scholarly journals 598 Local radiation in combination with CpG and anti-OX40 induces enhanced T cell activation and proliferation

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A628-A628
Author(s):  
Dan Spiegelman ◽  
Alexander Pieper ◽  
Luke Zangl ◽  
Arika Feils ◽  
Anna Hoefges ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Regression ◽  
Tumor Model ◽  
Cd8 T Cell ◽  
External Beam ◽  
In Situ Vaccine

BackgroundWe, and others, have previously shown that the in-situ vaccine of hypomethylated CG-enriched oligodeoxynucleotide (CpG) with agonist anti-OX40 antibody (OX40) is effective at curing mice in the A20 lymphoma model [1–4]. In separate preclinical models where CpG+OX40 fails to cause tumor regression, radiation therapy (RT) prior to the in-situ vaccine enhances the anti-tumor effect of CpG+OX40 [4]. We investigated the immune response, and specifically the activity of T cells, following treatment with RT+CpG+OX40 in the B78 melanoma model where CpG+OX40 typically fails to cause tumor regression.MethodsC57BL/6 mice were inoculated with 2x106 B78 melanoma cells on the right flank and allowed to grow until the average tumor size was ~150mm3. In two independent experiments, mice were randomized (n=4–5 per group per experiment) and treated with one of the following: 1) PBS, 2) CpG+OX40, 3) RT, 4) RT+CpG+OX40. 12 Gy external beam RT was dosed to the flank tumor on day 0 and intratumoral CpG (50µg)+OX40 (20 µg) were given on days 5, 7, and 9 after RT. Spleens and tumor draining lymph nodes (TDLNs) were harvested on day 12. T cell activation and proliferation were assessed via flow cytometry.ResultsCompared to all other groups in the study, mice treated with RT+CpG+OX40 demonstrated significantly elevated levels of CD4+ and CD8+ T cell activation in the TDLNs, as measured by interferon gamma expression. Similar trends of CD4+ and CD8+ T cell activation were measured in the spleens. Splenic CD8+ T cells from RT+CpG+OX40 treated mice demonstrated significantly elevated levels of proliferation over PBS and RT, as measured by Ki67.ConclusionsIn B78 melanoma, a weakly immunologic tumor model, combining RT with the in-situ vaccine CpG+OX40 enhances the activity of T cells, evidenced by significantly increased CD4+ and CD8+ T cell activation in the TDLN and spleen and elevated CD8+ T cell proliferation in the spleen.ReferencesHouot, R. and Levy, R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood, 2009. 113(15):3546–52.Marabelle, A., et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest, 2013. 123(6):2447–63.Sagiv-Barfi, I., et al. Eradication of spontaneous malignancy by local immunotherapy. Sci Transl Med, 2018. 10(426).Zangl, LM. Et al. External Beam Radiotherapy Required for Tumor Regression When Using CpG-Oligodeoxynucleotide and Anti-OX40 in an Immunologically Cold Tumor Model. Red Journal. 2019. 105:S88.

Development and characterization of a HCMV multiantigen therapeutic vaccine for GBM using the UNITE platform.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14565-e14565
Author(s):  
Amit Adhikari ◽  
Juliete Macauley ◽  
Yoshimi Johnson ◽  
Mike Connolly ◽  
Tim Coleman ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Response

e14565 Background: Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months which has remained unchanged despite technological advances in the standard of care. GBM cells specifically express human cytomegalovirus (HCMV) proteins providing a unique opportunity for targeted therapy. Methods: We utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to develop a multi-antigen DNA vaccine (ITI-1001) that codes for the HCMV proteins- pp65, gB and IE-1. The UNITE platform involves lysosomal targeting technology, fusing lysosome-associated protein 1 (LAMP1) with target antigens resulting in increased antigen presentation by MHC-I and II. ELISpot, flow cytometry and ELISA techniques were used to evaluate the vaccine immunogenicity and a syngeneic, orthotopic GBM mouse model that expresses HCMV proteins was used for efficacy studies. The tumor microenvironment studies were done using flow cytometry and MSD assay. Results: ITI-1001 vaccination showed a robust antigen-specific CD4 and CD8 T cell response in addition to a strong humoral response. Using GBM mouse model, therapeutic treatment of ITI-1001 vaccine resulted in ̃56% survival with subsequent long-term immunity. Investigating the tumor microenvironment showed significant CD4 T cell infiltration as well as enhanced Th1 and CD8 T cell activation. Regulatory T cells were also upregulated upon ITI-1001 vaccination and would be an attractive target to further improve this therapy. In addition, tumor burden negatively correlated with number of activated CD4 T cells (CD4 IFNγ+) reiterating the importance of CD4 activation in ITI-1001 efficacy and potentially identifying treatment responders and non-responders. Further characterization of these two groups showed high infiltration of CD3+, CD4+ and CD8+ T cells in responders compared with non- responders along with higher CD8 T cell activation. Conclusions: Thus, we show that vaccination with HCMV antigens using the ITI-1001-UNITE platform generates strong cellular and humoral immune responses, triggering significant anti-tumor activity that leads to enhanced survival in mice with GBM.

Abstract P283: Gamma Delta T Cells Drive CD4 + and CD8 + T Cell Activation in Hypertension

Hypertension ◽  
2018 ◽  
Vol 72 (Suppl_1) ◽  
Author(s):  
Pierre Paradis ◽  
Antoine Caillon ◽  
Ernesto L Schiffrin
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Gamma Delta T Cells ◽  
Gamma Delta

scholarly journals IL4I1 Accelerates the Expansion of Effector CD8+ T Cells at the Expense of Memory Precursors by Increasing the Threshold of T-Cell Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Marie-Line Puiffe ◽  
Aurélie Dupont ◽  
Nouhoum Sako ◽  
Jérôme Gatineau ◽  
José L. Cohen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cell Clone ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Clone

IL4I1 is an immunoregulatory enzyme that inhibits CD8 T-cell proliferation in vitro and in the tumoral context. Here, we dissected the effect of IL4I1 on CD8 T-cell priming by studying the differentiation of a transgenic CD8 T-cell clone and the endogenous repertoire in a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection. Unexpectedly, we show that IL4I1 accelerates the expansion of functional effector CD8 T cells during the first several days after infection and increases the average affinity of the elicited repertoire, supporting more efficient LCMV clearance in WT mice than IL4I1-deficient mice. Conversely, IL4I1 restrains the differentiation of CD8 T-cells into long-lived memory precursors and favors the memory response to the most immunodominant peptides. IL4I1 expression does not affect the phenotype or antigen-presenting functions of dendritic cells (DCs), but directly reduces the stability of T-DC immune synapses in vitro, thus dampening T-cell activation. Overall, our results support a model in which IL4I1 increases the threshold of T-cell activation, indirectly promoting the priming of high-affinity clones while limiting memory T-cell differentiation.

scholarly journals CD8+ T Cell Activation Leads to Constitutive Formation of Liver Tissue-Resident Memory T Cells that Seed a Large and Flexible Niche in the Liver

Cell Reports ◽  
2018 ◽  
Vol 25 (1) ◽  
pp. 68-79.e4 ◽  
Author(s):  
Lauren E. Holz ◽  
Julia E. Prier ◽  
David Freestone ◽  
Thiago M. Steiner ◽  
Kieran English ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Liver Tissue ◽  
Cell Activation ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Resident Memory T Cells

scholarly journals A Critical Role for Cd40–Cd40 Ligand Interactions in Amplification of the Mucosal Cd8 T Cell Response

1999 ◽  
Vol 190 (9) ◽  
pp. 1275-1284 ◽  
Author(s):  
Leo Lefrançois ◽  
Sara Olson ◽  
David Masopust
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cd40 Ligand ◽  
Interleukin 12 ◽  
Cd8 Cells

The role of CD40 ligand (CD40L) in CD8 T cell activation was assessed by tracking antigen-specific T cells in vivo using both adoptive transfer of T cell receptor transgenic T cells and major histocompatibility complex (MHC) class I tetramers. Soluble antigen immunization induced entry of CD8 cells into the intestinal mucosa and cytotoxic T lymphocyte (CTL) differentiation, whereas CD8 cells in secondary lymphoid tissue proliferated but were not cytolytic. Immunization concurrent with CD40L blockade or in the absence of CD40 demonstrated that accumulation of CD8 T cells in the mucosa was CD40L dependent. Furthermore, activation was mediated through CD40L expressed by the CD8 cells, since inhibition by anti-CD40L monoclonal antibodies occurred after adoptive transfer to CD40L-deficient mice. However, mucosal CD8 T cells in normal and CD40−/− mice were equivalent killers, indicating that CD40L was not required for CTL differentiation. Appearance of virus-specific mucosal, but not splenic, CD8 cells also relied heavily on CD40–CD40L interactions. The mucosal CTL response of transferred CD8 T cells was MHC class II and interleukin 12 independent. The results established a novel pathway of direct CD40L-mediated CD8 T cell activation.

Prostate Cancer Immunology: Biology, Therapeutics, and Challenges

2005 ◽  
Vol 23 (32) ◽  
pp. 8262-8269 ◽  
Author(s):  
W. Scott Webster ◽  
Eric J. Small ◽  
Brian I. Rini ◽  
Eugene D. Kwon
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Advanced Prostate Cancer ◽  
Cell Activation ◽  
Tumor Regression ◽  
Prostate Cancer Treatment ◽  
Mechanistic Basis ◽  
Antigen Presenting

A number of recently developed and promising approaches to antitumoral immunotherapy are being investigated as potential treatments for advanced prostate cancer. These approaches largely revolve around strategies to increase antigen-specific T-cell activation against prostate tumors as well as precise manipulations of critical co-regulatory receptors that help to maintain and prolong the activity of antigen-presenting cells and T cells that are capable of mediating tumor regression. Herein, we describe the experience with the most recent and promising approaches pertaining to prostate cancer immunotherapy. Additionally, we discuss the mechanistic basis for these approaches as well as current limitations that must still be addressed in order to propel immunotherapy into the forefront of prostate cancer treatment.

T Cell Responses during Long-Term Continuous Infusion of MT103 (MEDI-538; Anti-CD19 BiTE) in Patients with Relapsed B-NHL: Data from Dose-Escalation Study MT103-104.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2725-2725 ◽  
Author(s):  
Matthias Klinger ◽  
Peter Kufer ◽  
Petra Kirchinger ◽  
Ralf Lutterbüse ◽  
Eugen Leo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Cell Expansion ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Counts ◽  
T Cell Expansion

Abstract MT103 (MEDI-538) is a bispecific single-chain antibody construct directed at CD3 on human T cells and CD19 on human B lymphoma and normal B cells. Transient linkage of B and T cells by MT103 provides T cells with a T cell receptor (TCR)-like signal leading to redirected lysis of B cell targets without apparent need of costimulation and inducing T cells to proliferate, secrete cytokines and upregulate surface activation markers. TCR-like signalling by MT103 is strictly dependent on the presence of target cells. Redirected lysis of CD19-positive cells by MT103 is seen at low picomolar concentrations and at low effector-to-target ratios. The in-vivo half-life of MT103 is approximately two hours. In the ongoing dose escalation study MT103-104, patients with relapsed B-NHL have so far received continuous infusion of MT103 at maintenance flow-rates of 0.5, 1.5, 5 and 15 μg/m2/24h for 4 or 8 weeks following a 3+3 dose escalation design. Serum concentrations of MT103 remained constant over the entire treatment period at a level depending on the respective maintenance flow-rate. Depletion of circulating B (lymphoma) cells could be observed more frequently with increasing dose levels (DL) from DL1 to DL3, and in all evaluable patients at DL4. Three of six evaluable patients at DL4 showed clinical responses (2 PR, 1 CR) according to standardized Cheson criteria, but no patient of DL1-3. The time courses of absolute CD4 and CD8 T cell counts in peripheral blood were determined by flow cytometry. CD8 T lymphocytes were further subdivided for analysis into naïve T cells, TCM (central memory T cells), TEM (effector memory T cells) and TEMRA (non-proliferating terminally differentiated CTL), and CD4 T lymphocytes into naïve T cells, TCM and TEM. Activation of CD4 and CD8 T cell subsets was determined by measuring upregulation of CD69, CD25 and HLA-DR. Serum levels of cytokines were determined as additional biomarkers for T cell activation. In 50% of patients at DL1 to DL3, CD4 and CD8 T cell counts increased during the course of treatment - over pre-treatment levels. The TEM subset from both CD4 and CD8 T cells accounted for most of the observed increases, while the naïve T cell subsets showed no increase but also no signs of apoptosis. The non-proliferative TEMRA subset of CD8 T cells also remained unchanged in most patients. This indicated that the selective increase of proliferation-competent TEM subsets was attributed to MT103-induced T cell proliferation. At DL4, all evaluable patients showed signs of T cell expansion after 2 weeks of MT103 infusion, which was most pronounced in those who developed a partial or complete remission. The increase of CD8 T cell counts was more pronounced than that of CD4 T cells. T cell expansion was accompanied by upregulation of T cell activation markers as well as by increases in serum concentrations of cytokines like IFN-γ. T cell expansion and activation reverted in all cases when the infusion of MT103 was stopped. In summary, MT103 induced a reversible secondary T cell response involving T cell activation and proliferation as well as T cell cytotoxicity against circulating B cells and lymphoma tissue. The dose-dependent T cell expansion observed during long-term infusion of MT103, particularly within the cytotoxic TEM subset of CD8 T cells, appears to play a key role for clinical activity.

Efficacy, safety, and immune activation with pegylated human IL-10 (AM0010) in combination with an anti-PD1 in advanced NSCLC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9091-9091
Author(s):  
Deborah Jean Lee Wong ◽  
Jeffrey Gary Schneider ◽  
Raid Aljumaily ◽  
Wolfgang Michael Korn ◽  
Jeffrey R. Infante ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Advanced Nsclc ◽  
De Novo ◽  
Cd8 T Cell ◽  
Outcome Data ◽  
Low Grade

9091 Background: Although IL-10 has anti-inflammatory properties, it stimulates cytotoxicity and proliferation of intratumoral antigen activated CD8+ T cell at higher concentrations. AM0010 is anticipated to activate antigen stimulated, intratumoral CD8 T cells while PD-1 inhibits them, providing the rationale for combining AM0010 and anti-PD-1 antibody. Methods: We treated a cohort of 34 NSCLC pts with AM0010 (10-20mg/kg QD, SC) and a PD-1 inhibitor [pembrolizumab (2mg/kg, q3wk IV; n=5) or nivolumab (3mg/kg, q2wk IV; n=29)]. Tumor responses were assessed by irRC every 8 weeks. Immune responses were measured by analysis of serum cytokines (Luminex), activation of blood derived T cells (FACS) and peripheral T cell clonality (TCR sequencing). Tumor PD-L1 expression was confirmed by IHC (22C3). Results: Pts had a median of 2 prior therapies. Median follow-up is 9.6 mo (range 0.5-77.3) in this fully enrolled cohort. AM0010 plus anti-PD-1 was well-tolerated. TrAEs were reversible and transient, with most being low grade, most commonly fatigue and pyrexia. G3/4 TrAEs were thrombocytopenia (7), anemia (6), fatigue (4), rash (3), pyrexia (2), hypertriglyceridemia (1) and pneumonitis (1). As of Jan. 31 2017, 22 pts had at least 1 tumor assessment. Partial responses (PRs) were observed in 8 pts (36.4%). 17 of these 22 pts had tissue for analysis of percent of tumor cells with PD-L1 expression (22C3): 58.8% had <1%, 17.7% had 1-49% and 23.5% had >50%. Best response data stratified for PD-L1 are shown in the table. Median PFS and OS for the entire cohort have not been reached. Updated outcome data that includes all enrolled pts will be available at the meeting. AM0010 plus anti-PD1 increased serum Th1 cytokines (IL-18, IFNγ), the number and proliferation of PD1+ Lag3+ activated CD8+ T cells and a de-novo oligoclonal expansion of T cell clones in the blood while decreasing TGFβ. Conclusions: AM0010 in combination with anti-PD1 is well-tolerated in advanced NSCLC pts. The efficacy and the observed CD8+ T cell activation is promising. Clinical trial information: NCT02009449. [Table: see text]

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