structure of the reduced systems and in the powerfulness of obtaining approximated solutions for such equations that have weakly singular kernels. The proposed method shows a good performance and high accuracy orders. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
175. Mathematical modelling of cancer stem cell-targeted immunotherapy.
- Author
-
Sigal, Daniel, Przedborski, Michelle, Sivaloganathan, Darshan, and Kohandel, Mohammad
- Subjects
- *
CANCER stem cells , *CYTOTOXIC T cells , *IMMUNOTHERAPY , *MATHEMATICAL models , *ORDINARY differential equations , *DENDRITIC cells , *TUMOR growth - Abstract
• Mathematical modelling of the interactions of cancer stem cells (CSCs), non-CSCs, cytotoxic T-cells (CTCs), and dendritic cells (DCs) to replicate the following experimental results: Grafting mice with CSCs produces more, and larger tumors than transfusing mice with nCSCs. Giving mice dendritic cell vaccines or CTC treatment prepared with CSCs is more effective than giving mice CTC treatment prepared with nCSCs. • Mathematical modelling of how chemotherapy and immunotherapy could work together to minimize tumor size and future tumor growth: Although chemotherapy is more effective at reducing current tumor burden, CSC-specific therapy reduces tumorogenicity, and decreases future tumor burden. The cancer stem cell hypothesis states that tumors are heterogeneous and comprised of several different cell types that have a range of reproductive potentials. Cancer stem cells (CSCs), represent one class of cells that has both reproductive potential and the ability to differentiate. These cells are thought to drive the progression of aggressive and recurring cancers since they give rise to all other constituent cells within a tumor. With the development of immunotherapy in the last decade, the specific targeting of CSCs has become feasible and presents a novel therapeutic approach. In this paper, we construct a mathematical model to study how specific components of the immune system, namely dendritic cells and cytotoxic T-cells interact with different cancer cell types (CSCs and non-CSCs). Using a system of ordinary differential equations, we model the effects of immunotherapy, specifically dendritic cell vaccines and T-cell adoptive therapy, on tumor growth, with and without chemotherapy. The model reproduces several results observed in the literature, including temporal measurements of tumor size from in vivo experiments, and it is used to predict the optimal treatment schedule when combining different treatment modalities. Importantly, the model also demonstrates that chemotherapy increases tumorigenicity whereas CSC-targeted immunotherapy decreases it. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
176. Autophagy represses hepatic carcinogenesis.
- Author
-
Paillet, Juliette and Kroemer, Guido
- Subjects
- *
LIVER cancer , *AUTOPHAGY , *LIVER cells , *FATTY liver , *CYTOTOXIC T cells , *IMMUNOSENESCENCE , *PHYSIOLOGICAL aspects of aging - Abstract
Hepatocyte-specific knockout of the essential autophagy gene Autophagy-related 7 (Atg7) is sufficient to cause hepatic carcinogenesis. A recent paper by Lee et al. unveils the molecular pathway accounting for hepatic hypertrophy and hyperplasia followed by malignant transformation. This pathway involves the overactivation of the transcription factor yes-associated protein (YAP), which turns out to be an autophagic substrate. Of note, the transcriptional signature activated in mouse hepatocytes lacking Atg7 resembles that found in non-alcoholic steatohepatitis (NASH), as well as in the steatohepatitic subtype of human hepatocellular carcinomas. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
177. The Evolving Role of CD8+CD28− Immunosenescent T Cells in Cancer Immunology.
- Author
-
Huff, Wei X., Kwon, Jae Hyun, Henriquez, Mario, Fetcko, Kaleigh, and Dey, Mahua
- Subjects
- *
TELOMERES , *T cells , *CYTOTOXIC T cells , *CANCER cells , *CELLULAR aging , *CYTOKINE receptors - Abstract
Functional, tumor-specific CD8+ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8+ effector T cell dysfunction. Among the many facets of CD8+ T cell dysfunction that have been recognized—tolerance, anergy, exhaustion, and senescence—CD8+ T cell senescence is incompletely understood. Naïve CD8+ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8+CD28− senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8+CD28− senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8+ T cells could improve the efficacy of future anti-tumor immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
178. Failure of immunosurveillance accelerates aging.
- Author
-
Perez-Lanzon, Maria, Zitvogel, Laurence, and Kroemer, Guido
- Subjects
- *
CYTOTOXIC T cells , *GENETIC code , *GENE knockout , *KILLER cells , *IMMUNE system - Abstract
Immunosurveillance is generally conceived as a mechanism through which the immune system detects and eliminates (pre-)malignant cells, thus reducing the risk of developing cancer. A recent paper by Ovadya et al. demonstrates that knockout of the gene coding for perforin-1 causes accelerated accumulation of senescent cells in multiple mouse organs, thereby speeding up the aging process. These results suggest that immunosurveillance plays a much broader role in maintaining organismal health than it had been suspected. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
179. Design considerations for early-phase clinical trials of immune-oncology agents.
- Author
-
Wages, Nolan A., Chiuzan, Cody, and Panageas, Katherine S.
- Subjects
- *
MONOCLONAL antibodies , *CHIMERIC antigen receptors , *IMMUNOTHERAPY , *CANCER treatment , *TUMORS , *CYTOTOXIC T cells , *DRUGS , *ONCOLOGY - Abstract
Background: With numerous and fast approvals of different agents including immune checkpoint inhibitors, monoclonal antibodies, or chimeric antigen receptor (CAR) T-cell therapy, immunotherapy is now an established form of cancer treatment. These agents have demonstrated impressive clinical activity across many tumor types, but also revealed different toxicity profiles and mechanisms of action. The classic assumptions imposed by cytotoxic agents may no longer be applicable, requiring new strategies for dose selection and trial design. Description: This main goal of this article is to summarize and highlight main challenges of early-phase study design of immunotherapies from a statistical perspective. We compared the underlying toxicity and efficacy assumptions of cytotoxic versus immune-oncology agents, proposed novel endpoints to be included in the dose-selection process, and reviewed design considerations to be considered for early-phase trials. When available, references to software and/or web-based applications were also provided to ease the implementation. Throughout the paper, concrete examples from completed (pembrolizumab, nivolumab) or ongoing trials were used to motivate the main ideas including recommendation of alternative designs. Conclusion: Further advances in the effectiveness of cancer immunotherapies will require new approaches that include redefining the optimal dose to be carried forward in later phases, incorporating additional endpoints in the dose selection process (PK, PD, immune-based biomarkers), developing personalized biomarker profiles, or testing drug combination therapies to improve efficacy and reduce toxicity. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
180. Cytotoxic T Lymphocytes and Vaccine Development.
- Author
-
Zhengguo Xiao, Klonowski, Kim, and Hanchun Yang
- Subjects
- *
CYTOTOXIC T cells , *LYMPHOCYTES , *VACCINE research , *AIDS vaccines , *SCIENCE publishing - Abstract
The authors reflect on the response their call for papers to be published in the January 1, 2012 issue. They note their satisfaction with the large number of submissions, the quick and accurate response of authors to all the reviews and editorial comments, and the broad area of cytotoxic T lymphocytes (CTL) research the manuscripts covered, including novel strategies for vaccination against chronic infections such as HIV.
- Published
- 2010
- Full Text
- View/download PDF
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.