Journal Articles

Conventional therapies

Immunological effects of conventional cancer therapies such as chemotherapy, radiotherapy or targeted therapy

Targeted overexpression of prostacyclin synthase inhibits lung tumor progression by recruiting CD4+ T lymphocytes in tumors that express MHC class II

More

Lung-specific overexpression of prostacyclin synthase (PGIS) decreases tumor initiation in murine lung cancer models. Prostacyclin analogs prevent lung tumor formation in mice and reverse bronchial dysplasia in former smokers. However, the effect of prostacyclin on lung cancer progression has not been well studied. We investigated the effects of pulmonary PGIS overexpression in an orthotopic immunocompetent mouse model of lung cancer using two murine lung cancer cell lines. Pulmonary PGIS overexpression significantly inhibited CMT167 lung tumor growth, increased CXCL9 expression, and increased CD4+ tumor-infiltrating lymphocytes. Immunodepletion of CD4+ T cells abolished the inhibitory effect of pulmonary PGIS overexpression on CMT167 lung tumor growth. In contrast, pulmonary PGIS overexpression failed to inhibit growth of a second murine lung cancer cell line, Lewis Lung Carcinoma (LLC) cells, and failed to increase CXCL9 expression or CD4+ T lymphocytes in LLC lung tumors. Transcriptome profiling of CMT167 cells and LLC cells recovered from tumor-bearing mice demonstrated that in vivo, CMT167 cells but not LLC cells express MHC class II genes and cofactors necessary for MHC class II processing and presentation. These data demonstrate that prostacyclin can inhibit lung cancer progression and suggest that prostacyclin analogs may serve as novel immunomodulatory agents in a subset of lung cancer patients. Moreover, expression of MHC Class II by lung cancer cells may represent a biomarker for response to prostacyclin.

Author Info: (1) Department of Medicine, Veterans Affairs Medical Center, Denver, CO, USA. Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (2) Departments

Author Info: (1) Department of Medicine, Veterans Affairs Medical Center, Denver, CO, USA. Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (2) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (3) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (4) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (5) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (6) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (7) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (8) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (9) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (10) Department of Medicine, Veterans Affairs Medical Center, Denver, CO, USA. Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (11) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Departments of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (12) Departments of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (13) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Departments of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Less

A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma

More

Background: Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/- MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rationale for combining targeted agents with immunotherapy. Methods: Patients with unresectable Stage III or IV BRAF(V600E) mutant melanoma were enrolled in a single-center prospective study (n = 6). Patients were eligible to receive two courses of HD-IL-2 and vemurafenib twice daily. The primary endpoint was progression-free survival (PFS) with secondary objectives including overall survival (OS), response rates (RR), and safety of combination therapy as compared to historical controls. Immune profiling was performed in longitudinal tissue samples, when available. Results: Overall RR was 83.3% (95% CI: 36%-99%) and 66.6% at 12 weeks. All patients eventually progressed, with three progressing on treatment and three progressing after the vemurafenib continuation phase ended. Median PFS was 35.8 weeks (95% CI: 16-57 weeks). Median OS was not reached; however, the time at which 75% of patients were still alive was 104.4 weeks. Change in circulating BRAF(V600E) levels correlated with response. Though combination therapy was associated with enhanced CD8 T cell infiltrate, an increase in regulatory T cell frequency was seen with HD-IL-2 administration, suggesting a potential limitation in this strategy. Conclusion: Combination vemurafenib and HD-IL-2 is well tolerated and associated with treatment responses. However, the HD-IL-2 induced increase in Tregs may abrogate potential synergy. Given the efficacy of regimens targeting the PD-1 pathway, strategies combining these regimens with BRAF-targeted therapy are currently underway, and the role of combination vemurafenib and HD-IL-2 is uncertain. Trial Registration: Clinical trial information: NCT01754376; https://clinicaltrials.gov/show/NCT01754376.

Author Info: (1) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (2) Department of Surgical Oncology, The University

Author Info: (1) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (2) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (3) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (4) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (5) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. (6) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (7) Department of Medicine, Harvard Medical School, Boston, MA. Department of Pathology, Massachusetts General Hospital, Boston, MA. (8) Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA. Harvard University and Massachusetts Institute of Technology, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. (9) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (10) Department of Medicine, Harvard Medical School, Boston, MA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. (11) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (12) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (13) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (14) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (15) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.

Less

PD-L1 expression in medulloblastoma: an evaluation by subgroup

More

Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor. Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression. In vitro, IFN-gamma robustly stimulated the expression of PD-L1 in all cell lines while radiation induced variable expression. Forced high MYC expression did not significantly alter PD-L1. Methods: Human MB tumor samples were evaluated for expression of PD-L1 and immune cell markers in relation to molecular subgroup assignment. PD-L1 expression was functionally analyzed under conditions of interferon gamma (IFN-gamma), radiation, and MYC overexpression. Conclusions: MB expresses low levels of PD-L1 facilitating immune escape. Importantly, TH1 cytokine stimulation appears to be the most potent inducer of PD-L1 expression in vitro suggesting that an inflamed tumor microenvironment is necessary for PD-1 pathway activation in this tumor.

Author Info: (1) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (2) Johns Hopkins School of Medicine, Sidney Kimmel

Author Info: (1) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (2) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Immunology, Baltimore, MD, USA. (3) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (4) Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA. (5) Johns Hopkins School of Medicine, Department of Pathobiology, Baltimore, MD, USA. (6) Johns Hopkins School of Medicine, Department of Ophthalmology, Baltimore, MD, USA. (7) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Biology, Baltimore, MD, USA. (8) Johns Hopkins School of Medicine, Department of Pathology, Division of Kidney and Urologic Pathology, Baltimore, MD, USA. (9) Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA. (10) Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA. (11) Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA. (12) In Jackson, MS, USA. (13) Johns Hopkins School of Medicine, Department of Pathology, Division of Kidney and Urologic Pathology, Baltimore, MD, USA. (14) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA. (15) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (16) Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA. (17) Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA. (18) Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA. (19) Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA. (20) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Immunology, Baltimore, MD, USA. (21) Columbia University Medical Center, Division of Hematology/Oncology, New York, NY, USA. (22) Johns Hopkins School of Medicine, Department of Neurosurgery, Division of Neurosurgical Oncology, Baltimore, MD, USA.

Less

Bacterial ghosts as adjuvant to oxaliplatin chemotherapy in colorectal carcinomatosis

More

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality worldwide. At late stage of the disease CRC often shows (multiple) metastatic lesions in the peritoneal cavity which cannot be efficiently targeted by systemic chemotherapy. This is one major factor contributing to poor prognosis. Oxaliplatin is one of the most commonly used systemic treatment options for advanced CRC. However, drug resistance - often due to insufficient drug delivery - is still hampering successful treatment. The anticancer activity of oxaliplatin includes besides DNA damage also a strong immunogenic component. Consequently, the aim of this study was to investigate the effect of bacterial ghosts (BGs) as adjuvant immunostimulant on oxaliplatin efficacy. BGs are empty envelopes of gram-negative bacteria with a distinct immune-stimulatory potential. Indeed, we were able to show that the combination of BGs with oxaliplatin treatment had strong synergistic anticancer activity against the CT26 allograft, resulting in prolonged survival and even a complete remission in this murine model of CRC carcinomatosis. This synergistic effect was based on an enhanced induction of immunogenic cell death and activation of an efficient T-cell response leading to long-term anti-tumor memory effects. Taken together, co-application of BGs strengthens the immunogenic component of the oxaliplatin anticancer response and thus represents a promising natural immune-adjuvant to chemotherapy in advanced CRC.

Author Info: (1) Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Research Cluster "Translational Cancer Therapy Research", University

Author Info: (1) Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Austria. (2) Laboratory of MacroMolecular Cancer Therapeutics ( MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria. (3) BIRD-C GmbH & CoKG, Vienna, Austria. (4) Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. (5) Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. (6) Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. (7) Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Austria. (8) BIRD-C GmbH & CoKG, Vienna, Austria. (9) Laboratory of MacroMolecular Cancer Therapeutics ( MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria. (10) Laboratory of MacroMolecular Cancer Therapeutics ( MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria. (11) Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. (12) Laboratory of MacroMolecular Cancer Therapeutics ( MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria. (13) BIRD-C GmbH & CoKG, Vienna, Austria. (14) Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria. Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Austria. (15) Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria. (16) Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria. Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Austria. (17) Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. (18) Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Austria. (19) Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Austria.

Less

Low dose gemcitabine increases the cytotoxicity of human Vgamma9Vdelta2 T cells in bladder cancer cells in vitro and in an orthotopic xenograft model

More

Human gammadeltaT cell immunotherapy is well tolerated and has shown promising results in clinical trials; however, its antitumor efficacy is limited, including results in solid tumors. Ex-vivo expanded gammadeltaT cell stimulated by zoledronic acid (ZOL) activates the gammadeltaT cell subpopulation of so called Vgamma9Vdelta2 T cells. To improve the clinical outcomes of Vgamma9Vdelta2 T cell (abbreviated as gammadeltaT cell here) immunotherapy, we aimed to increase the cytotoxicity of gammadeltaT cells by focusing on two issues: recognition of tumor cells by gammadeltaT cells and the effector (gammadeltaT cell)-to-target (tumor cell) (E/T) ratio. Ex vivo-expanded gammadeltaT cells showed potent cytotoxicity against urinary bladder cancer (UBC) cells in in vitro assays. Combination treatment with standard anticancer agents showed that low dose gemcitabine pretreatment significantly enhanced the cytotoxicity of gammadeltaT cells by upregulating the expression of MICA and MICB (MICA/B), which are tumor-associated antigens recognized by gammadeltaT cells. These effects were abrogated by small interfering RNA-mediated knockdown of MICA/B in UBC cells, suggesting that pre-exposing cancer cells to anticancer agents could be a promising strategy. A bladder instillation approach was used to increase the E/T ratio. The efficacy of ex vivo-expanded gammadeltaT cell immunotherapy was examined in an orthotopic xenograft model. In Vivo Imaging System analysis revealed the potent cytotoxicity of weekly intravesical administration of gammadeltaT cells, and weekly gemcitabine pretreatment enhanced the cytotoxicity of gammadeltaT cells in vivo. In conclusion, intravesical gammadeltaT cell immunotherapy and combination therapy with low dose gemcitabine may be a promising strategy in UBC.

Author Info: (1) Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5 Nakauchi, Yamashina-ku, Kyoto, Japan. Department of Urology, Kyoto Prefectural University of Medicine, Kajii-cho 465

Author Info: (1) Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5 Nakauchi, Yamashina-ku, Kyoto, Japan. Department of Urology, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kamigyo-ku, Kyoto, Japan. (2) Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5 Nakauchi, Yamashina-ku, Kyoto, Japan. (3) Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5 Nakauchi, Yamashina-ku, Kyoto, Japan. Department of Urology, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kamigyo-ku, Kyoto, Japan. (4) Department of Urology, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kamigyo-ku, Kyoto, Japan. (5) Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5 Nakauchi, Yamashina-ku, Kyoto, Japan.

Less

Combination of interferon-expressing oncolytic adenovirus with chemotherapy and radiation is highly synergistic in hamster model of pancreatic cancer

More

Recent clinical trials utilizing Interferon-alpha (IFN) in combination with chemoradiation have demonstrated significant improvements in the survival of patients with pancreatic cancer. However, efficacy was limited by the systemic toxicity of IFN and low intratumoral levels of the cytokine. We sought to address these drawbacks by using an Oncolytic Adenovirus expressing IFN (OAd-hamIFN) in combination with chemotherapy and/or radiation in regimens mimicking the IFN-based therapies used in clinical trials. IFN expressed from OAd-hamIFN potentiated the cytotoxicity of radiation and chemotherapy (5-FU, Gemcitabine, and Cisplatin), and enhanced pancreatic cancer cell death in both in vitro and in vivo experimental settings. Notably, synergism was demonstrated in therapeutic groups that combined the interferon-expressing oncolytic virus with chemotherapy and radiation. In an in vivo immunocompetent hamster model, treatment regimens combining oncolytic virus therapy with 5-FU and radiation demonstrated significant tumor growth inhibition and enhanced survival. This is the first study to report synergism between an IFN-expressing oncolytic adenovirus and chemoradiation-based therapies. When combined with an IFN-expressing OAd, there is a significant enhancement of radiation and especially chemoradiation, which may broaden the application of this new therapeutic approach to the pancreatic cancer patients who cannot tolerate existing chemotherapy regimens.

Author Info: (1) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. (2) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. (3) Department of

Author Info: (1) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. (2) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. (3) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. (4) Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (5) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. Institute of Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (6) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.

Less

TK inhibitor pazopanib primes DCs by downregulation of the beta-catenin pathway

More

Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immuneomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches. In this study we investigated the influence of the TKI pazopanib on dendritic cell (DC) performance and immune priming. Pazopanib improved DC differentiation and performance by promoting upregulation of the maturation markers HLA-DR, CD40, and CCR7; decreasing IL10 production and endocytosis; and increasing T-cell proliferation. PD-L1 expression was also downregulated. Our results demonstrate that pazopanib inhibits the Erk/beta-catenin pathway, suggesting this pathway might be involved in increased DC activation. Similar results were confirmed in DCs differentiated from mRCC patients during pazopanib treatment. In treated patients pazopanib appeared to enhance a circulating CD4+ T-cell population that expresses CD137 (4-1BB). These results suggest that a potentially exploitable immunomodulatory effect induced by pazopanib could improve responses of patients with mRCC in customized protocols combining TKIs with ICI immunotherapy.

Author Info: (1) Department of Experimental Medicine, Sapienza University of Rome ilaria.zizzari@uniroma1.it. (2) Experimental Medicine. (3) Oncology Unit, S. Andrea Hospital, Sapienza University of Rome. (4) Department

Author Info: (1) Department of Experimental Medicine, Sapienza University of Rome ilaria.zizzari@uniroma1.it. (2) Experimental Medicine. (3) Oncology Unit, S. Andrea Hospital, Sapienza University of Rome. (4) Department of Radiological, Oncological and Pathological Science, Division of Oncology, Policlinico Umberto I Hospital, Sapienza University of Rome. (5) Division of Medical Oncology B, San Camillo Forlanini Hospital. (6) Department of Medical Oncology, Policlinico Umberto I. (7) Experimental Medicine, Sapienza University of Rome. (8) Sapienza University of Rome. (9) Experimental Medicine, Sapienza University of Rome. (10) Department of Medical Oncology, Fondazione Policlinico A. Gemelli. (11) Department of Medical Oncology, Fondazione Policlinico A. Gemelli. (12) Oncology Unit, Department of Clinical and Molecular Medicine, Sapienza University of Rome. (13) Experimental Medicine.

Less

Dual inhibition of STAT1 and STAT3 activation downregulates expression of PD-L1 in human breast cancer cells

More

OBJECTIVES: Breast cancer is the most commonly diagnosed cancer, and it is a leading cause of cancer-related deaths in females worldwide. Triple-negative breast cancer (TNBC) constitutes 15% of breast cancer and shows distinct metastasis profiles with poor prognosis. Strong PD-L1 expression has been observed in some tumors, supporting their escape from immune surveillance. Targeting PD-L1 could be a promising therapeutic approach in breast cancer patients. We investigated potential molecular mechanisms for constitutive expression of PD-L1 by inhibiting upstream STAT1 and STAT3 signals. METHODS: PD-L1 expression in three breast cancer cell lines was measured using quantitative PCR and western blotting. Activation of STAT1 and STAT3 was blocked using pharmacological inhibitors and siRNA. The mechanism underlying the constitutive expression of PD-L1 was investigated using ChIP and co-immunoprecipitation assays. RESULTS: We found that individual inhibition of STAT1 and STAT3 activation partially downregulated PD-L1, while combined inhibition completely downregulated PD-L1 expression. Moreover, our results suggest that pSTAT1-pSTAT3 dimerize in cytosol and translocate to the nucleus, where they bind to PD-L1 promoter and induce PD-L1 expression. CONCLUSION: These findings provide a rationale for combined targeting of STAT1 and STAT3 for the development of immune-based cancer therapies for down regulation of PD-L1 expression.

Author Info: (1) a Cancer Research Center , Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation , Doha , Qatar

Author Info: (1) a Cancer Research Center , Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation , Doha , Qatar. (2) a Cancer Research Center , Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation , Doha , Qatar. (3) b College of Medicine and Health Sciences , United Arab Emirates University , Al Ain , United Arab Emirates. (4) a Cancer Research Center , Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation , Doha , Qatar. c Institute of Cancer Sciences , University of Manchester , Manchester , United Kingdom.

Less

Vinorelbine, cyclophosphamide and 5-FU effects on the circulating and intratumoural landscape of immune cells improve anti-PD-L1 efficacy in preclinical models of breast cancer and lymphoma

More

BACKGROUND: Anti-PD-1 and anti-PD-L1 checkpoint inhibitors (CIs) are clinically active in many types of cancer. However, only a minority of patients achieve a complete and/or long-lasting clinical response. We studied the effects of different doses of three widely used, orally active chemotherapeutics (vinorelbine, cyclophosphamide and 5-FU) over local and metastatic tumour growth, and the landscape of circulating and tumour-infiltrating immune cells involved in CI activity. METHODS: Immunocompetent Balb/c mice were used to generate models of breast cancer (BC) and B-cell lymphoma. Vinorelbine, cyclophosphamide and 5-FU (alone or in combination with CIs), were given at low-dose metronomic, medium, or maximum tolerable dosages. RESULTS: Cyclophosphamide increased circulating myeloid derived suppressor cells (MDSC). Vinorelbine, cyclophosphamide and 5-FU reduced circulating APCs. Vinorelbine and cyclophosphamide (at medium/high doses) reduced circulating Tregs. Cyclophosphamide (at low doses) and 5-FU (at medium doses) slightly increased circulating Tregs. Cyclophosphamide was the most potent drug in reducing circulating CD3+CD8+ and CD3+CD4+ T cells. Vinorelbine, cyclophosphamide and 5-FU reduced the number of circulating B cells, with cyclophosphamide showing the most potent effect. Vinorelbine reduced circulating NKs, whereas cyclophosphamide and 5-FU, at low doses, increased circulating NKs. In spite of reduced circulating T, B and NK effector cells, preclinical synergy was observed between chemotherapeutics and anti-PD-L1. Most-effective combinatorial regimens where associated with neoplastic lesions enriched in B cells, and, in BC-bearing mice (but not in mice with lymphoma) also in NK cells. CONCLUSIONS: Vinorelbine, cyclophosphamide and 5-FU have significant preclinical effects on circulating and tumour-infiltrating immune cells and can be used to obtain synergy with anti-PD-L1.

Author Info: (1) Laboratory of Hematology-Oncology and Hemo-Lympho Pathology Unit, European Institute of Oncology, Milan, Italy. (2) Laboratory of Hematology-Oncology and Hemo-Lympho Pathology Unit, European Institute of

Author Info: (1) Laboratory of Hematology-Oncology and Hemo-Lympho Pathology Unit, European Institute of Oncology, Milan, Italy. (2) Laboratory of Hematology-Oncology and Hemo-Lympho Pathology Unit, European Institute of Oncology, Milan, Italy. (3) Laboratory of Hematology-Oncology and Hemo-Lympho Pathology Unit, European Institute of Oncology, Milan, Italy. (4) Hemo-Lympho Pathology Unit, European Institute of Oncology, Milan, Italy. (5) Laboratory of Hematology-Oncology and Hemo-Lympho Pathology Unit, European Institute of Oncology, Milan, Italy. (6) Laboratory of Hematology-Oncology and Hemo-Lympho Pathology Unit, European Institute of Oncology, Milan, Italy. francesco.bertolini@ieo.it.

Less

Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity

More

INTRODUCTION: There is evidence that the combination of ipilimumab and stereotactic radiosurgery (SRS) for brain metastases improves outcomes. We investigated clinical outcomes, radiation toxicity, and impact of ipilimumab timing in patients treated with SRS for melanoma brain metastases. METHODS: We retrospectively identified 91 patients treated with SRS at our institution for melanoma brain metastases from 2006 to 2015. Concurrent ipilimumab administration was defined as within +/- 4 weeks of SRS procedure. Acute and late toxicities were graded with CTCAE v4.03. Overall survival (OS), local failure, distant brain failure, and failure-free survival were analyzed with the Kaplan-Meier method. OS was analyzed with Cox regression. RESULTS: Twenty-three patients received ipilimumab concurrent with SRS, 28 patients non-concurrently, and 40 patients did not receive ipilimumab. The median age was 62 years and 91% had KPS >/= 80. The median follow-up time was 7.4 months. Patients who received ipilimumab had a median OS of 15.1 months compared to 7.8 months in patients who did not (p = 0.02). In multivariate analysis, ipilimumab (p = 0.02) and diagnosis-specific graded prognostic assessment (p = 0.02) were associated with OS. There were no differences in intracranial control by ipilimumab administration or timing. The incidence of radiation necrosis was 5%, with most events occurring in patients who received ipilimumab. CONCLUSIONS: Patients who received ipilimumab had improved OS even after adjusting for prognostic factors. Ipilimumab did not appear to increase risk for acute toxicity. The majority of radiation necrosis events, however, occurred in patients who received ipilimumab. Our results support the continued use of SRS and ipilimumab as clinically appropriate.

Author Info: (1) Harvard Medical School, Boston, MA, USA. kevin_diao@hms.harvard.edu. Department of Radiation Oncology, Keck School of Medicine of USC, Los Angeles, CA, USA. kevin_diao@hms.harvard.edu. (2) Department

Author Info: (1) Harvard Medical School, Boston, MA, USA. kevin_diao@hms.harvard.edu. Department of Radiation Oncology, Keck School of Medicine of USC, Los Angeles, CA, USA. kevin_diao@hms.harvard.edu. (2) Department of Radiation Oncology, Keck School of Medicine of USC, Los Angeles, CA, USA. (3) Department of Radiation Oncology, Keck School of Medicine of USC, Los Angeles, CA, USA. (4) Department of Radiation Oncology, Keck School of Medicine of USC, Los Angeles, CA, USA. (5) Department of Radiation Oncology, Keck School of Medicine of USC, Los Angeles, CA, USA. (6) Department of Clinical Neurology, Keck School of Medicine of USC, Los Angeles, CA, USA. (7) Division of Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA, USA. (8) Department of Neurological Surgery, Keck School of Medicine of USC, Los Angeles, CA, USA. (9) Department of Radiation Oncology, Keck School of Medicine of USC, Los Angeles, CA, USA.

Less