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mice immune cancer PD-L1 radiation

Jie Lan, Rui Li, Li-Mei Yin, Lei Deng, Jun Gui, Bao-Qing Chen, Lin Zhou, Mao-Bin Meng, Qiao-Rong Huang, Xian-Ming Mo, Yu-Quan Wei, Bo Lu, Adam Dicker, Jian-Xin Xue, You Lu
PURPOSE: Ablative hypofractionated radiation therapy (AHFRT) presents a therapeutic advantage compared with conventional fractionated radiation therapy (CFRT) for primary and oligometastatic cancers. However, the underlying mechanisms remain largely unknown. In the present study, we compared the immune alterations in response to AHFRT versus CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT. METHODS AND MATERIALS: We established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biologically equivalent dose...
May 1, 2018: International Journal of Radiation Oncology, Biology, Physics
Arutselvan Natarajan, Chirag B Patel, Frezghi Habte, Sanjiv S Gambhir
The immune checkpoint programmed death 1 receptor (PD-1) expressed on some tumor-infiltrating lymphocytes, and its ligand (PD-L1) expressed on tumor cells, enable cancers to evade the immune system. Blocking PD-1 with the monoclonal antibody pembrolizumab is a promising immunotherapy strategy. Thus, noninvasively quantifying the presence of PD-1 expression in the tumor microenvironment prior to initiation of immune checkpoint blockade may identify the patients likely to respond to therapy. We have developed a 64 Cu-pembrolizumab radiotracer and evaluated human dosimetry...
January 12, 2018: Scientific Reports
David J Donnelly, Ralph Adam Smith, Paul Morin, Dasa Lipovsek, Jochem Gokemeijer, Daniel Cohen, Virginie Lafont, Tritin Tran, Erin Lee Cole, Martin Wright, Joonyoung Kim, Adrienne Pena, Daniel Kukral, Douglas D Dischino, Patrick Chow, Jinping Gan, Olufemi Adelakun, Xi-Tao Wang, Kai Cao, David Lueng, Samuel Bonacorsi, Wendy Hayes
The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti-PD-L1 Adnectin after (18)F-fluorine labeling. Methods: An anti-PD-L1 Adnectin was labeled with (18)F in two steps. This synthesis featured fluorination of a novel prosthetic group, followed by a copper-free click conjugation to a modified Adnectin to generate (18)F-BMS-986192...
October 12, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Matthew T Silvestrini, Elizabeth S Ingham, Lisa M Mahakian, Azadeh Kheirolomoom, Yu Liu, Brett Z Fite, Sarah M Tam, Samantha T Tucci, Katherine D Watson, Andrew W Wong, Arta M Monjazeb, Neil E Hubbard, William J Murphy, Alexander D Borowsky, Katherine W Ferrara
Focal therapies play an important role in the treatment of cancers where palliation is desired, local control is needed, or surgical resection is not feasible. Pairing immunotherapy with such focal treatments is particularly attractive; however, there is emerging evidence that focal therapy can have a positive or negative impact on the efficacy of immunotherapy. Thermal ablation is an appealing modality to pair with such protocols, as tumors can be rapidly debulked (cell death occurring within minutes to hours), tumor antigens can be released locally, and treatment can be conducted and repeated without the concerns of radiation-based therapies...
March 23, 2017: JCI Insight
Elizabeth Marie Krcik
PURPOSE: To analyze current preclinical trials and early clinical trials on the effects of concomitant anti-programmed death ligand 1 (anti-PD-L1) immunotherapy and radiation therapy on progression-free survival (PFS) and overall survival (OS) for advanced melanoma and metastatic non-small cell lung cancer (NSCLC) patients. METHODS: A literature review was conducted to find current articles about radiation and anti-PD-L1 combinatorial therapy to gain knowledge about T-lymphocyte (T-cell) mediated immune responses, preclinical mouse tumor trials, and early clinical trials...
September 2016: Radiologic Technology
Simon J Dovedi, Amy L Adlard, Yosuke Ota, Masashi Murata, Eiji Sugaru, Erina Koga-Yamakawa, Ken Eguchi, Yuko Hirose, Setsuko Yamamoto, Hiroki Umehara, Jamie Honeychurch, Eleanor J Cheadle, Gareth Hughes, Philip J Jewsbury, Robert W Wilkinson, Ian J Stratford, Timothy M Illidge
Strategies to augment anti-cancer immune responses have recently demonstrated therapeutic utility. To date clinical success has been achieved through targeting co-inhibitory checkpoints such as CTLA-4, PD-1, and PD-L1. However, approaches that target co-activatory pathways are also being actively being developed. Here we report that the novel TLR7-selective agonist DSR-29133 is well tolerated in mice and leads to acute immune activation. Administration of DSR-29133 leads to the induction of IFNα/γ, IP-10, TNFα, IL-1Ra and IL-12p70, and to a reduction in tumor burden in syngeneic models of renal cancer (Renca), metastatic osteosarcoma (LM8) and colorectal cancer (CT26)...
March 29, 2016: Oncotarget
X B Zhuang, N Xing, Q Zhang, S J Yuan, W Chen, T K Qiao
Immunotherapy is a hot issue in cancer research over the years and tumor cell vaccine is one of the increasing number of studies. Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. CpG Oligodeoxynucleotides (CpG ODNs), synthetic oligonucleotides containing a cytosine-phosphate-guanine(CpG) motif, was shown to enhance immune responses to a wide variety of antigens. In this study, we generated the radioresistant Lewis lung cancer cell by repeated X-ray radiation and inactivated it as a whole tumor cell vaccine to enhance the immunogenicity of tumor cell vaccine...
2015: Neoplasma
Christina Twyman-Saint Victor, Andrew J Rech, Amit Maity, Ramesh Rengan, Kristen E Pauken, Erietta Stelekati, Joseph L Benci, Bihui Xu, Hannah Dada, Pamela M Odorizzi, Ramin S Herati, Kathleen D Mansfield, Dana Patsch, Ravi K Amaravadi, Lynn M Schuchter, Hemant Ishwaran, Rosemarie Mick, Daniel A Pryma, Xiaowei Xu, Michael D Feldman, Tara C Gangadhar, Stephen M Hahn, E John Wherry, Robert H Vonderheide, Andy J Minn
Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common...
April 16, 2015: Nature
Michael B Bernstein, Charlie T Garnett, Huogang Zhang, Anna Velcich, Max M Wattenberg, Sofia R Gameiro, Shalom Kalnicki, James W Hodge, Chandan Guha
We sought to determine if single-dose external beam radiation therapy (EBRT) could modulate the expression signature of T-cell costimulatory and coinhibitory molecules in human prostate cancer (PCa) cell lines in vitro. We investigated the functional impact of irradiated PCa cells with a modulated costimulatory profile on responder T-cell activity. We used three PCa cell lines (DU145, PC3, and LNCaP) and two epithelial cell lines from noncancerous prostate and lung tissue. After 72 hours of EBRT, surface expression of four immunostimulatory molecules (CD70, CD275/ICOSL, CD134L/OX40L, and CD137L/41BBL) and two immunosuppressive markers (CTLA-4/CD152 and PD-L1/CD274) were evaluated by flow cytometry...
May 2014: Cancer Biotherapy & Radiopharmaceuticals
Paula D Bos, George Plitas, Dipayan Rudra, Sue Y Lee, Alexander Y Rudensky
Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer. Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3(DTR) knockin mice. T reg cell ablation resulted in significant determent of primary and metastatic tumor progression...
October 21, 2013: Journal of Experimental Medicine
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