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Cancer Immunology Research

Karl R VanDerMeid, Michael R Elliott, Andrea M Baran, Paul M Barr, Charles C Chu, Clive S Zent
CD20 monoclonal antibodies (CD20 mAbs) induce cellular cytotoxicity, which is traditionally measured by antibody-dependent cellular cytotoxicity (ADCC) assays. However, data suggest that antibody-dependent cellular phagocytosis (ADCP) is the primary cytotoxic mechanism. We directly compared in vitro ADCP versus ADCC using primary human cells. After establishing the primacy of ADCP, we examined next generation CD20 mAbs, including clinically relevant drug combinations for their effects on ADCP. ADCP and ADCC induction by rituximab, ofatumumab, obinutuzumab, or ocaratuzumab was measured using treatment-naïve chronic lymphocytic leukemia (CLL) target cells and either human monocyte-derived macrophages (for ADCP) or NK cells (for ADCC)...
August 8, 2018: Cancer Immunology Research
Lee Kyung Hong, Yuhui Chen, Christof C Smith, Stephanie A Montgomery, Benjamin G Vincent, Gianpietro Dotti, Barbara Savoldo
Tumor antigen heterogeneity limits success of chimeric antigen receptor (CAR) T-cell therapies. Embryonal carcinomas (ECs) and mixed testicular germ cell tumors (TGCTs) containing EC, which are the most aggressive TGCT subtypes, are useful for dissecting this issue as ECs express the CD30 antigen but also contain CD30-/dim cells. We found that CD30-redirected CAR T cells (CD30.CAR T cells) exhibit antitumor activity in vitro against the human EC cell lines Tera-1, Tera-2 and NCCIT, and putative EC stem cells identified by Hoechst dye staining...
August 7, 2018: Cancer Immunology Research
Dennis O Adeegbe, Shengwu Liu, Maureen Hattersley, Michaela Bowden, Chensheng W Zhou, Shuai Li, Raven Vlahos, Michael Grondine, Igor Dolgalev, Elena Ivanova, Max M Quinn, Peng Gao, Peter S Hammerman, James E Bradner, J Alan Diehl, Anil K Rustgi, Adam J Bass, Aristotelis Tsirigos, Gordon J Freeman, Huawei Chen, Kwok-Kin Wong
KRAS mutation is present in approximately 30% of human lung adenocarcinomas. Although recent advances in targeted therapy have shown great promise, effective targeting of KRAS remains elusive, and concurrent alterations in tumor suppressors render KRAS-mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS-mutant tumors are immunosuppressive mechanisms, such as increased presence of suppressive regulatory T cells (Tregs) in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells...
August 7, 2018: Cancer Immunology Research
Pupu Li, Xinfeng Chen, Guohui Qin, Dongli Yue, Zhen Zhang, Yu Ping, Dan Wang, Xuan Zhao, Mengjia Song, Qitai Zhao, Jieyao Li, Shasha Liu, Dong Wang, Chaoqi Zhang, Jingyao Lian, Ling Cao, Feng Li, Lan Huang, Liping Wang, Li Yang, Jianmin Huang, Hong Li, Bin Zhang, Yi Zhang
Maelstrom (MAEL) is a novel cancer/testis-associated gene, which is not only expressed in the male testicular germ cells among human normal tissues, but is also aberrantly expressed in various cancer tissues. In our study, MAEL was characterized as a tumor-promoting gene and was significantly associated with esophageal squamous cell carcinoma (ESCC) recurrence and unfavorable prognosis. Kaplan-Meier analysis showed that patients with high MAEL expression had a shorter survival time. Functional experiments showed that MAEL promoted tumor cell growth and inhibited cell apoptosis...
August 6, 2018: Cancer Immunology Research
Saba Ghassemi, Selene Nunez-Cruz, Roddy S O'Connor, Joseph A Fraietta, Prachi R Patel, John Scholler, David M Barrett, Stefan M Lundh, Megan M Davis, Felipe Bedoya, John Leferovich, Simon F Lacey, Bruce L Levine, Stephan A Grupp, Carl H June, J Joseph Melenhorst, Michael C Milone
The success of chimeric antigen receptor (CAR)-mediated immunotherapy in acute lymphoblastic leukemia (ALL) highlights the potential of T-cell therapies with directed cytotoxicity against specific tumor antigens. The efficacy of CAR T-cell therapy depends on the engraftment and persistence of T cells following adoptive transfer. Most protocols for T-cell engineering routinely expand T cells ex vivo for 9-14 days. Because the potential for engraftment and persistence is related to the state of T-cell differentiation, we hypothesized that reducing the duration of ex vivo culture would limit differentiation and enhance the efficacy of CAR T-cell therapy...
July 20, 2018: Cancer Immunology Research
Jingwei Ma, Keke Wei, Huafeng Zhang, Ke Tang, Fei Li, Tianzhen Zhang, Junwei Liu, Pingwei Xu, Yuandong Yu, Weiwei Sun, LiYan Zhu, Jie Chen, Li Zhou, Xiaoyu Liang, Jiadi Lv, Roland Fiskesund, Yuying Liu, Bo Huang
Tumor cell-derived microparticles (T-MP) contain tumor antigen profiles as well as innate signals, endowing them with vaccine potential; however, the precise mechanism by which DCs present T-MP antigens to T cells remains unclear. Here, we show that T-MPs activate a lysosomal pathway that is required for DCs presenting tumor antigens of T-MPs. DCs endocytose T-MPs to lysosomes, where T-MPs increase lysosomal pH from 5.0 to a peak of 8.5 via NOX2-catalyzed reactive oxygen species (ROS) production. This increased pH, coupled with T-MP-driven lysosomal centripetal migration, promotes the formation of MHC class I-tumor antigen peptide complexes...
July 17, 2018: Cancer Immunology Research
Paul A Beavis, Melissa A Henderson, Lauren Giuffrida, Alexander J Davenport, Emma V Petley, Imran G House, Junyun Lai, Kevin Sek, Nicole Milenkovski, Liza B John, Sherly Mardiana, Clare Y Slaney, Joseph A Trapani, Sherene Loi, Michael H Kershaw, Nicole M Haynes, Phillip K Darcy
Immunotherapy is widely accepted as a powerful new treatment modality for the treatment of cancer. The most successful form of immunotherapy to date has been the blockade of the immune checkpoints PD-1 and CTLA-4. Combining inhibitors of both PD-1 and CTLA-4 increases the proportion of patients that respond to immunotherapy. However, most patients still do not respond to checkpoint inhibitors, and prognostic biomarkers are currently lacking. Therefore a better understanding of the mechanism by which these checkpoint inhibitors enhance antitumor immune responses is required to more accurately predict which patients are likely to respond and further enhance this treatment modality...
July 17, 2018: Cancer Immunology Research
Jeremy Lewin, Scott Davidson, Nathaniel D Anderson, Beatrice Y Lau, Jacalyn Kelly, Uri Tabori, Samer Salah, Marcus O Butler, Kyaw L Aung, Adam Shlien, Brendan C Dickson, Albiruni Ryan Abdul Razak
Alveolar soft part sarcoma (ASPS) is a morphologically distinctive mesenchymal tumor characterized by a canonical ASPL-TFE3 fusion product. In the metastatic setting, standard cytotoxic chemotherapies are typically ineffective. Studies have suggested modest clinical response to multi-targeted receptor tyrosine kinase inhibitors. Here, we report sustained partial responses in two patients with immune checkpoint inhibition treated with either durvalumab (anti-PD-L1) alone or in combination with tremelimumab (anti-CTLA-4) which appeared unrelated to tumor immune infiltrates or mutational burden...
July 17, 2018: Cancer Immunology Research
Sophie M Poznanski, Tina Nham, Marianne V Chew, Amanda J Lee, Joanne A Hammill, Isabella Y Fan, Martin Butcher, Jonathan L Bramson, Dean A Lee, Hal W Hirte, Ali A Ashkar
Natural Killer (NK) cells are useful for cancer immunotherapy and have proven clinically effective against hematological malignancies. However, immunotherapies for poor prognosis solid malignancies, including ovarian cancer, have not been as successful due to immunosuppression by solid tumors. Although re-arming patients' own NK cells to treat cancer is an attractive option, success of that strategy is limited by the impaired function of NK cells from cancer patients and by inhibition by self-MHC. In this study, we show that expansion converts healthy donor and immunosuppressed ovarian cancer patient NK cells to a cytotoxic CD56superbrightCD16+ subset with activation state and antitumor functions that increase with CD56 brightness...
July 17, 2018: Cancer Immunology Research
Genevieve P Hartley, Lyndah Chow, Dylan T Ammons, William H Wheat, Steven W Dow
Tumor-associated macrophages (TAMs) express PD-L1 and contribute to the immune-suppressive tumor microenvironment. Although the role of the PD-L1 and PD-1 interaction to regulate T-cell suppression is established, less is known about PD-L1 signaling in macrophages and how these signals may affect the function of TAM. We used in vitro and in vivo models to investigate PD-L1 signaling in macrophages and the effects of PD-L1 antibody treatment on TAM responses. Treatment of mouse and human macrophages with PD-L1 antibodies increased spontaneous macrophage proliferation, survival, and activation (costimulatory molecule expression, cytokine production)...
July 16, 2018: Cancer Immunology Research
J Bryan Iorgulescu, Maya Harary, Cheryl K Zogg, Keith L Ligon, David A Reardon, F Stephen Hodi, Ayal A Aizer, Timothy R Smith
The successes of checkpoint blockade immunotherapy (CBI) and BRAFV600 -targeted therapy trials have generated substantial promise for revolutionizing the management of patients with advanced melanoma. However, because early clinical trials of CBIs and BRAFV600 -targeted therapy either excluded or included disproportionately fewer cases of melanoma brain metastases (MBMs), the survival benefit of these novel therapies for MBM remains unknown. We, therefore, evaluated the characteristics, management, and overall survival (OS) of patients who presented with cutaneous MBMs during 2010 to 2015 using the National Cancer Database, which comprises 70% of all newly diagnosed U...
July 12, 2018: Cancer Immunology Research
Huafeng Zhang, Yuandong Yu, Li Zhou, Jingwei Ma, Ke Tang, Pingwei Xu, Tiantian Ji, Xiaoyu Liang, Jiadi Lv, Wenqian Dong, Tianzhen Zhang, Degao Chen, Jing Xie, Yuying Liu, Bo Huang
Despite the frequency of lung metastasis and its associated mortality, the mechanisms behind metastatic tumor cell survival and colonization in the lungs remain elusive. Here, we show that tumor cell-released microparticles (T-MPs) from the primary tumor site play a critical role in the metastatic process. The T-MPs remodeled the lung parenchyma via a macrophage-dependent pathway, to create an altered inflammatory and mechanical response to tumor cell invasion. Mechanistically, we show that circulating T-MPs readily enter the lung parenchyma, where they are taken up by local macrophages and induce CCL2 production...
July 12, 2018: Cancer Immunology Research
Angelamaria Rizzo, Martina Di Giovangiulio, Carmine Stolfi, Eleonora Franzè, Hans-Joerg Fehling, Rita Carsetti, Ezio Giorda, Alfredo Colantoni, Angela Ortenzi, Massimo Rugge, Claudia Mescoli, Giovanni Monteleone, Massimo C Fantini
Chronic inflammation drives colitis-associated colorectal cancer (CAC) in inflammatory bowel disease (IBD). FoxP3+ regulatory T cells (Tregs) co-expressing the Th17-related transcription factor RORγt accumulate in the lamina propria of IBD patients, where they are thought to represent an intermediate stage of development toward a Th17 proinflammatory phenotype. However, the role of these cells in CAC is unknown. RORγt+FoxP3+ cells were investigated in human samples of CAC, and their phenotypic stability and function were investigated in an azoxymethane/dextran sulfate sodium model of CAC using Treg fate mapping reporter and Treg-specific RORγt conditional knockout mice...
July 10, 2018: Cancer Immunology Research
Fernando Costa Santini, Hira Rizvi, Andrew J Plodkowski, Andy Ni, Mario E Lacouture, Maya Gambarin-Gelwan, Olivia Wilkins, Elizabeth Panora, Darragh F Halpenny, Niamh M Long, Mark G Kris, Charles M Rudin, Jamie E Chaft, Matthew D Hellmann
Consideration of retreatment following recovery from an irAE is a common clinical scenario, but the safety and benefit of retreatment is unknown. We identified patients with advanced non-small cell lung cancer (NSCLC) treated with anti-PD-L1 who had treatment held due to serious irAEs and divided them into two groups: those retreated with anti-PD-L1 (retreatment cohort) or those in whom anti-PD-L1 was stopped (discontinuation cohort). Of 482 patients with NSCLC treated with anti-PD-L1, 68 (14%) developed a serious irAE requiring treatment interruption...
July 10, 2018: Cancer Immunology Research
Jing Chang, Haiyong Peng, Brian C Shaffer, Sivasubramanian Baskar, Ina C Wecken, Matthew G Cyr, Gustavo J Martinez, Jo Soden, Jim Freeth, Adrian Wiestner, Christoph Rader
Although the five-year survival rate of chronic lymphocytic leukemia (CLL) patients has risen to >80%, the only potentially curative treatment is allogeneic hematopoietic stem cell transplantation (alloHSCT). To identify possible new monoclonal antibody (mAb) drugs and targets for CLL, we previously developed a phage display-based human mAb platform to mine the antibody repertoire of patients who responded to alloHSCT. We had selected a group of highly homologous post-alloHSCT mAbs that bound to an unknown CLL cell surface antigen...
July 6, 2018: Cancer Immunology Research
Elin Bernson, Alexander Hallner, Frida Ewald Sander, Malin Nicklasson, Malin S Nilsson, Karin Christenson, Ebru Aydin, Jan-Åke Liljeqvist, Mats Brune, Robin Foa, Johan Aurelius, Anna Martner, Kristoffer Hellstrand, Fredrik B Thoren
Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to impact favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of AML patients not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 non-transplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996)...
July 6, 2018: Cancer Immunology Research
Bhalchandra Mirlekar, Daniel Michaud, Ryan Searcy, Kevin Greene, Yuliya Pylayeva-Gupta
Although successes in cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic ductal adenocarcinoma (PDA). Mechanisms that contribute to the poor antitumor immune response in PDA are not well understood. Here, we demonstrated that cytokine IL35 is a major immunosuppressive driver in PDA and potentiates tumor growth via the suppression of endogenous antitumor T-cell responses. The growth of pancreatic tumors in mice deficient for IL35 was significantly reduced...
July 6, 2018: Cancer Immunology Research
Juming Yan, Stacey Allen, Dipti Vijayan, Xian-Yang Li, Heidi Harjunpää, Kazuyoshi Takeda, Jing Liu, Daniel J Cua, Mark J Smyth, Michele W L Teng
Tumor-induced immunosuppression is mediated through various mechanisms including engagement of immune checkpoint receptors on effector cells, function of immunoregulatory cells such as regulatory T cells and myeloid-derived suppressor cells, and deployment of immunosuppressive cytokines such as TGFβ and IL10. IL23 is a cytokine that negatively affects antitumor immunity. In this study, we investigated whether IL23-deficient (IL23p19-/- ) and IL23R-deficient (IL23R-/- ) mice phenocopied each other, with respect to their tumor control...
June 19, 2018: Cancer Immunology Research
Kelly D Moynihan, Rebecca L Holden, Naveen K Mehta, Chensu Wang, Mark R Karver, Jens Dinter, Simon Liang, Wuhbet Abraham, Mariane B Melo, Angela Q Zhang, Na Li, Sylvie Le Gall, Bradley Pentelute, Darrell J Irvine
Antitumor T-cell responses have the potential to be curative in cancer patients, but the induction of potent T-cell immunity through vaccination remains a largely unmet goal of immunotherapy. We previously reported that the immunogenicity of peptide vaccines could be increased by maximizing delivery to lymph nodes (LNs), where T-cell responses are generated. This was achieved by conjugating the peptide to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-PEG (DSPE-PEG) to promote albumin binding, which resulted in enhanced lymphatic drainage and improved T-cell responses...
June 18, 2018: Cancer Immunology Research
Julie M Diamond, Claire Vanpouille-Box, Sheila Spada, Nils-Petter Rudqvist, Jessica R Chapman, Beatrix M Ueberheide, Karsten A Pilones, Yasmeen Sarfraz, Silvia C Formenti, Sandra Demaria
Radiotherapy (RT) used at immunogenic doses leads to accumulation of cytosolic double-stranded DNA (dsDNA) in cancer cells, which activates type I IFN (IFN-I) via the cGAS/STING pathway. Cancer cell-derived IFN-I is required to recruit BATF3-dependent dendritic cells (DC) to poorly immunogenic tumors and trigger antitumor T-cell responses in combination with immune checkpoint blockade. We have previously demonstrated that the exonuclease TREX1 regulates radiation immunogenicity by degrading cytosolic dsDNA...
June 15, 2018: Cancer Immunology Research
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