Activation-Dependent Expression of an Interleukin-2 Transgene Mediated by Transduction with a Lentiviral Vector Enhances T Cell Functions.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5273-5273
Author(s):  
Qi Sun ◽  
Karen Chorney ◽  
Carol Stine ◽  
Kenneth G. Lucas
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Lentiviral Vector ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Immune Functions ◽  
Cell Functions ◽  
Genetically Engineer ◽  
Ifn Γ

Abstract Adoptive T cell immunotherapy (ATCI) is an evolving strategy that explores antigen-specific T cells manipulated ex vivo as therapeutic agents. Although the concept of ATCI has been tested clinically, with success in the treatment of post-transplant EBV induced lymphoproliferative disease, one of the major obstacles hindering its application to other malignancies is the procurement of tumor-specific T cells that possess potent anti-tumor functions even in the inhibitory environment at the tumor sites. This study aims to genetically engineer enriched viral specific T cells for improved immune functions. A self-inactivating lentiviral vector (SIN) CD69p-IL2 was constructed to encode the transgene interleukin-2 (IL2) under the control of a human CD69 promoter (CD69p), and this vector was tested in ex vivo cultivated EBV-specific T cells. SIN vector allows a high degree of autonomy for the internal promoter, and CD69 expression in the T cells is closely associated with T cell activation. Experiments showed that the SIN vectors efficiently transduced EBV-specific T cells, both CD4 and CD8. Furthermore, the newly cloned CD69p exhibited a higher degree of responsiveness to physiological antigen stimulation than the early promoter from the cytomegalovirus (CMVp). In response to stimulation by EBV-infected B cells, the percentage of IL2 expressing cells was 2 fold higher for the activated CD69p-IL2 transduced T cells than the non-transduced, or the CMVp-IL2 transduced, counterparts. In correlation with the stronger IL2 expression, 3 fold more T cells expressed the anti-viral cytokine interferon-γ (IFN-γ) in the CD69p-IL2 transduced T cells than the CMVp-IL2 transduced, and the IFN-γ expression at the single cell level was 2 fold higher in the former, indicating an enhanced functionality. While the culture supernatant from the CMVp-IL2 transduced T cells contained IL2 at a concentration 2000 fold higher than the non-transduced T cells, the IL2 level in the media from the CD69p-IL2 transduced T cells was comparable to that in the control, suggesting the IL2 expression mediated by the CD69p more relevant to T cell functions than the CMVp. These results may serve as a foundation for the further development and clinical application of specific T cells engineered for enhanced immune functions.

scholarly journals Identification of mtROS-sensitive processes in activated CD4+ T cells

2020 ◽  
Author(s):  
Daniel Meston ◽  
Wenjie Bi ◽  
Tina Rietschel ◽  
Marco van Ham ◽  
Lars I. Leichert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Transcriptional Regulators ◽  
Cysteine Residues ◽  
Immune Functions ◽  
Cell Functions ◽  
Proteomic Approach

AbstractT lymphocytes are key components in adaptive immunity and their activation naturally involves mitochondrial-derived oxygen species (mtROS). In particular, H2O2 has been implicated as an important signaling molecule regulating major T cell functions. H2O2 targets the oxidation status of functional cysteine residues but knowledge if and where this happens in T cell signaling networks is widely missing. This study aimed to identify mtROS-sensitive processes in activated primary human CD4+ T cells. By using a thiol-specific redox proteomic approach we examined the oxidation state of 4784 cysteine-containing peptides of ex vivo stimulated T cells from healthy individuals. Upon activation, a shift in oxidation was observed at catalytic cysteine residues of peroxiredoxins (PRDX5 & PRDX6), and T cells were found to maintain their global thiol-redox homeostasis. In parallel, a distinct set of 88 cysteine residues were found to be differentially oxidized upon T cell activation suggesting novel functional thiol switches. In mitochondria, cysteine oxidations selectively modified regulators of respiration (NDUFA2, NDUFA8, and UQCRH) confirming electron leakage from electron transport complexes I and III. The majority of oxidations occurred outside mitochondria and enriched sensitive thiols at regulators of cytoskeleton dynamics (e.g. CYFIP2 and ARPC1B) and known immune functions including the non-receptor tyrosine phosphatase PTPN7. Conversely, cysteine reduction occurred predominantly at transcriptional regulators and sites that coordinate zinc-binding in zinc-finger motifs. Indeed, fluorescence microscopy revealed a colocalization of zinc-rich microenvironments and mitochondria in T cells suggesting mtROS-dependent zinc-release of identified transcriptional regulators including ZFP36, RPL37A and CRIP2. In conclusion, this study complements knowledge on the mtROS signaling network and suggests zinc-dependent thiol switches as a mechanism of how mtROS affects transcription and translation in T cells.

scholarly journals P12.05 Evaluating the compatibility of tumor treating electric fields with key antitumoral immune functions

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii60-iii60
Author(s):  
G Diamant ◽  
H Simchony ◽  
T Shiloach ◽  
A Globerson-Levin ◽  
L Gasri Plotnitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Function ◽  
Rational Approach ◽  
Immune Functions ◽  
Color Flow ◽  
Cell Functions ◽  
Car T Cells ◽  
Car T

Abstract BACKGROUND TTFields has the ability to induce immunogenic cell death (ICD). As immunotherapy and TTFields have different mechanisms of action (MOA), combining these therapies is a rational approach. Contrarily, TTFields may interfere with immune functions critical for effective T cell function. MATERIAL AND METHODS We cultured T cells from healthy donors’ peripheral blood or from viably dissociated glioblastoma samples under normal or TTFields conditions, with or without superantigen-stimulation. In order to assess T cell responses we used eight-color flow cytometry by monitoring select pivotal antitumoral functions: proliferation (CFSE), IFNγ secretion, cytotoxic degranulation (CD107a), activation/exhaustion (PD1) and viability. Evaluation of direct cytotoxicity was done by using chimeric antigen receptor (CAR) T cells. RESULTS TTFields did not change T cell activation rates for all evaluated functions with the exception of reduced proliferation - in line with TTFields’ MOA. TTFields substantially reduced the viability of activated proliferating T cells, moderately affected activated nonproliferating T cells and had almost no effect on the viability of non-activated cells. Polyfunctionality analysis of T-cells, associated with effective antitumoral responses, demonstrated that under TTFields, the activated non-proliferating T cells retained polyfunctional capabilities. PD1-expressing TILs, a subset containing most of the tumor antigen-specific TILs, exhibited unaltered viability and functionality under TTFields. CAR T-cells, which utilize the same killing machinery as unmodified T cells, exhibited unaltered cytotoxic capability under TTFields. Immunohistochemical evaluation of GBM samples before TTFields treatment and after recurrence showed that some patients had accommodated large increases in their CD8 and CD4 counts. RNA-Seq performed on GBM samples from 6 standardly-treated and 6 TTFields-treated patients before treatment and after recurrence. The data shows differential increases in TTFields-treated patients to controls, in the expression of immune genes associated with favorable prognosis (e.g. t-bet, NKG2D, ICOS-L, CD70) and concurrent decreases in genes associated with poor prognosis (e.g. IL4, TSLP, various complement genes). CONCLUSION The preclinical data showed that all antitumoral T cell functions examined, but proliferation, were unhindered by TTFields. The clinical data showed that TTFields may shift treated tumors to a state more conducive of antitumoral immune responses. Our findings support the further preclinical and clinical investigation into combining TTFields with immunotherapy.

scholarly journals Differential CD147 Functional Epitopes on Distinct Leukocyte Subsets

2021 ◽  
Vol 12 ◽  
Author(s):  
Supansa Pata ◽  
Sirirat Surinkaew ◽  
Nuchjira Takheaw ◽  
Witida Laopajon ◽  
Kantinan Chuensirikulchai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Inflammatory Diseases ◽  
Cell Contact ◽  
Cell Functions ◽  
Tnf Α ◽  
Ifn Γ

CD147, a member of the immunoglobulin (Ig) superfamily, is widely expressed in several cell types. CD147 molecules have multiple cellular functions, such as migration, adhesion, invasion, energy metabolism and T cell activation. In particular, recent studies have demonstrated the potential application of CD147 as an effective therapeutic target for cancer, as well as autoimmune and inflammatory diseases. In this study, we elucidated the functional epitopes on CD147 extracellular domains in T cell regulation using specific monoclonal antibodies (mAbs). Upon T cell activation, the anti-CD147 domain 1 mAbs M6-1E9 and M6-1D4 and the anti-CD147 domain 2 mAb MEM-M6/6 significantly reduced surface expression of CD69 and CD25 and T cell proliferation. To investigate whether functional epitopes of CD147 are differentially expressed on distinct leukocyte subsets, PBMCs, monocyte-depleted PBMCs and purified T cells were activated in the presence of anti-CD147 mAbs. The mAb M6-1E9 inhibited T cell functions via activation of CD147 on monocytes with obligatory cell-cell contact. Engagement of the CD147 epitope by the M6-1E9 mAb downregulated CD80 and CD86 expression on monocytes and IL-2, TNF-α, IFN-γ and IL-17 production in T cells. In contrast, the mAb M6-1D4 inhibited T cell function via activation of CD147 on T cells by downregulating IL-2, TNF-α and IFN-γ. Herein, we demonstrated that certain epitopes of CD147, expressed on both monocytes and T cells, are involved in the regulation of T cell activation.

Mechanism of Interleukin-10 Inhibition of T-Helper Cell Activation by Superantigen at the Level of the Cell Cycle

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 208-216 ◽  
Author(s):  
George Q. Perrin ◽  
Howard M. Johnson ◽  
Prem S. Subramaniam
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Interleukin 10 ◽  
Inhibitory Protein ◽  
Cell Functions

Abstract We have analyzed the effects of interleukin-10 (IL-10) on the entry of quiescent CD4+ T cells into the cell cycle upon stimulation with the superantigen staphylococcal enterotoxin B (SEB). IL-10 arrested cells at G0/G1. IL-10 treatment prevented the downregulation of p27Kip1, an inhibitory protein that controls progression out of the G0 phase of the cell cycle. IL-10 also prevented the upregulation of the G1 cyclins D2 and D3, proteins necessary for entry and progression through the G1 phase of the cell cycle. Associated with the inhibition of the cell cycle, IL-10 suppressed SEB induction of interleukin-2 (IL-2). Addition of exogenous IL-2 to IL-10–treated cells significantly reversed the antiproliferative effects of IL-10. Moreover, IL-10 effects on the early G1proteins p27Kip1 and cyclin D2 were similarly reversed by exogenous IL-2. Although this reversal by IL-2 was pronounced, it was not complete, suggesting that IL-10 may have some effects not directly related to the suppression of IL-2 production. Cell separation experiments suggest that IL-10 can effect purified CD4+ T cells directly, providing functional evidence for the presence of IL-10 receptors on CD4+ T cells. IL-10 also inhibited expression of IL-2 transcriptional regulators c-fos and c-jun, which also inhibit other cell functions. Our studies show that the mechanism of IL-10 regulation of quiescent CD4+ T-cell activation is mainly by blocking induction of IL-2 that is critical to downregulation of p27Kip1 and upregulation of D cyclins in T-cell activation and entry into the cell cycle.

Mechanism of Interleukin-10 Inhibition of T-Helper Cell Activation by Superantigen at the Level of the Cell Cycle

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 208-216
Author(s):  
George Q. Perrin ◽  
Howard M. Johnson ◽  
Prem S. Subramaniam
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Interleukin 10 ◽  
Inhibitory Protein ◽  
Cell Functions

We have analyzed the effects of interleukin-10 (IL-10) on the entry of quiescent CD4+ T cells into the cell cycle upon stimulation with the superantigen staphylococcal enterotoxin B (SEB). IL-10 arrested cells at G0/G1. IL-10 treatment prevented the downregulation of p27Kip1, an inhibitory protein that controls progression out of the G0 phase of the cell cycle. IL-10 also prevented the upregulation of the G1 cyclins D2 and D3, proteins necessary for entry and progression through the G1 phase of the cell cycle. Associated with the inhibition of the cell cycle, IL-10 suppressed SEB induction of interleukin-2 (IL-2). Addition of exogenous IL-2 to IL-10–treated cells significantly reversed the antiproliferative effects of IL-10. Moreover, IL-10 effects on the early G1proteins p27Kip1 and cyclin D2 were similarly reversed by exogenous IL-2. Although this reversal by IL-2 was pronounced, it was not complete, suggesting that IL-10 may have some effects not directly related to the suppression of IL-2 production. Cell separation experiments suggest that IL-10 can effect purified CD4+ T cells directly, providing functional evidence for the presence of IL-10 receptors on CD4+ T cells. IL-10 also inhibited expression of IL-2 transcriptional regulators c-fos and c-jun, which also inhibit other cell functions. Our studies show that the mechanism of IL-10 regulation of quiescent CD4+ T-cell activation is mainly by blocking induction of IL-2 that is critical to downregulation of p27Kip1 and upregulation of D cyclins in T-cell activation and entry into the cell cycle.

Prolonged survival and tissue trafficking following adoptive transfer of CD4ζ gene-modified autologous CD4+ and CD8+ T cells in human immunodeficiency virus–infected subjects

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 785-793 ◽  
Author(s):  
Ronald T. Mitsuyasu ◽  
Peter A. Anton ◽  
Steven G. Deeks ◽  
David T. Scadden ◽  
Elizabeth Connick ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Cd4 Counts ◽  
Hiv Rna ◽  
Immunodeficiency Virus

Abstract We have genetically engineered CD4+ and CD8+ T cells with human immunodeficiency virus (HIV) specificity by inserting a gene, CD4ζ, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (ζ) chain of the T-cell receptor (which mediates T-cell activation). Twenty-four HIV-positive subjects received a single infusion of 2 to 3 × 1010 autologous CD4ζ-modified CD4+and CD8+ T cells administered with (n = 11) or without (n = 13) interleukin-2 (IL-2). Subjects had CD4 counts greater than 50/μL and viral loads of at least 1000 copies/mL at entry. T cells were costimulated ex vivo through CD3 and CD28 and expanded for approximately 2 weeks. CD4ζ was detected in 1% to 3% of blood mononuclear cells at 8 weeks and 0.1% at 1 year after infusion, and survival was not enhanced by IL-2. Trafficking of gene-modified T cells to bulk rectal tissue and/or isolated lamina propria lymphocytes was documented in a subset of 5 of 5 patients at 14 days and 2 of 3 at 1 year. A greater than 0.5 log mean decrease in rectal tissue–associated HIV RNA was observed for at least 14 days, suggesting compartmental antiviral activity of CD4ζ T cells. CD4+ counts increased by 73/μL at 8 weeks in the group receiving IL-2. There was no significant mean change in plasma HIV RNA or blood proviral DNA in either treatment arm. This sustained, high-level persistence of gene-modified T cells demonstrates the feasibility of ex vivo T-cell gene therapy in HIV-infected adults and suggests the importance of providing HIV-specific T-helper function.

scholarly journals Antigen Presenting Cells from Tumor and Colon of Colorectal Cancer Patients Are Distinct in Activation and Functional Status, but Comparably Responsive to Activated T Cells

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5247
Author(s):  
Frank Liang ◽  
Azar Rezapour ◽  
Louis Szeponik ◽  
Samuel Alsén ◽  
Yvonne Wettergren ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Functional Status ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Activated T Cells ◽  
Ifn Γ ◽  
Colorectal Cancer Patients

Although mouse models of CRC treatments have demonstrated robust immune activation, it remains unclear to what extent CRC patients’ APCs and TILs interact to fuel or quench treatment-induced immune responses. Our ex vivo characterization of tumor and adjacent colon cell suspensions suggest that contrasting environments in these tissues promoted inversed expression of T cell co-stimulatory CD80, and co-inhibitory programmed death (PD)-ligand1 (PD-L1) on intratumoral vs. colonic APCs. While putative tumor-specific CD103+CD39+CD8+ TILs expressed lower CD69 (early activation marker) and higher PD-1 (extended activation/exhaustion marker) than colonic counterparts, the latter had instead higher CD69 and lower PD-1 levels. Functional comparisons showed that intratumoral APCs were inferior to colonic APCs regarding protein uptake and upregulation of CD80 and PD-L1 after protein degradation. Our attempt to model CRC treatment-induced T cell activation in vitro showed less interferon (IFN)-γ production by TILs than colonic T cells. In this model, we also measured APCs’ CD80 and PD-L1 expression in response to activated co-residing T cells. These markers were comparable in the two tissues, despite higher IFN- γ exposure for colonic APCs. Thus, APCs within distinct intratumoral and colonic milieus showed different activation and functional status, but were similarly responsive to signals from induced T cell activation.

Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2821-2827 ◽  
Author(s):  
Sarah Glennie ◽  
Inês Soeiro ◽  
Peter J. Dyson ◽  
Eric W.-F. Lam ◽  
Francesco Dazzi
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Activation Markers ◽  
Ifn Γ

AbstractIt has been shown that mesenchymal stem cells (MSCs) induce T cells to become unresponsive. We characterized the phenotype of these T cells by dissecting the effect of MSCs on T-cell activation, proliferation, and effector function. For this purpose, an in vitro murine model was used in which T-cell responses were generated against the male HY minor histocompatibility antigen. In the presence of MSCs, the expression of early activation markers CD25 and CD69 was unaffected but interferon-γ (IFN-γ) production was reduced. The inhibitory effect of MSCs was directed mainly at the level of cell proliferation. Analysis of the cell cycle showed that T cells, stimulated in the presence of MSCs, were arrested at the G1 phase. At the molecular level, cyclin D2 expression was profoundly inhibited, whereas p27kip1 was up-regulated. When MSCs were removed from the cultures and restimulated with the cognate peptide, T cells produced IFN-γ but failed to proliferate. The addition of exogenous interleukin-2 (IL-2) did not restore proliferation. MSCs did not preferentially target any T-cell subset, and the inhibition was also extended to B cells. MSC-mediated inhibition induces an unresponsive T-cell profile that is fully consistent with that observed in division arrest anergy.

scholarly journals Interleukin-2 and Loss of Immunity in Experimental Mycobacterium avium Infection

2002 ◽  
Vol 70 (1) ◽  
pp. 27-35 ◽  
Author(s):  
Stuart I. Mannering ◽  
Christina Cheers
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Mycobacterium Avium ◽  
Interleukin 2 ◽  
T Cell Proliferation ◽  
Steady Increase ◽  
Activation Markers ◽  
Ifn Γ

ABSTRACT Experimental infection of mice with a virulent strain of Mycobacterium avium leads to a slowly progressive disease, which we have previously shown culminates in loss of gamma interferon (IFN-γ) production by T lymphocytes and death of the animals approximately 40 weeks after infection. Here we investigated the changes in T-cell activation, the production of interleukin-2 (IL-2), and the response to IL-2 throughout M. avium infection as a possible explanation for this loss. We found that there is a steady increase in the percentage of T cells expressing activation markers right to the end of infection. However, in vivo T-cell proliferation, measured as a percentage of CD4+ and CD8+ cells incorporating 5-bromo-2′-deoxyuridine, initially increased but then remained constant. In the final stages of infection there was a decline in proliferation of activated (CD62L−) T cells. Since IL-2 is a major driver of T-cell proliferation, we asked whether this was due to loss of IL-2 responsiveness or production. However, CD25 (IL-2Rα) continued to be highly expressed in the terminal stages of infection, and although IL-2 production declined, addition of recombinant IL-2 to cultures could not rescue the final loss of IFN-γ production.

419 Pharmacodynamic biomarkers demonstrate T-cell activation in patients treated with the oral PD-L1 inhibitor INCB086550 in a phase 1 clinical trial

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A445-A445
Author(s):  
Sarina Piha-Paul ◽  
Tara Mitchell ◽  
Solmaz Sahebjam ◽  
Janice Mehnert ◽  
Thomas Karasic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Ex Vivo ◽  
Phase 1 ◽  
Fold Increase ◽  
T Cell Proliferation ◽  
Ifn Γ

BackgroundPharmacological blockade of the PD-1:PD-L1 interaction with monoclonal antibodies (mAbs) has shown durable clinical responses and overall survival benefit in a variety of malignancies.1 2 Importantly, the most meaningful responses have been associated with enhancement of the antitumor effector functions of T cells as evidenced by increased peripheral T-cell proliferation, infiltration of T cells in tumors, together with increased expression of key interferon-γ (IFNγ) pathway genes, including CXCL9, CXCL10, and granzyme B in both biopsy and peripheral blood samples.3 4 To date, available therapies targeting this pathway are mAbs, but the potential advantages of a small molecule, orally administered, direct antagonist of PD-1:PD-L1 binding have led to the development of INCB086550. INCB086550 is being evaluated in a phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with solid tumors. This preliminary report describes peripheral pharmacodynamic activity.MethodsPeripheral blood was collected at baseline and at multiple time points posttreatment from 16 patients treated with INCB086550 QD (100, 200 mg) or BID (200, 400 mg). Pharmacodynamic assessments included binding of drug to PD-L1 and secretion of cytokines, IL-2 and IFN-γ with ex vivo restimulation. Measurement of downstream pharmacodynamic effects included evaluation of immune activation markers on peripheral blood cells by flow cytometry and measurement of a panel of interferon-related cytokines in plasma.ResultsFollowing INCB086550 treatment, the ex vivo stimulation of whole blood from patients showed a dose-related reduction of up to 85% in free PD-L1 on cells after 2 hours and increases as high as 3-fold of interleukin-2 secretion after 6 hours. Increases in the proliferation of circulating T cells, as measured by Ki-67, were dose-related and as high as 2.5-fold posttreatment. Plasma concentrations of CXCL9 and CXCL10 increased following INCB086550 treatment by 1.3- and 1.4-fold, respectively. A dose-related 1.2-fold increase in the plasma concentration of soluble target (PD-L1) and a 3.4-fold increase in IFN-γ was also observed posttreatment. Other proteins related to T-cell function, including but not limited to granzyme B, granzyme H, and LAG3, also increased following drug treatment.ConclusionsThese results indicate that oral administration of INCB086550 provides dose-related pharmacodynamic T-cell activation similar to data reported for PD-(L)1 mAbs and evidence that INCB086550 is biologically active in blocking PD-1:PD-L1 interactions, leading to T-cell proliferation and activation in patients. This trial continues to evaluate the intratumoral pharmacodynamic activity, safety, and efficacy of INCB086550.Ethics ApprovalThe study was approved by institutional review boards or independent ethics committees of participating institutions.ReferencesFreeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–1034.Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677–704.Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568–571.Herbst RS, Soria JC, Kowanetz, M, et al.. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–567.

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