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Cancer neoantigens

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https://www.readbyqxmd.com/read/29907590/autologous-t-cells-targeting-four-neoantigens-induce-tumor-regression
#1
(no author information available yet)
Autologous T-cell transfer achieves a durable regression in a patient with metastatic breast cancer.
June 15, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29906453/immunization-with-tumor-neoantigens-displayed-on-t7-phage-nanoparticles-elicits-plasma-antibody-and-vaccine-draining-lymph-node-b-cell-responses
#2
Girja S Shukla, Yu-Jing Sun, Stephanie C Pero, Giselle S Sholler, David N Krag
The aim of this preclinical study was to evaluate T7 bacteriophage as a nanoparticle platform for expression of neoantigens that could allow rapid generation of vaccines for potential studies in human cancer patients. We have generated recombinant T7 phage vaccines carrying neoepitopes derived from mutated proteins of B16-F10 melanoma tumor cells. With the single mutated amino acid (AA) centered, peptides were expressed on the outer coat of T7 phage. All peptides with 11 and 34 AAs were successfully expressed...
June 12, 2018: Journal of Immunological Methods
https://www.readbyqxmd.com/read/29906450/inactivation-of-cdk12-delineates-a-distinct-immunogenic-class-of-advanced-prostate-cancer
#3
Yi-Mi Wu, Marcin Cieślik, Robert J Lonigro, Pankaj Vats, Melissa A Reimers, Xuhong Cao, Yu Ning, Lisha Wang, Lakshmi P Kunju, Navonil de Sarkar, Elisabeth I Heath, Jonathan Chou, Felix Y Feng, Peter S Nelson, Johann S de Bono, Weiping Zou, Bruce Montgomery, Ajjai Alva, Dan R Robinson, Arul M Chinnaiyan
Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication...
June 14, 2018: Cell
https://www.readbyqxmd.com/read/29900056/complex-pattern-of-immune-evasion-in-msi-colorectal-cancer
#4
Mine Ozcan, Jonas Janikovits, Magnus von Knebel Doeberitz, Matthias Kloor
Mismatch repair (MMR)-deficient cancers accumulate multiple insertion/deletion mutations at coding microsatellites (cMS), which give rise to frameshift peptide neoantigens. The high mutational neoantigen load of MMR-deficient cancers is reflected by pronounced anti-tumoral immune responses of the host and high responsiveness towards immune checkpoint blockade. However, immune evasion mechanisms can interfere with the immune response against MMR-deficient tumors. We here performed a comprehensive analysis of immune evasion in MMR-deficient colorectal cancers, focusing on HLA class I-mediated antigen presentation...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29900052/time-tumor-immunity-in-the-microenvironment-classification-based-on-tumor-cd274-pd-l1-expression-status-and-tumor-infiltrating-lymphocytes-in-colorectal-carcinomas
#5
Tsuyoshi Hamada, Thing Rinda Soong, Yohei Masugi, Keisuke Kosumi, Jonathan A Nowak, Annacarolina da Silva, Xinmeng Jasmine Mu, Tyler S Twombly, Hideo Koh, Juhong Yang, Mingyang Song, Li Liu, Mancang Gu, Yan Shi, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Sachet A Shukla, Catherine J Wu, Levi A Garraway, Xuehong Zhang, Kana Wu, Jeffrey A Meyerhardt, Andrew T Chan, Jonathan N Glickman, Scott J Rodig, Gordon J Freeman, Charles S Fuchs, Reiko Nishihara, Marios Giannakis, Shuji Ogino
Inhibitors targeting the PDCD1 (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 ( PDCD1 ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer. Using 812 colon and rectal carcinoma cases from the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association of tumor characteristics and survival outcomes with four TIME subtypes (TIME 1, CD274 low /TILabsent ; TIME 2, CD274 high /TILpresent ; TIME 3, CD274 low /TILpresent ; and TIME 4, CD274 high /TILabsent )...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29891528/advances-in-immunotherapy-for-metastatic-merkel-cell-carcinoma-a-clinician-s-guide
#6
REVIEW
Kelly G Paulson, Shailender Bhatia
Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer. The clinical impact of MCC has been increasing due to steadily rising incidence rates. Since 2001, more than 24,000 cases of MCC have been reported to the US National Program of Cancer Registries database, and in 2018, more than 2,500 incident cases are expected. MCC is highly aggressive, and one-third of patients will either present with or develop metastatic disease. Outcomes in patients with metastatic MCC have historically been poor; median time to progression with cytotoxic chemotherapy is only 3 months...
June 2018: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29874943/methods-for-improving-the-immunogenicity-and-efficacy-of-cancer-vaccines
#7
Lorenzo Pilla, Soldano Ferrone, Cristina Maccalli
Cancer vaccines represent one of the oldest immunotherapy strategies. A variety of tumor associated antigens have been exploited to investigate their immunogenicity as well as multiple strategies for vaccine administration. These efforts have led to the development of several clinical trials in tumors with different histological origins, to test the clinical efficacy of cancer vaccines. However, suboptimal clinical results have been reported mainly due to the lack of optimized strategies to induce strong and sustained systemic tumor antigen-specific immune responses...
June 6, 2018: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29785121/association-between-angiogenesis-and-cytotoxic-signatures-in-the-tumor-microenvironment-of-gastric-cancer
#8
Yi Feng, Ying Dai, Zhihua Gong, Jia-Nan Cheng, Longhui Zhang, Chengdu Sun, Xianghua Zeng, Qingzhu Jia, Bo Zhu
Background: A suppressive immune microenvironment and pathological angiogenesis are hallmarks of gastric cancer. Theoretically, immune checkpoint inhibitors (ICIs) stimulate pre-primed neoantigen-specific T cells, and antiangiogenic agents then facilitate their infiltration into the tumor niche by promoting vascular normalization. Currently, the interconnections of these two phenotypes and their relevance to the tumor microenvironment (TME) have not been fully characterized in gastric cancer...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29784854/molecular-subtype-specific-immunocompetent-models-of-high-grade-urothelial-carcinoma-reveal-differential-neoantigen-expression-and-response-to-immunotherapy
#9
Ryoichi Saito, Christof C Smith, Takanobu Utsumi, Lisa M Bixby, Jordan Kardos, Sara E Wobker, Kyle G Stewart, Shengjie Chai, Ujjawal Manocha, Kevin Matthew Byrd, Jeffrey S Damrauer, Scott E Williams, Benjamin G Vincent, William Y Kim
High-grade urothelial cancer contains intrinsic molecular subtypes that exhibit differences in underlying tumor biology and can be divided into luminal-like and basal-like subtypes. We describe here the first subtype-specific murine models of bladder cancer and show that Upk3a-CreERT2; Trp53L/L; PtenL/L; Rosa26LSL-Luc (UPPL: luminal-like) and BBN (basal-like) tumors are more faithful to human bladder cancer than the widely-used MB49 cells. Following engraftment into immunocompetent C57BL/6 mice, BBN tumors were more responsive to PD-1 inhibition than UPPL tumors...
May 21, 2018: Cancer Research
https://www.readbyqxmd.com/read/29772069/nature-of-tumor-rejection-antigens-in-ovarian-cancer
#10
REVIEW
Muzamil Y Want, Amit A Lugade, Sebastiano Battaglia, Kunle Odunsi
Major progress in the analysis of human immune responses to cancer has been made through the molecular characterization of human tumor antigens. The development of therapeutic strategies for eliciting immune-mediated rejection of tumors has accelerated due to the elucidation of the molecular basis for tumor cell recognition and destruction by immune cells. Of the various human tumor antigens defined to date in ovarian cancer, the cancer-testis (CT) family of antigens have studied extensively pre-clinically and clinically due their testis-restricted expression in normal tissues and ability to elicit robust immune responses...
May 17, 2018: Immunology
https://www.readbyqxmd.com/read/29769722/bystander-cd8-t-cells-are-abundant-and-phenotypically-distinct-in-human-tumour-infiltrates
#11
Yannick Simoni, Etienne Becht, Michael Fehlings, Chiew Yee Loh, Si-Lin Koo, Karen Wei Weng Teng, Joe Poh Sheng Yeong, Rahul Nahar, Tong Zhang, Hassen Kared, Kaibo Duan, Nicholas Ang, Michael Poidinger, Yin Yeng Lee, Anis Larbi, Alexis J Khng, Emile Tan, Cherylin Fu, Ronnie Mathew, Melissa Teo, Wan Teck Lim, Chee Keong Toh, Boon-Hean Ong, Tina Koh, Axel M Hillmer, Angela Takano, Tony Kiat Hon Lim, Eng Huat Tan, Weiwei Zhai, Daniel S W Tan, Iain Beehuat Tan, Evan W Newell
Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types1-4 . Patients and tumours may respond unpredictably to immunotherapy partly owing to heterogeneity of the immune composition and phenotypic profiles of tumour-infiltrating lymphocytes (TILs) within individual tumours and between patients5,6 . Although there is evidence that tumour-mutation-derived neoantigen-specific T cells play a role in tumour control2,4,7-10 , in most cases the antigen specificities of phenotypically diverse tumour-infiltrating T cells are largely unknown...
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29754820/interfaces-of-malignant-and-immunologic-clonal-dynamics-in-ovarian-cancer
#12
Allen W Zhang, Andrew McPherson, Katy Milne, David R Kroeger, Phineas T Hamilton, Alex Miranda, Tyler Funnell, Nicole Little, Camila P E de Souza, Sonya Laan, Stacey LeDoux, Dawn R Cochrane, Jamie L P Lim, Winnie Yang, Andrew Roth, Maia A Smith, Julie Ho, Kane Tse, Thomas Zeng, Inna Shlafman, Michael R Mayo, Richard Moore, Henrik Failmezger, Andreas Heindl, Yi Kan Wang, Ali Bashashati, Diljot S Grewal, Scott D Brown, Daniel Lai, Adrian N C Wan, Cydney B Nielsen, Curtis Huebner, Basile Tessier-Cloutier, Michael S Anglesio, Alexandre Bouchard-Côté, Yinyin Yuan, Wyeth W Wasserman, C Blake Gilks, Anthony N Karnezis, Samuel Aparicio, Jessica N McAlpine, David G Huntsman, Robert A Holt, Brad H Nelson, Sohrab P Shah
High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity...
May 7, 2018: Cell
https://www.readbyqxmd.com/read/29751996/update-on-tumor-neoantigens-and-their-utility-why-it-is-good-to-be-different
#13
REVIEW
Chung-Han Lee, Roman Yelensky, Karin Jooss, Timothy A Chan
Antitumor rejection by the immune system is a complex process that is regulated by several factors. Among these factors are the quality and quantity of mutational events that occur in cancer cells. Perhaps one of the most important types of mutations that influence antitumor immunity is the neoantigen, that is, a non-self-antigen that arises as a result of somatic mutation. Recent work has demonstrated that neoantigens hold significant promise for developing new diagnostic and therapeutic modalities. Therapeutic targeting of neoantigens is important for achieving benefit following therapy with immune checkpoint blockade agents or for cancer vaccines targeting mutations...
May 8, 2018: Trends in Immunology
https://www.readbyqxmd.com/read/29747685/car-t-cell-therapy-for-breast-cancer-harnessing-the-tumor-milieu-to-drive-t-cell-activation
#14
Pradip Bajgain, Supannikar Tawinwung, Lindsey D'Elia, Sujita Sukumaran, Norihiro Watanabe, Valentina Hoyos, Premal Lulla, Malcolm K Brenner, Ann M Leen, Juan F Vera
BACKGROUND: The adoptive transfer of T cells redirected to tumor via chimeric antigen receptors (CARs) has produced clinical benefits for the treatment of hematologic diseases. To extend this approach to breast cancer, we generated CAR T cells directed against mucin1 (MUC1), an aberrantly glycosylated neoantigen that is overexpressed by malignant cells and whose expression has been correlated with poor prognosis. Furthermore, to protect our tumor-targeted cells from the elevated levels of immune-inhibitory cytokines present in the tumor milieu, we co-expressed an inverted cytokine receptor linking the IL4 receptor exodomain with the IL7 receptor endodomain (4/7ICR) in order to transform the suppressive IL4 signal into one that would enhance the anti-tumor effects of our CAR T cells at the tumor site...
May 10, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29743717/integrating-oncolytic-viruses-in-combination-cancer-immunotherapy
#15
REVIEW
Praveen K Bommareddy, Megha Shettigar, Howard L Kaufman
Oncolytic viruses can be usefully integrated into tumour immunotherapies, as they target multiple steps within the cancer-immunity cycle. Oncolytic viruses directly lyse tumour cells, leading to the release of soluble antigens, danger signals and type I interferons, which drive antitumour immunity. In addition, some oncolytic viruses can be engineered to express therapeutic genes or can functionally alter tumour-associated endothelial cells, further enhancing T cell recruitment into immune-excluded or immune-deserted tumour microenvironments...
May 9, 2018: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/29732013/successful-rechallenge-with-ceritinib-after-leukocytoclastic-vasculitis-during-ceritinib-treatment-for-non-small-cell-lung-cancer-harboring-the-eml4-alk-fusion-protein
#16
Tamio Okimoto, Yukari Tsubata, Takamasa Hotta, Megumi Hamaguchi, Takae Okuno, Yohei Shiratsuki, Akari Kodama, Mika Nakao, Yoshihiro Amano, Shunichi Hamaguchi, Noriaki Kurimoto, Reiko Tobita, Takeshi Isobe
Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) dramatically improve progression-free survival compared to cytotoxic agents. It is therefore important to manage patients with ALK-TKIs until drug resistance occurs. Leukocytoclastic vasculitis (LCV) is a rare complication during cancer treatment and is associated with a variety of factors. Currently, it is unclear whether we should withdraw a treatment when drug-induced LCV develops. We report a 40-year-old man with advanced pulmonary adenocarcinoma harboring the EML4-ALK fusion protein who developed LCV during ceritinib treatment...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29724044/mechanisms-of-intrinsic-tumor-resistance-to-immunotherapy
#17
REVIEW
John Rieth, Subbaya Subramanian
An increased understanding of the interactions between the immune system and tumors has opened the door to immunotherapy for cancer patients. Despite some success with checkpoint inhibitors including ipilimumab, pembrolizumab, and nivolumab, most cancer patients remain unresponsive to such immunotherapy, likely due to intrinsic tumor resistance. The mechanisms most likely involve reducing the quantity and/or quality of antitumor lymphocytes, which ultimately are driven by any number of developments: tumor mutations and adaptations, reduced neoantigen generation or expression, indoleamine 2,3-dioxygenase (IDO) overexpression, loss of phosphatase and tensin homologue (PTEN) expression, and overexpression of the Wnt⁻β-catenin pathway...
May 2, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29721371/complimentary-mechanisms-of-dual-checkpoint-blockade-expand-unique-t-cell-repertoires-and-activate-adaptive-anti-tumor-immunity-in-triple-negative-breast-tumors
#18
Erika J Crosby, Junping Wei, Xiao Yi Yang, Gangjun Lei, Tao Wang, Cong-Xiao Liu, Pankaj Agarwal, Alan J Korman, Michael A Morse, Kenneth Gouin, Simon R V Knott, H Kim Lyerly, Zachary C Hartman
Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29721177/a-pilot-study-of-durvalumab-and-tremelimumab-and-immunogenomic-dynamics-in-metastatic-breast-cancer
#19
Cesar August Santa-Maria, Taigo Kato, Jae-Hyun Park, Kazuma Kiyotani, Alfred Rademaker, Ami N Shah, Leeaht Gross, Luis Z Blanco, Sarika Jain, Lisa Flaum, Claudia Tellez, Regina Stein, Regina Uthe, William J Gradishar, Massimo Cristofanilli, Yusuke Nakamura, Francis J Giles
Immune checkpoint inhibitors produce modest responses in metastatic breast cancer, however, combination approaches may improve responses. A single arm pilot study was designed to determine the overall response rate (ORR) of durvalumab and tremelimumab, and evaluate immunogenomic dynamics in metastatic endocrine receptor (ER) positive or triple negative breast cancer (TNBC). Simon two-stage design indicated at least four responses from the first 18 patients were needed to proceed with the second stage. T-cell receptor (TCR) sequencing and immune-gene expression profiling were conducted at baseline and two months, whole exome sequencing was conducted at baseline...
April 10, 2018: Oncotarget
https://www.readbyqxmd.com/read/29720506/induction-of-neoantigen-specific-cytotoxic-t-cells-and-construction-of-t-cell-receptor-engineered-t-cells-for-ovarian-cancer
#20
Tatsuo Matsuda, Matthias Leisegang, Jae-Hyun Park, Lili Ren, Taigo Kato, Yuji Ikeda, Makiko Harada, Kazuma Kiyotani, Ernst Lengyel, Gini F Fleming, Yusuke Nakamura
PURPOSE: Current evolution of cancer immunotherapies, such as immune checkpoint blockade, has implicated neoantigens as major targets of anti-cancer cytotoxic T cells. Adoptive T cell therapy with neoantigen-specific T cell receptor (TCR)-engineered T cells would be an attractive therapeutic option for advanced cancers where the host anti-tumor immune function is strongly inhibited. We previously developed a rapid and efficient pipeline for production of neoantigen-specific TCR-engineered T cells using peripheral blood from an HLA-matched healthy donor...
May 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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