scholarly journals IRIS: Big data-informed discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing

2019 ◽  
Author(s):  
Yang Pan ◽  
Alexander H. Lee ◽  
Harry T. Yang ◽  
Yuanyuan Wang ◽  
Yang Xu ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Large Scale ◽  
Tumor Antigens ◽  
Cell Receptor ◽  
Car T ◽  
Transcriptomics Data ◽  
Computational Platform ◽  
Data Informed

AbstractAberrant alternative splicing (AS) is widespread in cancer, leading to an extensive but largely unexploited repertoire of potential immunotherapy targets. Here we describe IRIS, a computational platform leveraging large-scale cancer and normal transcriptomics data to discover AS-derived tumor antigens for T-cell receptor (TCR) and chimeric antigen receptor T-cell (CAR-T) therapies. Applying IRIS to RNA-Seq data from 22 glioblastomas resected from patients, we identified candidate epitopes and validated their recognition by patient T cells, demonstrating IRIS’s utility for expanding targeted cancer immunotherapy.

scholarly journals CRISPR/Cas9 revitalizes adoptive T-cell therapy for cancer immunotherapy

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Sasan Ghaffari ◽  
Nastaran Khalili ◽  
Nima Rezaei
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Cell Receptor ◽  
Adoptive T Cell Therapy ◽  
Therapeutic Modality ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

AbstractCancer immunotherapy has gained attention as the supreme therapeutic modality for the treatment of various malignancies. Adoptive T-cell therapy (ACT) is one of the most distinctive modalities of this therapeutic approach, which seeks to harness the potential of combating cancer cells by using autologous or allogenic tumor-specific T-cells. However, a plethora of circumstances must be optimized to produce functional, durable, and efficient T-cells. Recently, the potential of ACT has been further realized by the introduction of novel gene-editing platforms such as the CRISPR/Cas9 system; this technique has been utilized to create T-cells furnished with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR) that have precise tumor antigen recognition, minimal side effects and treatment-related toxicities, robust proliferation and cytotoxicity, and nominal exhaustion. Here, we aim to review and categorize the recent breakthroughs of genetically modified TCR/CAR T-cells through CRISPR/Cas9 technology and address the pearls and pitfalls of each method. In addition, we investigate the latest ongoing clinical trials that are applying CRISPR-associated TCR/CAR T-cells for the treatment of cancers.

scholarly journals Bi- and Tri-Specific T Cell Engager-Armed Oncolytic Viruses: Next-Generation Cancer Immunotherapy

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 204 ◽  
Author(s):  
Zong Sheng Guo ◽  
Michael T. Lotze ◽  
Zhi Zhu ◽  
Walter J. Storkus ◽  
Xiao-Tong Song
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
T Cell Receptor ◽  
Tumor Antigens ◽  
Cell Receptor ◽  
Oncolytic Viruses ◽  
Current Status ◽  
Great Promise ◽  
Specific Antibodies ◽  
Anti Cancer

Oncolytic viruses (OVs) are potent anti-cancer biologics with a bright future, having substantial evidence of efficacy in patients with cancer. Bi- and tri-specific antibodies targeting tumor antigens and capable of activating T cell receptor signaling have also shown great promise in cancer immunotherapy. In a cutting-edge strategy, investigators have incorporated the two independent anti-cancer modalities, transforming them into bi- or tri-specific T cell engager (BiTE or TriTE)-armed OVs for targeted immunotherapy. Since 2014, multiple research teams have studied this combinatorial strategy, and it showed substantial efficacy in various tumor models. Here, we first provide a brief overview of the current status of oncolytic virotherapy and the use of multi-specific antibodies for cancer immunotherapy. We then summarize progress on BiTE and TriTE antibodies as a novel class of cancer therapeutics in preclinical and clinical studies, followed by a discussion of BiTE- or TriTE-armed OVs for cancer therapy in translational models. In addition, T cell receptor mimics (TCRm) have been developed into BiTEs and are expected to greatly expand the application of BiTEs and BiTE-armed OVs for the effective targeting of intracellular tumor antigens. Future applications of such innovative combination strategies are emerging as precision cancer immunotherapies.

scholarly journals CAR T Cells: Precision Cancer Immunotherapy

2018 ◽  
Vol 10 (3) ◽  
pp. 203-16
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Adoptive Cell Therapy ◽  
Cell Receptor ◽  
Car T Cells ◽  
Car T

BACKGROUND: Current cancer drugs and treatments are aiming at eradicating tumor cells, but often are more toxic then effective, killing also the normal cells and not selectively the tumor cells. There is good personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity, which called adoptive cell therapy (ACT). A review of the unique biology of T cell therapy and of recent clinical experience compels a reassessment of target antigens that traditionally have been viewed from the perspective of weaker immunotherapeutic modalities.CONTENT: Chimeric antigen receptors (CAR) are recombinant receptors which provide both antigen-binding and T cell-activating functions. Many kind of CARs has been reported for the past few years, targeting an array of cell surface tumor antigens. Their biologic functions have extremely changed following the introduction of tripartite receptors comprising a costimulatory domain, termed second-generation CARs. The combination of CARs with costimulatory ligands, chimeric costimulatory receptors, or cytokines can be done to further enhance T cell potency, specificity and safety. CARs reflects a new class of drugs with exciting potential for cancer immunotherapy.SUMMARY: CAR-T cells have been arising as a new modality for cancer immunotherapy because of their potent efficacy against terminal cancers. They are known to exert higher efficacy than monoclonal antibodies and antibodydrug conjugates, and act via mechanisms distinct from T cell receptor-engineered T cells. These cells are constructed by transducing genes encoding fusion proteins of cancer antigen-recognizing single-chain Fv linked to intracellular signaling domains of T cell receptors.KEYWORDS: chimeric antigen receptor, CAR T cells, adoptive cell therapy, ACT, T cell receptor, TCR, cancer, immunotherapy

scholarly journals MR1-restricted T cells: the new dawn of cancer immunotherapy

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Zhiding Wang ◽  
Mengzhen Wang ◽  
Jinghong Chen ◽  
Linlin Zhang ◽  
Li Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Rapid Development ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Host Cells ◽  
Additional Information ◽  
Car T Cells ◽  
Car T

Abstract Cancer immunotherapy has recently undergone rapid development into a validated therapy for clinical use. The adoptive transfer of engineered autologous T cells, such as chimeric antigen receptor (CAR) T cells, has been remarkably successful in patients with leukemia and lymphoma with cluster of differentiation (CD)19 expression. Because of the higher number of antigen choices and reduced incidence of cytokine release syndrome (CRS) than CAR-T cells, T cell receptor (TCR)-T cells are also considered a promising immunotherapy. More therapeutic targets for other cancers need to be explored due to the human leukocyte antigen (HLA)-restricted recognition of TCR-T. Major histocompatibility complex (MHC), class I-related (MR1)-restricted T cells can recognize metabolites presented by MR1 in the context of host cells infected with pathogens. MR1 is expressed by all types of human cells. Recent studies have shown that one clone of a MR1-restricted T (MR1-T) cell can recognize many types of cancer cells without HLA-restriction. These studies provide additional information on MR1-T cells for cancer immunotherapy. This review describes the complexity of MR1-T cell TCR in diseases and the future of cancer immunotherapy.

scholarly journals GIANA allows computationally-efficient TCR clustering and multi-disease repertoire classification by isometric transformation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hongyi Zhang ◽  
Xiaowei Zhan ◽  
Bo Li
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Large Scale ◽  
Cell Receptor ◽  
Alignment Algorithm ◽  
Computationally Efficient ◽  
Antigen Specificity ◽  
Non Invasive ◽  
Isometric Transformation ◽  
Specific Receptors

AbstractSimilarity in T-cell receptor (TCR) sequences implies shared antigen specificity between receptors, and could be used to discover novel therapeutic targets. However, existing methods that cluster T-cell receptor sequences by similarity are computationally inefficient, making them impractical to use on the ever-expanding datasets of the immune repertoire. Here, we developed GIANA (Geometric Isometry-based TCR AligNment Algorithm) a computationally efficient tool for this task that provides the same level of clustering specificity as TCRdist at 600 times its speed, and without sacrificing accuracy. GIANA also allows the rapid query of large reference cohorts within minutes. Using GIANA to cluster large-scale TCR datasets provides candidate disease-specific receptors, and provides a new solution to repertoire classification. Querying unseen TCR-seq samples against an existing reference differentiates samples from patients across various cohorts associated with cancer, infectious and autoimmune disease. Our results demonstrate how GIANA could be used as the basis for a TCR-based non-invasive multi-disease diagnostic platform.

scholarly journals Targeting CAR to the Peptide-MHC Complex Reveals Distinct Signaling Compared to That of TCR in a Jurkat T Cell Model

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 867
Author(s):  
Ling Wu ◽  
Joanna Brzostek ◽  
Shvetha Sankaran ◽  
Qianru Wei ◽  
Jiawei Yap ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Model ◽  
Cell Receptor ◽  
Target Cells ◽  
Tcr Signaling ◽  
Barr Virus ◽  
Car T ◽  
Epstein Barr ◽  
Lower Magnitude

Chimeric antigen receptor T cells (CAR-T) utilize T cell receptor (TCR) signaling cascades and the recognition functions of antibodies. This allows T cells, normally restricted by the major histocompatibility complex (MHC), to be redirected to target cells by their surface antigens, such as tumor associated antigens (TAAs). CAR-T technology has achieved significant successes in treatment of certain cancers, primarily liquid cancers. Nonetheless, many challenges hinder development of this therapy, such as cytokine release syndrome (CRS) and the efficacy of CAR-T treatments for solid tumors. These challenges show our inadequate understanding of this technology, particularly regarding CAR signaling, which has been less studied. To dissect CAR signaling, we designed a CAR that targets an epitope from latent membrane protein 2 A (LMP2 A) of the Epstein–Barr virus (EBV) presented on HLA*A02:01. Because of this, CAR and TCR signaling can be compared directly, allowing us to study the involvement of other signaling molecules, such as coreceptors. This comparison revealed that CAR was sufficient to bind monomeric antigens due to its high affinity but required oligomeric antigens for its activation. CAR sustained the transduced signal significantly longer, but at a lower magnitude, than did TCR. CD8 coreceptor was recruited to the CAR synapse but played a negligible role in signaling, unlike for TCR signaling. The distinct CAR signaling processes could provide explanations for clinical behavior of CAR-T therapy and suggest ways to improve the technology.

scholarly journals Large-scale proteomic analysis of tyrosine-phosphorylation induced by T-cell receptor or B-cell receptor activation reveals new signaling pathways

PROTEOMICS ◽  
2009 ◽  
Vol 9 (13) ◽  
pp. 3549-3563 ◽  
Author(s):  
Masaki Matsumoto ◽  
Koji Oyamada ◽  
Hidehisa Takahashi ◽  
Takamichi Sato ◽  
Shigetsugu Hatakeyama ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Signaling Pathways ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
Proteomic Analysis ◽  
Large Scale ◽  
Cell Receptor ◽  
Receptor Activation ◽  
B Cell Receptor

scholarly journals Cancer Immunotherapy: A Review

2016 ◽  
Vol 8 (1) ◽  
pp. 1 ◽  
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Tumor Antigens ◽  
Cytotoxic T Lymphocyte ◽  
Immune Surveillance ◽  
Cancer Therapeutics ◽  
Adoptive Cell Transfer ◽  
Cell Transfer ◽  
Genetically Engineer

BACKGROUND: The goals of treating patients with cancer are to cure the disease, prolong survival, and improve quality of life. Immune cells in the tumor microenvironment have an important role in regulating tumor progression. Therefore, stimulating immune reactions to tumors can be an attractive therapeutic and prevention strategy.CONTENT: During immune surveillance, the host provides defense against foreign antigens, while ensuring it limits activation against self antigens. By targeting surface antigens expressed on tumor cells, monoclonal antibodies have demonstrated efficacy as cancer therapeutics. Recent successful antibody-based strategies have focused on enhancing antitumor immune responses by targeting immune cells, irrespective of tumor antigens. The use of antibodies to block pathways inhibiting the endogenous immune response to cancer, known as checkpoint blockade therapy, has stirred up a great deal of excitement among scientists, physicians, and patients alike. Clinical trials evaluating the safety and efficacy of antibodies that block the T cell inhibitory molecules cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) have reported success in treating subsets of patients. Adoptive cell transfer (ACT) is a highly personalized cancer therapy that involve administration to the cancer-bearing host of immune cells with direct anticancer activity. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment.SUMMARY: For cancer treatment, 2011 marked the beginning of a new era. The underlying basis of cancer immunotherapy is to activate a patient’s own T cells so that they can kill their tumors. Reports of amazing recoveries abound, where patients remain cancer-free many years after receiving the therapy. The idea of harnessing immune cells to fight cancer is not new, but only recently have scientists amassed enough clinical data to demonstrate what a game-changer cancer immunotherapy can be. This field is no stranger to obstacles, so the future looks very promising indeed.KEYWORDS: immune checkpoint, adoptive cell transfer, neoantigen, monoclonal antibody

scholarly journals Antigen Selection for Enhanced Affinity T-Cell Receptor–Based Cancer Therapies

2016 ◽  
Vol 21 (8) ◽  
pp. 769-785 ◽  
Author(s):  
Emma S. Hickman ◽  
Martine E. Lomax ◽  
Bent K. Jakobsen
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
De Novo ◽  
Cell Receptor ◽  
T Cell Response ◽  
Adoptive Cell Transfer ◽  
Cytotoxic T Cell ◽  
Discovery Process ◽  
Cancer Antigens ◽  
The Impact

Evidence of adaptive immune responses in the prevention of cancer has been accumulating for decades. Spontaneous T-cell responses occur in multiple indications, bringing the study of de novo expressed cancer antigens to the fore and highlighting their potential as targets for cancer immunotherapy. Circumventing the immune-suppressive mechanisms that maintain tumor tolerance and driving an antitumor cytotoxic T-cell response in cancer patients may eradicate the tumor or block disease progression. Multiple strategies are being pursued to harness the cytotoxic potential of T cells clinically. Highly promising results are now emerging. The focus of this review is the target discovery process for cancer immune therapeutics based on affinity-matured T-cell receptors (TCRs). Target cancer antigens in the context of adoptive cell transfer technologies and soluble biologic agents are discussed. To appreciate the impact of TCR-based technology and understand the TCR discovery process, it is necessary to understand key differences between TCR-based therapy and other immunotherapy approaches. The review first summarizes key advances in the cancer immunotherapy field and then discusses the opportunities that TCR technology provides. The nature and breadth of molecular targets that are tractable to this approach are discussed, together with the challenges associated with finding them.

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