Abstract 4022: PT2385, a novel HIF-2α antagonist, combines with checkpoint inhibitor antibodies to inhibit tumor growth in preclinical models by modulating myeloid cells and enhancing T cell infiltration

2016 ◽  
Author(s):  
Guangzhou Han ◽  
Christina Stevens ◽  
Zhaodan Cao ◽  
Shanhai Xie ◽  
Melissa Maddie ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Checkpoint Inhibitor ◽  
Myeloid Cells ◽  
Cell Infiltration ◽  
Preclinical Models ◽  
Inhibit Tumor Growth ◽  
T Cell Infiltration

scholarly journals MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000328 ◽  
Author(s):  
Xiaoyu Jiang ◽  
Stephanie Dudzinski ◽  
Kathryn E Beckermann ◽  
Kirsten Young ◽  
Eliot McKinley ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Cell Size ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Cell Infiltration ◽  
Response Criteria ◽  
Non Invasive ◽  
T Cell Infiltration

BackgroundImmune checkpoint inhibitors, the most widespread class of immunotherapies, have demonstrated unique response patterns that are not always adequately captured by traditional response criteria such as the Response Evaluation Criteria in Solid Tumors or even immune-specific response criteria. These response metrics rely on monitoring tumor growth, but an increase in tumor size and/or appearance after starting immunotherapy does not always represent tumor progression, but also can be a result of T cell infiltration and thus positive treatment response. Therefore, non-invasive and longitudinal monitoring of T cell infiltration are needed to assess the effects of immunotherapies such as checkpoint inhibitors. Here, we proposed an innovative concept that a sufficiently large influx of tumor infiltrating T cells, which have a smaller diameter than cancer cells, will change the diameter distribution and decrease the average size of cells within a volume to a degree that can be quantified by non-invasive MRI.MethodsWe validated our hypothesis by studying tumor response to combination immune-checkpoint blockade (ICB) of anti-PD-1 and anti-CTLA4 in a mouse model of colon adenocarcinoma (MC38). The response was monitored longitudinally using Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion (IMPULSED), a diffusion MRI-based method which has been previously shown to non-invasively map changes in intracellular structure and cell sizes with the spatial resolution of MRI, in cell cultures and in animal models. Tumors were collected for immunohistochemical and flow cytometry analyzes immediately after the last imaging session.ResultsImmunohistochemical analysis revealed that increased T cell infiltration of the tumors results in a decrease in mean cell size (eg, a 10% increase of CD3+ T cell fraction results a ~1 µm decrease in the mean cell size). IMPULSED showed that the ICB responders, mice with tumor volumes were less than 250 mm3 or had tumors with stable or decreased volumes, had significantly smaller mean cell sizes than both Control IgG-treated tumors and ICB non-responder tumors.ConclusionsIMPULSED-derived cell size could potentially serve as an imaging marker for differentiating responsive and non-responsive tumors after checkpoint inhibitor therapies, a current clinical challenge that is not solved by simply monitoring tumor growth.

scholarly journals P09.15 Targeting the stroma to enhance effector memory T cell infiltration and anti-tumor response to anti-PD1 antibody in pancreatic ductal adenocarcinoma

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A59.2-A60
Author(s):  
A Osipov ◽  
L Zheng
Keyword(s):  
T Cell ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cxcr4 Expression ◽  
Cell Infiltration ◽  
Ductal Adenocarcinoma ◽  
Effector Memory ◽  
Cell Populations ◽  
Memory T Cell ◽  
T Cell Infiltration

BackgroundPancreatic ductal adenocarcinoma (PDAC) is resistant to immune checkpoint inhibition. One of the major resistance mechanisms is attributed to myeloid cells as an immunosuppressive element within the stroma of PDAC. It has been reported that focal adhesion kinase inhibitor (FAKi) can suppress immunosuppressive myeloid cells such as tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSC), consequently sensitizing tumor to anti-PD1 antibody in mouse models of PDAC. Our group has previously shown in a murine model that targeting the stroma via PEGylated recombinant human hyaluronidase (PEGPH20) enhanced the anti-tumor activity of the whole cell vaccine (GVAX) by targeting CXCR4-expressing myeloid cells and led to an increase in infiltration of CCR7- effector memory T cell subsets. Here, we evaluate the hypothesis that FAK expressing myeloid cell subsets modulate T cell infiltration in human PDAC and FAKi can synergize with PEGPH20 by targeting myeloid cells in PDAC.Material and MethodsResected human PDAC tissue specimens treated with GVAX and anti-PD1 therapy was used to assess FAK expression in myeloid cell subsets and its impact on T cell infiltration. A sequential staining and stripping multiplex IHC technique that incorporates 28 myeloid and lymphoid biomarkers, as well as phosphorylated FAK (pFAK) combined with computational image processing was used to assess myeloid cell populations, T cell infiltration and FAK expression.An established murine model of metastatic PDAC treated with and without anti-PD1 therapy was used to assess the synergy and immune-modulating effect of FAKi and stromal degradation of hyaluronan via PEGPH20.ResultsIn human PDAC, FAK is widely expressed in TAMs and neutrophils. Increased FAK expression is associated with increased CXCR4 expression. Lower pFAK density in neutrophils and M2 TAMs, but not lower pFAK density in M1 TAMs, is associated with higher CD8+ T cell infiltration.FAKi and combination of FAKi with anti-PD1 extends survival in the mouse metastasis model of PDAC. Adding PEGPH20 to FAKi and anti-PD1 antibody significantly prolonged survival in this model. Comparing to the combination of FAKi and anti-PD1 antibody, adding PEGPH20 significantly decreased the number of CXCR4-expressing myeloid cells in the tumor microenvironment (TME) of PDAC and consequently led to an increase in the amount of CCR7+ central memory T cells. Additionally, the amount of G-MDSCs, inflammatory resident monocytes and PDL1 expressing myeloid cells in the TME of PDAC, was also decreased in PDAC treated with the triple combination of PEGPH20, FAKi and anti-PD1 antibody compared to FAKi and anti-PD1 antibody.ConclusionFAK is widely expressed in myeloid cell populations, directly correlated with CXCR4 expression and decreased FAK expression in a myeloid (M2 TAMs, neutrophil) inflamed stroma is associated with infiltration of effector CD8 T cells in human PDAC. Stromal degradation of hyaluronan via PEGPH20 combined with FAKi and anti-PD1 antibody further depletes immunosuppressive cells in the TME including G-MDSCs, inflammatory resident monocytes and PDL1 expressing myeloid cells and appears to target the CXCR4 pathway through PEGPH20. These findings support testing the combination of FAKi and anti-PD1 antibody with agents targeting CXCR4 directly or indirectly by PEGPH20 in human PDAC.Disclosure InformationA. Osipov: None. L. Zheng: None.

scholarly journals Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 57
Author(s):  
Man-Chin Chen ◽  
Christian Ronquillo Pangilinan ◽  
Che-Hsin Lee
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
Programmed Death Ligand 1 ◽  
T Cell Infiltration ◽  
Programmed Death

Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.

scholarly journals Rapid Copper Acquisition by Developing Murine Mesothelioma: Decreasing Bioavailable Copper Slows Tumor Growth, Normalizes Vessels and Promotes T Cell Infiltration

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e73684 ◽  
Author(s):  
Andrew Crowe ◽  
Connie Jackaman ◽  
Katie M. Beddoes ◽  
Belinda Ricciardo ◽  
Delia J. Nelson
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Cell Infiltration ◽  
T Cell Infiltration

Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3061-3061 ◽  
Author(s):  
Mark Selby ◽  
John Engelhardt ◽  
Li-Sheng Lu ◽  
Michael Quigley ◽  
Changyu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cell Infiltration ◽  
Preclinical Models ◽  
Concurrent Treatment ◽  
T Cell Infiltration ◽  
Synergistic Antitumor Activity

3061 Background: Interaction of immune checkpoint molecules PD-1 and CTLA-4 and their respective ligands attenuates antitumor T cell responses. In clinical studies, PD-1 blocking antibody (Ab) nivolumab (BMS-936558) or the CTLA-4 blocking Ab ipilimumab result in durable responses in multiple human malignancies. We describe the evaluation of concurrent treatment with anti-PD-1 and anti-CTLA-4 mAbs in preclinical models. Methods: Antitumor activity of treatment with murine homologs of anti-PD-1 (4H2-mIgG1) and anti-CTLA-4 (9D9-mIgG2b) was evaluated in MC38, a murine colon adenocarcinoma model. The effects of concurrent treatment on T cell infiltration of tumors, tumoral expression of PD-L1 and cytokine levels were explored. The preclinical safety profile of concurrent nivolumab + ipilimumab was assessed in a cynomolgus macaque model. Results: Concurrent treatment of MC38 tumors with 4H2-mIgG1 + 9D9-mIgG2b (10 mg/kg Q3d x 3) results in synergistic antitumor activity whereas efficacy with sequential dosing was similar to either agent alone. With concurrent treatment, dose reductions of one Ab relative to a fixed dose of the other resulted in retention of some antitumor activity. Anti-PD-1 enhanced CD8+ T cell infiltration of MC38 tumors and increased tumor PD-L1 expression. Anti-CTLA-4 treatment increased intratumoral CD8+ T cells and reduced intratumoral T regulatory cells. While concurrent treatment did not result in further increases in T cell infiltration, it increased expression of intratumoral cytokines. Anti-PD-1 resulted in down regulation of cell surface and intracellular levels of PD-1 in CD8+ T cells. In cynomolgus macaques, concurrent nivolumab + ipilimumab resulted in dose-dependent gastrointestinal toxicities (diarrhea; body weight loss) not observed in earlier cynomolgus studies with nivolumab and rarely with ipilimumab. These preclinical observations provided the rationale for a dose escalation trial (NCT01024231) of combined nivolumab + ipilimumab in advanced melanoma. Conclusions: Concurrent treatment with anti-PD-1/anti-CTLA-4 resulted in synergistic antitumor activity in preclinical models and supports the evaluation of the combination in clinical studies.

Abstract 2372: Tumoral p53 mutations differentially mediate poor T-cell infiltration and autologous T-cell killing in preclinical models

2019 ◽  
Author(s):  
Deborah A. Silverman ◽  
Emily Ashkin ◽  
Benjamin Whitfield ◽  
Simone Punt ◽  
Soraya Zorro Manrique ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Killing ◽  
Cell Infiltration ◽  
P53 Mutations ◽  
Preclinical Models ◽  
T Cell Infiltration

scholarly journals D-MT Prompts the Anti-Tumor Effect of Oxaliplatin by Inhibiting IDO Expression in a Mouse Model of Colon Cancer

2020 ◽  
Author(s):  
Tiesuo Zhao ◽  
Yongxi Zhang ◽  
Wenyan Fan ◽  
Jing Guo ◽  
Weiwei Ren ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cell ◽  
Tumor Growth ◽  
Malignant Tumors ◽  
Cell Infiltration ◽  
Indoleamine Dioxygenase ◽  
Growth And Survival ◽  
Tumor Bearing ◽  
T Cell Infiltration ◽  
Tumor Tissues

Abstract BackgroundColon cancer is one of the most common malignant tumors in the digestive system. Although oxaliplatin, a chemotherapy drug, has been clinically used to treat colon cancer, its therapeutic effect is unsatisfactory. MethodsIn the present work, it has been proved that indoleamine dioxygenase 2,3 (IDO), an immune checkpoint, is a result of tolerance to chemotherapy. Herein, the anti-tumor effect of treatment with oxaliplatin and D-MT, an IDO inhibitor, on the mice was observed by recording the tumor growth and survival of the mice, and detecting T cell infiltration in tumor tissues and the ratios of immune cells in the spleen by corresponding methods. ResultsWe found that the combination of oxaliplatin and D-MT significantly inhibited tumor growth, prolonged the survival of tumor-bearing mice, increased the cell apoptosis. More importantly, the combination treatment increased the ratios of CD4+ T, CD8+ T and NK cells from the spleen in tumor-bearing mice, and prompted T cell infiltration in tumor tissues. ConclusionThis study provided a new therapeutic strategy for colon cancer treatment in the clinic, especially for patients with oxaliplatin resistance.

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