scholarly journals Virus Induced Lymphocytes (VIL) as a novel viral antigen-specific T cell therapy for COVID-19 and potential future pandemics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rohan Sivapalan ◽  
Jinyan Liu ◽  
Krishnendu Chakraborty ◽  
Elisa Arthofer ◽  
Modassir Choudhry ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Therapy ◽  
Time Course ◽  
Mononuclear Cells ◽  
Adoptive Cell Therapy ◽  
Rapid Expansion ◽  
Effector Memory ◽  
Antigen Specificity ◽  
T Cell Therapy

AbstractThe a priori T cell repertoire and immune response against SARS-CoV-2 viral antigens may explain the varying clinical course and prognosis of patients having a mild COVID-19 infection as opposed to those developing more fulminant multisystem organ failure and associated mortality. Using a novel SARS-Cov-2-specific artificial antigen presenting cell (aAPC), coupled with a rapid expansion protocol (REP) as practiced in tumor infiltrating lymphocytes (TIL) therapy, we generate an immune catalytic quantity of Virus Induced Lymphocytes (VIL). Using T cell receptor (TCR)-specific aAPCs carrying co-stimulatory molecules and major histocompatibility complex (MHC) class-I immunodominant SARS-CoV-2 peptide-pentamer complexes, we expand virus-specific VIL derived from peripheral blood mononuclear cells (PBMC) of convalescent COVID-19 patients up to 1000-fold. This is achieved in a clinically relevant 7-day vein-to-vein time-course as a potential adoptive cell therapy (ACT) for COVID-19. We also evaluate this approach for other viral pathogens using Cytomegalovirus (CMV)-specific VIL from donors as a control. Rapidly expanded VIL are enriched in virus antigen-specificity and show an activated, polyfunctional cytokine profile and T effector memory phenotype which may contribute to a robust immune response. Virus-specific T cells can also be delivered allogeneically via MHC-typing and patient human leukocyte antigen (HLA)-matching to provide pragmatic treatment in a large-scale therapeutic setting. These data suggest that VIL may represent a novel therapeutic option that warrants further clinical investigation in the armamentarium against COVID-19 and other possible future pandemics.

scholarly journals A Novel Cell Therapy for COVID-19 and Potential Future Pandemics: Virus Induced Lymphocytes (VIL)

2020 ◽  
Author(s):  
Rohan Sivapalan ◽  
Jinyan Liu ◽  
Krishnendu Chakraborty ◽  
Elisa Arthofer ◽  
Modassir Choudhry ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Therapy ◽  
Time Course ◽  
Mononuclear Cells ◽  
Clinical Investigation ◽  
Adoptive Cell Therapy ◽  
Rapid Expansion ◽  
Effector Memory ◽  
Antigen Specificity

ABSTRACTThe a priori T cell repertoire and immune response against SARS-CoV-2 viral antigens may explain the varying clinical course and prognosis of patients having a mild COVID-19 infection as opposed to those developing more fulminant multisystem organ failure and associated mortality. Using a novel SARS-Cov-2-specific artificial antigen presenting cell (aAPC), coupled with a rapid expansion protocol (REP) as practiced in tumor infiltrating lymphocytes (TIL) therapy, we generate an immune catalytic quantity of Virus Induced Lymphocytes (VIL). Using T cell receptor (TCR)-specific aAPCs carrying co-stimulatory molecules and major histocompatibility complex (MHC) class-I immunodominant SARS-CoV-2 peptide-pentamer complexes, we expand virus-specific VIL derived from peripheral blood mononuclear cells (PBMC) of convalescent COVID-19 patients up to 1,000-fold. This is achieved in a clinically relevant 7-day vein-to-vein time-course as a potential adoptive cell therapy (ACT) for COVID-19. We also evaluate this approach for other viral pathogens using Cytomegalovirus (CMV)-specific VIL from donors as a control. Rapidly expanded VIL are enriched in virus antigen-specificity and show an activated, polyfunctional cytokine profile and T effector memory phenotype which may contribute to a robust immune response. Virus-specific T cells can also be delivered allogeneically via MHC-typing and patient human leukocyte antigen (HLA)-matching to provide pragmatic treatment in a large-scale therapeutic setting. These data suggest that VIL may represent a novel therapeutic option that warrants further clinical investigation in the armamentarium against COVID-19 and other possible future pandemics.

scholarly journals Off-the-Shelf Partial HLA Matching SARS-CoV-2 Antigen Specific T Cell Therapy: A New Possibility for COVID-19 Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Nayoun Kim ◽  
Jong-Min Lee ◽  
Eun-Jee Oh ◽  
Dong Wook Jekarl ◽  
Dong-Gun Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Third Party ◽  
Effector Memory ◽  
Antigen Specificity ◽  
Hla Matching ◽  
T Cell Therapy ◽  
Cell Immunity

BackgroundImmunological characteristics of COVID-19 show pathological hyperinflammation associated with lymphopenia and dysfunctional T cell responses. These features provide a rationale for restoring functional T cell immunity in COVID-19 patients by adoptive transfer of SARS-CoV-2 specific T cells.MethodsTo generate SARS-CoV-2 specific T cells, we isolated peripheral blood mononuclear cells from 7 COVID-19 recovered and 13 unexposed donors. Consequently, we stimulated cells with SARS-CoV-2 peptide mixtures covering spike, membrane and nucleocapsid proteins. Then, we culture expanded cells with IL-2 for 21 days. We assessed immunophenotypes, cytokine profiles, antigen specificity of the final cell products.ResultsOur results show that SARS-CoV-2 specific T cells could be expanded in both COVID-19 recovered and unexposed groups. Immunophenotypes were similar in both groups showing CD4+ T cell dominance, but CD8+ and CD3+CD56+ T cells were also present. Antigen specificity was determined by ELISPOT, intracellular cytokine assay, and cytotoxicity assays. One out of 14 individuals who were previously unexposed to SARS-CoV-2 failed to show antigen specificity. Moreover, ex-vivo expanded SARS-CoV-2 specific T cells mainly consisted of central and effector memory subsets with reduced alloreactivity against HLA-unmatched cells suggesting the possibility for the development of third-party partial HLA-matching products.DiscussionIn conclusion, our findings show that SARS-CoV-2 specific T cell can be readily expanded from both COVID-19 and unexposed individuals and can therefore be manufactured as a biopharmaceutical product to treat severe COVID-19 patients.One Sentence SummaryEx-vivo expanded SARS-CoV-2 antigen specific T cells developed as third-party partial HLA-matching products may be a promising approach for treating severe COVID-19 patients that do not respond to previous treatment options.

An Update on Adoptive T-Cell Therapy and Neoantigen Vaccines

2019 ◽  
pp. e70-e78 ◽  
Author(s):  
Patrick A. Ott ◽  
Gianpietro Dotti ◽  
Cassian Yee ◽  
Stephanie L. Goff
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Adoptive T Cell Therapy ◽  
Clinical Activity ◽  
Single Chain ◽  
T Cell Therapy ◽  
Substantial Impact ◽  
Mhc Molecules

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has demonstrated long-lasting antitumor activity in select patients with advanced melanoma. Cancer vaccines have been used for many decades and have shown some promise but overall relatively modest clinical activity across cancers. Technological advances in genome sequencing capabilities and T-cell engineering have had substantial impact on both adoptive cell therapy and the cancer vaccine field. The ability to identify neoantigens—a class of tumor antigens that is truly tumor specific and encoded by tumor mutations through rapid and relatively inexpensive next-generation sequencing—has already demonstrated the critical importance of these antigens as targets of antitumor-specific T-cell responses in the context of immune checkpoint blockade and other immunotherapies. Therapeutically targeting these antigens with either adoptive T-cell therapy or vaccine approaches has demonstrated early promise in the clinic in patients with advanced solid tumors. Chimeric antigen receptor (CAR) T cells, which are engineered by fusing an antigen-specific, single-chain antibody (scFv) with signaling molecules of the T-cell receptor (TCR)/CD3 complex creating an antibody-like structure on T cells that recognizes antigens independently of major histocompatibility complex (MHC) molecules, have demonstrated remarkable clinical activity in patients with advanced B-cell malignancies, leading to several approvals by the U.S. Food and Drug Administration (FDA).

Selecting T-Cell Subsets for Adoptive T-Cell Therapy to Optimize Potency and Persistence

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-39-SCI-39 ◽  
Author(s):  
Stanley Riddell ◽  
Cameron Turtle ◽  
Michael Hudecek ◽  
Daniel Sommermeyer ◽  
Michael C. Jensen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Transfer ◽  
Cell Therapy ◽  
Mononuclear Cells ◽  
Clinical Care ◽  
Lymphocytic Leukemia ◽  
Adoptive T Cell Therapy ◽  
T Cell Subsets ◽  
T Cell Therapy

Abstract Adoptive T-cell therapy with tumor-reactive T cells is emerging as a highly effective strategy for eliminating even the most advanced chemotherapy refractory malignancies. Endogenous T cells specific for tumor-associated antigens can sometimes be isolated and expanded from the patient’s blood or tumor infiltrate, or more expeditiously can be engineered by gene transfer to express a T-cell receptor specific for a tumor associated MHC/peptide complex or a synthetic chimeric antigen receptor (CAR) specific for a tumor associated cell surface molecule. The remarkable regression of advanced acute lymphocytic leukemia and lymphoma in patients treated with T cells engineered to express CD19-specific CARs illustrates the potential for this approach to transform clinical care. Therapeutic activity is variable in individual patients, however, and this appears to correlate with the ability of transferred, tumor-reactive T cells to persist and proliferate in vivo, and to retain effector function. These attributes may reflect both the qualities of the T cells that are isolated or engineered for therapy, and the local tumor microenvironment that may contain regulatory T cells; cells that express ligands that engage inhibitor receptors on effector T cells or cytokines that inhibit effector T-cell proliferation. The CD4+ and CD8+ T cell pools in normal individuals contain a variety of naïve, memory, and regulatory T-cell subsets that differ in epigenetic, transcriptional, and functional properties. Because most clinical protocols have used polyclonal peripheral blood mononuclear cells as recipients for CAR gene transfer, the composition of T-cell products that are being administered is highly variable, particularly when the T cells are obtained from cancer patients that have received prior cytotoxic chemotherapy that can skew the phenotypic composition of the peripheral T-cell pool. As a consequence, transferring tumor-targeting receptors into polyclonal unselected cell populations provides poor control over the cellular composition of the final T-cell product, which may in part explain the marked differences in efficacy and toxicity that have been observed in the clinic, and may complicate regulatory approval of these novel therapies. Methods to derive T cells from distinct naïve and memory T-cell subsets have been developed, enabling the rapid production of therapeutic T cells of uniform composition. The results of preclinical studies that illustrate the improved potency of defined T-cell products that are engineered with tumor-specific CARs, and the clinical implementation of this approach in B-cell malignancies will be presented. Disclosures: Riddell: Cell Medica: Consultancy, Membership on an entity’s Board of Directors or advisory committees; ZetaRx: Consultancy.

scholarly journals Immune Escape Mechanisms and Future Prospects for Immunotherapy in Neuroblastoma

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Thitinee Vanichapol ◽  
Somchai Chutipongtanate ◽  
Usanarat Anurathapan ◽  
Suradej Hongeng
Keyword(s):  
Immune System ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Function ◽  
Immune Cell ◽  
Immune Escape ◽  
Adoptive Cell Therapy ◽  
Immune Recognition ◽  
T Cell Therapy ◽  
Cell Therapies

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood with 5-year survival rate of 40% in high-risk patients despite intensive therapies. Recently, adoptive cell therapy, particularly chimeric antigen receptor (CAR) T cell therapy, represents a revolutionary treatment for hematological malignancies. However, there are challenges for this therapeutic strategy with solid tumors, as a result of the immunosuppressive nature of the tumor microenvironment (TME). Cancer cells have evolved multiple mechanisms to escape immune recognition or to modulate immune cell function. Several subtypes of immune cells that infiltrate tumors can foster tumor development, harbor immunosuppressive activity, and decrease an efficacy of adoptive cell therapies. Therefore, an understanding of the dual role of the immune system under the influences of the TME has been crucial for the development of effective therapeutic strategies against solid cancers. This review aims to depict key immune players and cellular pathways involved in the dynamic interplay between the TME and the immune system and also to address challenges and prospective development of adoptive T cell transfer for neuroblastoma.

IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors

Blood ◽  
2013 ◽  
Vol 121 (4) ◽  
pp. 573-584 ◽  
Author(s):  
Nicoletta Cieri ◽  
Barbara Camisa ◽  
Fabienne Cocchiarella ◽  
Mattia Forcato ◽  
Giacomo Oliveira ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Cell Subset ◽  
Gene Expression Signature ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
T Cell Subset

Abstract Long-living memory stem T cells (TSCM) with the ability to self-renew and the plasticity to differentiate into potent effectors could be valuable weapons in adoptive T-cell therapy against cancer. Nonetheless, procedures to specifically target this T-cell population remain elusive. Here, we show that it is possible to differentiate in vitro, expand, and gene modify in clinically compliant conditions CD8+ TSCM lymphocytes starting from naive precursors. Requirements for the generation of this T-cell subset, described as CD62L+CCR7+CD45RA+CD45R0+IL-7Rα+CD95+, are CD3/CD28 engagement and culture with IL-7 and IL-15. Accordingly, TSCM accumulates early after hematopoietic stem cell transplantation. The gene expression signature and functional phenotype define this population as a distinct memory T-lymphocyte subset, intermediate between naive and central memory cells. When transplanted in immunodeficient mice, gene-modified naive-derived TSCM prove superior to other memory lymphocytes for the ability to expand and differentiate into effectors able to mediate a potent xenogeneic GVHD. Furthermore, gene-modified TSCM are the only T-cell subset able to expand and mediate GVHD on serial transplantation, suggesting self-renewal capacity in a clinically relevant setting. These findings provide novel insights into the origin and requirements for TSCM generation and pave the way for their clinical rapid exploitation in adoptive cell therapy.

scholarly journals Chimeric Antigen Receptor-T Cells: A Pharmaceutical Scope

2021 ◽  
Vol 12 ◽  
Author(s):  
Alejandrina Hernández-López ◽  
Mario A. Téllez-González ◽  
Paul Mondragón-Terán ◽  
Angélica Meneses-Acosta
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Genetically Engineered ◽  
First Line ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Advanced Therapy ◽  
Car T

Cancer is among the leading causes of death worldwide. Therefore, improving cancer therapeutic strategies using novel alternatives is a top priority on the contemporary scientific agenda. An example of such strategies is immunotherapy, which is based on teaching the immune system to recognize, attack, and kill malignant cancer cells. Several types of immunotherapies are currently used to treat cancer, including adoptive cell therapy (ACT). Chimeric Antigen Receptors therapy (CAR therapy) is a kind of ATC where autologous T cells are genetically engineered to express CARs (CAR-T cells) to specifically kill the tumor cells. CAR-T cell therapy is an opportunity to treat patients that have not responded to other first-line cancer treatments. Nowadays, this type of therapy still has many challenges to overcome to be considered as a first-line clinical treatment. This emerging technology is still classified as an advanced therapy from the pharmaceutical point of view, hence, for it to be applied it must firstly meet certain requirements demanded by the authority. For this reason, the aim of this review is to present a global vision of different immunotherapies and focus on CAR-T cell technology analyzing its elements, its history, and its challenges. Furthermore, analyzing the opportunity areas for CAR-T technology to become an affordable treatment modality taking the basic, clinical, and practical aspects into consideration.

scholarly journals Human cord blood‐derived regulatory T ‐cell therapy modulates the central and peripheral immune response after traumatic brain injury

2020 ◽  
Vol 9 (8) ◽  
pp. 903-916 ◽  
Author(s):  
Henry W. Caplan ◽  
Karthik S. Prabhakara ◽  
Akshita Kumar ◽  
Naama E. Toledano‐Furman ◽  
Cecilia Martin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Immune Response ◽  
Brain Injury ◽  
T Cell ◽  
Cell Therapy ◽  
Cord Blood ◽  
Regulatory T Cell ◽  
Human Cord Blood ◽  
T Cell Therapy ◽  
Peripheral Immune Response

TCR-engineered T-cell therapy through personalized identification of CDR3 clonotypes.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15021-e15021
Author(s):  
Zishan Zhou ◽  
Yue Pu ◽  
Shanshan Xiao ◽  
Ping Wang ◽  
Yang Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Single Cell ◽  
Adoptive Cell Therapy ◽  
Cell Receptor ◽  
Illumina Hiseq ◽  
T Cell Therapy ◽  
Engineered T Cells

e15021 Background: T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancers. Unlike many shared tumor-specific antigens, such as melanoma-associated antigen (MAGE)-A3, MAGE-A4, and New York esophageal squamous cell carcinoma (NY-ESO)-1, neoantigen has garnered much attention as a potential precision immunotherapy. Personalized neoantigen selection serves a broader and more precision future for cancer patients. Methods: Dendritic cells (DCs) derived from adherent monocytes were pulsed with mixed peptides during the maturation phase. CD8+ cells positively selected from PBMCs were incubated with washed DCs. After 21day culture in X-VIVO medium with IL-7 and IL-15, cells were harvested and stimulated with peptides for 6 h. CD137+ cells were sorted by flow cytometric and immediately processed using the 10x Genomic Chromium Single Cell 5' Library & Gel Bead Kit and Chromium Single Cell V(D)J Enrichment Kit. The T-cell TCR libraries were constructed and sequenced on the Illumina HiSeq X Ten platform. The sequencing reads were aligned to the hg38 human reference genome and analyzed using the 10x Genomics Cell Ranger pipeline. The paired TCR α and β chain sequence of each cell was demonstrated with V(D)J analysis. TCR-T cells were constructed using the information of neoantigen specific TCR, and infused to patients. Results: Two patients were treated with the personalized TCR-T treatment. At the first stage, specialized immune cells were harvested and proceeded to single-cell TCR profiling. Then, the single cell sequencing of the first patient's sample revealed the top five neoantigen specific TCR CDR3 clonotypes with the proportion of 25%, 7.67%, 4.81%, 2.79%, and 2.54%, respectively. Similarly, the other patient had the top five TCR CDR3 sequenced with the proportion of 13.38%, 7.04%, 4.21%, 2.83%, and 1.94%, respectively. The results demonstrated that both patients had one or two dominant CDR3 clonotypes, which might reflect the strength of neoantigen in vivo. At the third stage, TCR-T cells were constructed, and infused to the patients. The clinical outcome will be evaluated in the near future. Conclusions: We have generated a pipeline for a highly personalized cancer therapy using TCR-engineered T cells. Although some questions remain to be answered, this novel approach may result in better clinical responses in future treatment.

Sign in / Sign up

Export Citation Format

Share Document