scholarly journals Harnessing the Effect of Adoptively Transferred Tumor-Reactive T Cells on Endogenous (Host-Derived) Antitumor Immunity

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Yolanda Nesbeth ◽  
Jose R. Conejo-Garcia
Keyword(s):  
T Cells ◽  
Antitumor Immunity ◽  
Ex Vivo ◽  
Adoptive T Cell Transfer ◽  
Epithelial Cancers ◽  
Expansion Procedure ◽  
Different Types ◽  
T Cell Transfer ◽  
Subsequent Administration

Adoptive T cell transfer therapy, the ex vivo activation, expansion, and subsequent administration of tumor-reactive T cells, is already the most effective therapy against certain types of cancer. However, recent evidence in animal models and clinical trials suggests that host conditioning interventions tailored for some of the most aggressive and frequent epithelial cancers will be needed to maximize the benefit of this approach. Similarly, the subsets, stage of differentiation, andex vivoexpansion procedure of tumor-reactive T cells to be adoptively transferred influence theirin vivoeffectiveness and may need to be adapted for different types of cancer and host conditioning interventions. The effects of adoptively transferred tumor-reactive T cells on the mechanisms of endogenous (host-derived) antitumor immunity, and how to maximize their combined effects, are further discussed.

scholarly journals A Correlation Between Differentiation Phenotypes of Infused T Cells and Anti-Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Hao Ren ◽  
Kunkun Cao ◽  
Mingjun Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Immunity ◽  
Ex Vivo ◽  
T Cell Therapy ◽  
Production Methods ◽  
Anti Cancer ◽  
Status Differentiation ◽  
Differentiation Status

T-cell therapy, usually with ex-vivo expansion, is very promising to treat cancer. Differentiation status of infused T cells is a crucial parameter for their persistence and antitumor immunity. Key phenotypic molecules are effective and efficient to analyze differentiation status. Differentiation status is crucial for T cell exhaustion, in-vivo lifespan, antitumor immunity, and even antitumor pharmacological interventions. Strategies including cytokines, Akt, Wnt and Notch signaling, epigenetics, and metabolites have been developed to produce less differentiated T cells. Clinical trials have shown better clinical outcomes from infusion of T cells with less differentiated phenotypes. CD27+, CCR7+ and CD62L+ have been the most clinically relevant phenotypic molecules, while Tscm and Tcm the most clinically relevant subtypes. Currently, CD27+, CD62L+ and CCR7+ are recommended in the differentiation phenotype to evaluate strategies of enhancing stemness. Future studies may discover highly clinically relevant differentiation phenotypes for specific T-cell production methods or specific subtypes of cancer patients, with the advantages of precision medicine.

scholarly journals IMMU-25. MAGNETIC PARTICLE IMAGING FOR NON-INVASIVE TRACKING OF ADOPTIVE CELL TRANSFER IN CANCER IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi124-vi124
Author(s):  
Angelie Rivera-Rodriguez ◽  
Lan Hoang-Minh ◽  
Leyda Marrero-Morales ◽  
Duane Mitchell ◽  
Carlos Rinaldi
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Cell Transfer ◽  
Cell Therapies ◽  
Non Invasive ◽  
Magnetic Particle Imaging ◽  
Particle Imaging ◽  
T Cell Transfer ◽  
Cytotoxic Function

Abstract BACKGROUND Adoptive cell therapies (ACT) are strategies being explored to boost the immune response against cancer. ACT cancer immunotherapies are effective against metastatic melanoma, leukemia, and lymphoma, but face challenges in treating other solid tumors, such as in the brain. A critical step for the success of ACT in solid cancers is achieving trafficking and persistence of T-cells at tumor sites. Glioblastoma (GBM) is the most common and aggressive cancer of the central nervous system in adults, with a prognosis of 15-18-month average patient survival after diagnosis. Biomedical imaging is often used to track cell therapies. Magnetic Particle Imaging (MPI) is a novel biomedical imaging modality enabling non-invasive visualization of the distribution of biocompatible superparamagnetic iron oxide (SPIO) tracers. OBJECTIVE Label T-cells with SPIO to non-invasively track adoptive T cell transfer immunotherapy with MPI in the context of brain cancer. METHODS Murine pmel-DsRed T-cells were isolated from the spleen of a transgenic C57BL/6 mouse, and were exposed to different SPIO concentrations ex vivo. Cell viability, phenotype, and cytotoxic function were analyzed to determine if T-cells were affected by the SPIO labeling. Moreover, in vivo experiments were performed in a murine GBM model, and labeled T-cells were injected intravenously and tracked using MPI. RESULTS The SPIO-labeling of T-cells did not affected cell viability, phenotype, or cell cytotoxic function at all tested incubation conditions. The internalized SPIO can be quantified and spatially detected using MPI both in vitro and in vivo. In addition, MPI in vivo tracking shows T-cells accumulation in liver and lungs, as well in the spleen and brain, as showed ex vivo. CONCLUSIONS SPIO-labeling of T-cells did not affected its cytotoxic function and MPI allows for in vivo tracking of adoptively T-cell transfer. MPI will provide better understanding of ACT dynamics to accelerate development of novel treatments.

scholarly journals Layilin augments integrin activation to promote antitumor immunity

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Kelly M. Mahuron ◽  
Joshua M. Moreau ◽  
Jeff E. Glasgow ◽  
Devi P. Boda ◽  
Mariela L. Pauli ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Ex Vivo ◽  
Cellular Adhesion ◽  
Lectin Domain ◽  
Activated State ◽  
Tumor Cell Killing ◽  
Specific Deletion

Tumor-infiltrating CD8+ T cells mediate antitumor immune responses. However, the mechanisms by which T cells remain poised to kill cancer cells despite expressing high levels of inhibitory receptors are unknown. Here, we report that layilin, a C-type lectin domain–containing membrane glycoprotein, is selectively expressed on highly activated, clonally expanded, but phenotypically exhausted CD8+ T cells in human melanoma. Lineage-specific deletion of layilin on murine CD8+ T cells reduced their accumulation in tumors and increased tumor growth in vivo. Congruently, gene editing of LAYN in human CD8+ T cells reduced direct tumor cell killing ex vivo. On a molecular level, layilin colocalized with integrin αLβ2 (LFA-1) on T cells, and cross-linking layilin promoted the activated state of this integrin. Accordingly, LAYN deletion resulted in attenuated LFA-1–dependent cellular adhesion. Collectively, our results identify layilin as part of a molecular pathway in which exhausted or “dysfunctional” CD8+ T cells enhance cellular adhesiveness to maintain their cytotoxic potential.

Adoptive Transfer of Hexon-Specific T-Cells as a Treatment of Adenovirus Reactivation Following Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 796-796
Author(s):  
Kathrin Opherk ◽  
Friedhelm R Schuster ◽  
Wolfgang Andreas Bethge ◽  
Peter Bader ◽  
Johann Greil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Immunotherapy ◽  
Therapeutic Option ◽  
T Cell Responses ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
Cell Responses ◽  
T Cell Transfer

Abstract Abstract 796 In pediatric patients human adenovirus (HAdV) was identified as a common viral pathogen responsible for significant morbidity and mortality post allo SCT. Antiviral chemotherapy is often insufficient. Given that T-cell immunity is crucial for protection against adenoviral infection/reactivation, cellular immunotherapy is a promising therapeutic option. The capsid protein Hexon has been shown to contain immunodominant T-cell epitopes, with T-cell responses in the majority of the healthy population. Therefore a prospective phase I/II clinical study was performed analysing safety and feasibility of adoptive Hexon-specific T-cell transfer in patients after allogeneic SCT and HAdV infection refractory to Cidofovir treatment. Hexon-specific T-cells were isolated from the SCT-donor by using the IFNγ secretion system and small T-cell populations were immediately infused, without in vitro expansion steps. Fourty pediatric and adult patients with a mean age of 15 years were treated according to the study protocol after haploidentical, matched unrelated and matched sibling donor SCT between day 11 and 327 post SCT. The T-cell dose varied from 300-25000 T-cells/kg. No acute toxicitiy was observed. In two patients GvHD °I-°II of the skin occured within two weeks after administration of specific T-cells, one patient also developed GvHD of the gut. In vivo T-cell responses were absent in all patients before adoptive T-cell transfer and detectable in 70% of evaluable patients within the first weeks after adoptive transfer, associated with a clinical and/or virological response to the adoptive T-cell transfer. However, in patients with adenoviral disease response rate was lower and 6 of 14 evaluable patients succumbed with the infection within few days, in spite of adoptive immunotherapy. This lead to the assumption, that adoptive treatment in patients with severe infection related morbidity was to late during the course of infection. In conclusion we could show that adoptive immunotherapy is safe, feasible and a promising therapeutic option in patients with HAdV infection. Infusion of small IFNγ producing Hexon-specific T-cells populations resulted in an in vivo expansion of specific T-cells in the majority of cases. Emergence of in vivo T-cell responses was closely associated with a clearance or reduction of the viral load. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A New Hope in Immunotherapy for Malignant Gliomas: Adoptive T Cell Transfer Therapy

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
Dong-Sup Chung ◽  
Hye-Jin Shin ◽  
Yong-Kil Hong
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Malignant Gliomas ◽  
Adoptive T Cell Therapy ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
T Cell Therapy ◽  
Promising Therapeutic Approach ◽  
T Cell Transfer

Immunotherapy emerged as a promising therapeutic approach to highly incurable malignant gliomas due to tumor-specific cytotoxicity, minimal side effect, and a durable antitumor effect by memory T cells. But, antitumor activities of endogenously activated T cells induced by immunotherapy such as vaccination are not sufficient to control tumors because tumor-specific antigens may be self-antigens and tumors have immune evasion mechanisms to avoid immune surveillance system of host. Although recent clinical results from vaccine strategy for malignant gliomas are encouraging, these trials have some limitations, particularly their failure to expand tumor antigen-specific T cells reproducibly and effectively. An alternative strategy to overcome these limitations is adoptive T cell transfer therapy, in which tumor-specific T cells are expandedex vivorapidly and then transferred to patients. Moreover, enhanced biologic functions of T cells generated by genetic engineering and modified immunosuppressive microenvironment of host by homeostatic T cell expansion and/or elimination of immunosuppressive cells and molecules can induce more potent antitumor T cell responses and make this strategy hold promise in promoting a patient response for malignant glioma treatment. Here we will review the past and current progresses and discuss a new hope in adoptive T cell therapy for malignant gliomas.

Adoptive Transfer of EBNA1-Specific T-Cells as a Treatment of Epstein-Barr-Virus Reactivation Following Allogeneic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2342-2342
Author(s):  
Vanya Icheva ◽  
Kathrin Opherk ◽  
Wolfgang A. Bethge ◽  
Simone Kayser ◽  
Johann Greil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr ◽  
T Cell Transfer

Abstract Abstract 2342 Reactivation of Epstein-Barr-Virus (EBV) after allogeneic stem cell transplantation (SCT) is responsible for significant morbidity and mortality. EBV is also assotiated with the development of some malingancies, such as Burkitt-Lymphoma or nasopharyngeal carcinoma (NPC). In particular, the EBV-induced lymphoproliferative disorder (PTLD) is a rare but severe condition after SCT. PTLD is often associated with insufficient immune responses against EBV in transplant recipients. There is no effective antiviral drug treatment against EBV by now. Given that T-cell immunity is crucial for protection against infection or reactivation of EBV, cellular immunotherapy is a promising therapeutic option. The Epstein-Barr-Virus Nuclear Antigen 1 (EBNA-1) has been shown to contain immunodominant T-cell epitopes with T-cell responses in the majority of the healthy population. Here we report adoptive EBNA-1-specific T-cell transfer in seven pediatric and adult patients with chemorefractory EBV-reactivation after allogenic SCT. Four patients had PTLD and one had metastatic relapse of a NPC. EBNA-1-specific T-cells were isolated from the SCT-donor by using an IFNγ-capture technique. These small T-cell populations were immediately infused to the patient without in vitro expansion steps. The adoptive T-cell transfer contained both, CD4+ T-helper cells and CD8+ cytotoxic T-cells. The patients with a mean age of 20 years were treated with antigen specific T-cells from haploidentical, matched unrelated or matched sibling donor SCT between day 72 and 410 post SCT. The T-cell dose varied from 150–7750 T-cells/ kg. No acute toxicity was observed. In vivo T-cell responses before adoptive T-cell transfer were absent and were detectable in all of the patients within the first weeks after adoptive transfer, associated with a partial clinical and/or virological response to the adoptive T-cell transfer. In three of the patients a second specific T-cell administration was needed to achieve an improvement of the EBV-related condition. PTLD or EBV-infection was not a cause of death in any of the other six patients. In conclusion we could show that adoptive T-cell-immunotherapy is safe, feasible and a promising therapeutic option in patients with EBV- infection and/or PTLD, having the advantage of not being immunosuppressive compared to chemotherapy against PTLD. Infusion of small IFNγ producing EBNA-1-specific T-cell populations resulted in an in vivo expansion of specific T-cells. Emergence of in vivo T-cell responses was closely associated with a clearance or reduction of the viral load. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through ‘reverse phenotyping’

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
David S. Fischer ◽  
Meshal Ansari ◽  
Karolin I. Wagner ◽  
Sebastian Jarosch ◽  
Yiqi Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Rna Sequencing ◽  
Ex Vivo ◽  
Severe Disease ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Single Cell Rna Sequencing

AbstractThe in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for ‘reverse phenotyping’. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.

scholarly journals IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii111-ii111
Author(s):  
Lan Hoang-Minh ◽  
Angelie Rivera-Rodriguez ◽  
Fernanda Pohl-Guimarães ◽  
Seth Currlin ◽  
Christina Von Roemeling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
T Cell Therapy ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

Cord blood comprises antigen-experienced T cells specific for maternal minor histocompatibility antigen HA-1

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1823-1827 ◽  
Author(s):  
Bregje Mommaas ◽  
Janine A. Stegehuis-Kamp ◽  
Astrid G. van Halteren ◽  
Michel Kester ◽  
Jürgen Enczmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cord Blood ◽  
Ex Vivo ◽  
Cytotoxic T Cells ◽  
Cord Blood Transplantation ◽  
Human Leukocyte ◽  
Leukemic Cells ◽  
Target Cells ◽  
Graft Versus Leukemia

AbstractUmbilical cord blood transplantation is applied as treatment for mainly pediatric patients with hematologic malignancies. The clinical results show a relatively low incidence of graft-versus-host disease and leukemia relapse. Since maternal cells traffic into the fetus during pregnancy, we questioned whether cord blood has the potential to generate cytotoxic T cells specific for the hematopoietic minor histocompatibility (H) antigen HA-1 that would support the graft-versus-leukemia effect. Here, we demonstrate the feasibility of ex vivo generation of minor H antigen HA-1-specific T cells from cord blood cells. Moreover, we observed pre-existing HA-1-specific T cells in cord blood samples. Both the circulating and the ex vivo-generated HA-1-specific T cells show specific and hematopoietic restricted lysis of human leukocyte antigen-A2pos/HA-1pos (HLA-A2pos/HA-1pos) target cells, including leukemic cells. The cord blood-derived HA-1-specific cytotoxic T cells are from child origin. Thus, the so-called naive cord blood can comprise cytotoxic T cells directed at the maternal minor H antigen HA-1. The apparent immunization status of cord blood may well contribute to the in vivo graft-versus-leukemia activity after transplantation. Moreover, since the fetus cannot be primed against Y chromosome-encoded minor H antigens, cord blood is an attractive stem cell source for male patients. (Blood. 2005;105:1823-1827)

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