scholarly journals Activation of Tumor-Specific CD8+ T Cells after Intratumoral Ad5-TRAIL/CpG Oligodeoxynucleotide Combination Therapy

2007 ◽  
Vol 67 (24) ◽  
pp. 11980-11990 ◽  
Author(s):  
R. L. VanOosten ◽  
T. S. Griffith
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Cd8 T Cells ◽  
Cpg Oligodeoxynucleotide

Increases in T Cell Telomere Length in HIV Infection after Antiretroviral Combination Therapy for HIV-1 Infection Implicate Distinct Population Dynamics in CD4+ and CD8+ T Cells

1999 ◽  
Vol 92 (1) ◽  
pp. 14-24 ◽  
Author(s):  
Sumesh Kaushal ◽  
Alan L. Landay ◽  
Michael M. Lederman ◽  
Elizabeth Connick ◽  
John Spritzler ◽  
...  
Keyword(s):  
T Cells ◽  
Population Dynamics ◽  
T Cell ◽  
Combination Therapy ◽  
Hiv Infection ◽  
Telomere Length ◽  
Cd8 T Cells ◽  
Distinct Population ◽  
Hiv 1

scholarly journals Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3948
Author(s):  
Kazumasa Oya ◽  
Yoshiyuki Nakamura ◽  
Zhu Zhenjie ◽  
Ryota Tanaka ◽  
Naoko Okiyama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Antitumor Effect ◽  
Skin Lesions ◽  
Ifn Γ ◽  
Deficient Mice

The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

452 Combination treatment using KISIMATM protein-based cancer vaccine and systemic STING agonist results in profound modulation of tumor microenvironment and improved tumor control

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A479-A479
Author(s):  
Matteo Rossi ◽  
Elodie Belnoue ◽  
Susanna Carboni ◽  
Wilma Besson-Di Berardino ◽  
Erika Riva ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Cancer Vaccine ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Tumor Control ◽  
Therapeutic Vaccination ◽  
Potent Tumor

BackgroundKISIMATM platform allows the development of protein-based cancer vaccines able to induce a potent, tumor-specific CD8 and CD4 T cells response. While the cell penetrating peptide and the Anaxa portions confer, respectively, the cell delivery and self-adjuvanticity properties, the multiantigenic domain allows the targeting of different cancer antigens, resulting in anti-tumoral efficacy in different murine models.1 The first clinical candidate developed from KISIMATM is currently tested, together with anti-PD-1 blockade, in a phase I study in metastatic colorectal cancer patients. Stimulator of interferon genes agonists (STINGa) were shown to induce a potent type I interferon response in preclinical studies. The intratumoral administration of STINGa, to promote tumor inflammation, was shown to result in a protective spontaneous immune response in several murine tumor models. However, the encouraging preclinical results are not supported by recent clinical data, challenging the efficacy of unspecific monotherapy.As it is more and more clear that an effective cancer immunotherapy will require the combination of different treatment strategies, we investigate here the efficacy of combining KISIMATM cancer vaccine with STINGa treatment.MethodsMice were vaccinated with subcutaneous (s.c.) injection of KISIMATM vaccine combined with s.c. administration of STINGa. Safety and immunogenicity were assessed by measuring temperature, serum cytokines and the peripheral antigen-specific response. Anti-tumoral efficacy as well as in depth monitoring of TILs and tumor microenvironment modulation were assessed following therapeutic vaccination in a HPV16 E6 and E7 expressing TC-1 cold tumor model.ResultsCombination treatment was well tolerated and promoted the development of circulating antigen-specific CD8 T cells. In TC-1 tumor bearing mice, KISIMATM therapeutic vaccination resulted in the infiltration of both antigen-specific CD8 and CD4 T cells within the tumor, as well as a switch of tumor associated macrophages polarization toward the more inflammatory type 1. Combination therapy further increased the tumor microenvironment modulation induced by KISIMATM vaccine, promoting the polarization of inflammatory Thelper 1 CD4 T cells and increasing the effector function of antigen-specific CD8 T cells. The profound modulation of the tumor microenvironment induced by combination therapy enhanced the beneficial effect of KISIMATM vaccination, resulting in a prolonged tumor control.ConclusionsCombination of KISIMATM cancer vaccine with systemic STINGa treatment induces the development of a potent, tumor-specific immune response resulting in a profound modulation of the TME. As check-point inhibitor (CPI) therapy is ineffective on poorly infiltrated tumors, combination with therapies able to highly enhance tumor infiltration by T cells could expand CPI indications.Ethics ApprovalThe study was approved by the Canton of Geneva Ethic Board, under the license number GE165/19ReferenceBelnoue E, et al. Targeting self and neo-epitopes with a modular self-adjuvanting cancer vaccine. JCI Insight 2019. 4:11.

scholarly journals Increased Immunogenicity of a Minimally Immunogenic Tumor after Cancer-Targeting Near Infrared Photoimmunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3747
Author(s):  
Hiroaki Wakiyama ◽  
Aki Furusawa ◽  
Ryuhei Okada ◽  
Fuyuki Inagaki ◽  
Takuya Kato ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Near Infrared ◽  
Cancer Targeting ◽  
Immunogenic Tumor

Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective cancer treatment that employs an antibody photoabsorber conjugate (APC) composed of a targeting monoclonal antibody (mAb) conjugated with a photoactivatable phthalocyanine-derivative dye. Once injected and allowed to bind to a tumor, the APC is activated by local near-infrared light which kills cancer cells and induces a strong immune response in the tumor microenvironment by unmasking of new tumor antigens emerging from damaged tumor cells. Due to its ability to incite an immune reaction, even in poorly immunogenic tumors, NIR-PIT has the potential to enhance immunogenicity in tumors especially after immune checkpoint inhibition. In this study, we employ a poorly immunogenic MOC2-luc syngeneic tumor model and evaluate the efficacy of cancer-targeting CD44-targeted NIR-PIT. Increased infiltration of CD8+ T cells observed after NIR-PIT suggested an enhanced immune environment. Next, we evaluated tumor progression and survival after the combination of CD44-targeted NIR-PIT and short-term administration of an anti-PD1 immune checkpoint inhibitor (ICI) to further activate CD8+ T cells. Additionally, in mice in which the tumors were eradicated by this combination therapy, a re-challenge with fresh MOC2-luc cells demonstrated failure of tumor implantation implying acquired long-term immunity against the cancer cells. Combination therapy decreased tumor progression and prolonged survival significantly. Therefore, we concluded that NIR-PIT was able to convert a minimally immunogenic tumor unresponsive to anti-PD-1 ICI into a highly immunogenic tumor responsive to anti-PD-1 ICI, and this therapy was capable of inducing long-term immunity against the treated cancer.

scholarly journals 141 PBMC-based cancer vaccines generated with microfluidics squeezing demonstrate synergistic and durable tumor reduction in combination with PD1 checkpoint and FAP targeted IL-2 variants

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A155-A155
Author(s):  
Matthew Booty ◽  
Adam Stockmann ◽  
Olivia Pryor ◽  
Melissa Myint ◽  
Christine Trumpfheller ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Median Survival ◽  
Cancer Vaccine ◽  
Cd8 T Cells ◽  
Cancer Vaccines ◽  
Tumor Model ◽  
Mechanistic Study ◽  
Engineering System ◽  
Tumor Implant

BackgroundWe engineered unfractionated peripheral blood mononuclear cells (PBMCs) to function as antigen presenting cells (APCs) that generate potent CD8+ T cell responses. We investigated the combined efficacy of PBMC-based cancer vaccine with targeted interleukin 2 variants (IL2v); anti-Programmed Cell Death Protein 1 (muPD1-IL2v) and anti-Fibroblast Activation Protein (muFAP-IL2v).MethodsWe generated PBMC-based cancer vaccine with microfluidic cell engineering system (Cell Squeeze®), which facilitates direct cytosolic antigen delivery and enables cell subsets within PBMCs to function as APCs. The immunocytokines used contain IL2v fused with antibody counterparts that enable targeting to tumor-associated stroma or immune cells (aFAP and aPD-1, respectively) with modified FcR binding. The IL2v moiety, compared with wild-type IL-2, has abolished binding to IL-2Ra (CD25) resulting in IL-2Rgb binding only, thus fully maintaining activity on NK and CD8+ T cells, while avoiding Treg activity and CD25 mediated toxicity.ResultsIn the murine TC-1 HPV tumor model, SQZ-PBMC-based vaccines show efficacy as monotherapy (1e6 cells administered iv on day 14 post-tumor implant), while SQZ combination therapy with targeted immunocytokines, muPD1-IL2v and muFAP-IL2v (2 mg/kg or 1 mg/kg, respectively, administered iv on days 21, 28, and 35 post-tumor implant) significantly delayed tumor growth and improved survival in murine TC-1 HPV tumor model. Median survival of combination treated groups remained undefined at day 84 post-tumor implant, while the monotherapy treated groups had calculated median survival times of 36.5, 42, and 70 days for the muFAP-IL2v, muPD1-IL2v, and SQZ monotherapy groups, respectively. Following initial tumor clearance, tumor-free mice (2/12 animals for SQZ monotherapy; 8/12 animals for SQZ with muFAP-IL2v; 11/11 animals for SQZ with muPD1-IL2v) were all re-challenged at day 84 and all remained tumor free at least 7 weeks post re-challenge, suggesting the generation of anti-tumor memory response. In a mechanistic study, SQZ-PBMCs in combination with muPD1-IL2v resulted in increased expansion of intra-tumoral, antigen-specific CD8+ T cells compared with separate administration of either therapy (~3.6-fold over SQZ alone; ~2000-fold over muPD1-IL2v alone; per mg of tumor). Combination therapy also resulted in improved IFNγ and TNFα cytokine production by SQZ-elicited CD8+ T cells (~1.7-fold and ~9-fold, respectively, over SQZ monotherapy).ConclusionsMonotherapy with SQZ-PBMC-based cancer vaccines can drive anti-tumor responses in murine systems. These responses are enhanced by combined administration of targeted immunocytokines. Monotherapy with SQZ-PBMC-HPV is currently under clinical evaluation for HPV16+ tumor indications. These preclinical data support the combination of SQZ-PBMC with FAP-IL2v or PD1-IL2v targeted immunocytokine as promising cancer immunotherapies.

scholarly journals Presentation of Soluble Antigens to CD8+ T Cells by CpG Oligodeoxynucleotide-Primed Human Naive B Cells

2011 ◽  
Vol 186 (4) ◽  
pp. 2080-2086 ◽  
Author(s):  
Wei Jiang ◽  
Michael M. Lederman ◽  
Clifford V. Harding ◽  
Scott F. Sieg
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
Cpg Oligodeoxynucleotide

Synergistic Control of Acute GvHD: Effectively Down-Regulating T Cell Proliferation and Cytotoxicity with Combined mTOR Inhibition and CD28:CD80/86 Costimulation Blockade.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2998-2998
Author(s):  
Natalia Kozyr ◽  
Swetha Ramakrishnan ◽  
Aneesah Polnett ◽  
Kelly Hamby ◽  
Divya Tiwari ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
T Cell Proliferation ◽  
Costimulation Blockade ◽  
Ki 67 ◽  
Mtor Inhibition

Abstract Abstract 2998 Introduction: GvHD remains the most deadly complication of HSCT despite current prevention strategies. To address the unmet need for better GvHD control, we have created a non-human primate (NHP) model with which to rigorously test mechanism and efficacy of novel therapeutics. In this study, we determined whether a novel combination of mTOR inhibition (with sirolimus) and CD28:CD80/86 costimulation blockade (with belatacept) could control GvHD. Here we show for the first time that these two agents combine synergistically to prevent both the clinical and immunologic manifestations of primate aGvHD. Methods: Rhesus macaque recipients were irradiated (9.6 Gy in 2 fractions at 7cGy/min), and then transplanted with G-CSF-mobilized PBSC from a haplo-identical donor (1–5×108 TNC/kg). Recipients were treated with either sirolimus alone (n = 4, troughs targeted at 5–10 ng/mL), belatacept alone (receiving weekly doses of 20 mg/kg), or combination therapy. Clinical GvHD was monitored using our previously described NHP grading scale (Miller et al., Blood 2010), and multiparameter flow cytometric analysis was performed. Results: Untreated controls (n = 5) developed rapid, severe histopathologically-proven aGvHD and succumbed rapidly (MST = 7 days). Recipients treated with either sirolimus or belatacept alone were partially protected from the clinical manifestations of GvHD. Sirolimus-treated recipients (n = 6) developed predominantly GI disease (with diarrhea but no elevation of bilirubin) and had an MST of 14 days (Figure 1). Recipients treated with belatacept alone (n = 3) developed primarily liver aGvHD (bilirubin rapidly rising to 6–30 × normal with histologically-confirmed lymphocytic infiltration) and an MST of 11 days. In striking contrast, recipients treated with combined sirolimus + belatacept (n = 5) demonstrated neither uncontrolled diarrhea nor hyperbilirubinemia at the timed terminal analysis (1 month post-transplant). We employed multiparameter flow cytometry to determine the immunologic consequences of sirolimus and belatacept on T cell proliferation (using Ki-67 expression) and cytotoxity (using granzyme B expression). We found that the clinical synergy observed with combined therapy was recapitulated immunologically. Thus, while untreated aGvHD was associated with rampant CD8+ proliferation (with 83 +/− 14% Ki-67+ CD8+ vs 4.7 +/− 0.6% pre-transplant), sirolimus or belatacept as monotherapy both partially controlled proliferation (35 +/− 3% and 65 +/− 23% Ki-67+ CD8+ with sirolimus or belatacept, respectively). Combined sirolimus + belatacept dramatically reduced proliferation (to 8 +/− 3%, favorably comparing with 13% Ki-67+ CD8+ T cells using standard Calcineurin Inhibitor/Methotrexate (CNI/MTX) prophylaxis). Sirolimus and belatacept both also partially controlled GvHD-related T cell cytotoxicity. Thus, while untreated aGvHD was associated with excessive granzyme B expression in CD8+ T cells (82 +/− 2% granzyme Bvery high CD8+ cells vs 0.3 +/− 0.2% pre-transplant) sirolimus or belatacept monotherapy also partially controlled cytotoxicity (8 +/− 1% and 35 +/− 1% granzyme Bvery high with sirolimus or belatacept, respectively). Combination therapy dramatically reduced the proportion of these cells, to 1.5 +/− 0.8 % granzyme Bvery high, favorably comparing with 4% granzyme Bvery high using CNI/MTX. The ability of sirolimus, belatacept, or the combination to control Ki-67 and Granzyme B expression closely correlated with survival (Figure 2A, B) supporting a pathogenic role for these highly proliferative and cytotoxic cells in aGvHD pathology. Moreover, significant co-expression of granzyme B in the Ki-67+ cells was observed (Figure 2C) suggesting that dual-positive Ki-67/Granzyme B cells may mark a pathogenic population, amenable to tracking in the peripheral blood. Implications: These results reveal a previously undiscovered synergy between sirolimus and belatacept in the control of primate aGvHD, and provide support for future clinical investigation of this novel prevention strategy. They also identify CD8+/Ki-67+/Granzyme Bvery high dual-positive T cells as a potentially sensitive biomarker of GvHD pathogenesis, amenable to monitoring in either the blood or in GvHD target organs. Disclosures: No relevant conflicts of interest to declare.

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