BACKGROUND. The molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS). METHODS. In a single-center prospective cohort of intubated pediatric ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage associated molecular patterns were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models. RESULTS. In 279 subjects (64 [23%] non-survivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in non-survivors. Survivors and non-survivors showed different biomarker trajectories. IL-1α, sTNFR1, ANG2, and SPD increased in non-survivors, while DAMPs remained persistently elevated. ANG2 and P3NP were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality. CONCLUSIONS. Pediatric ARDS survivors and non-survivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in non-survivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.
Nadir Yehya, Thomas J. Booth, Gnana D. Ardhanari, Jill M. Thompson, L.K. Metthew Lam, Jacob E. Till, Mark V. Mai, Garrett Keim, Daniel J. McKeone, E. Scott Halstead, Patrick Lahni, Brian M. Varisco, Wanding Zhou, Erica L. Carpenter, Jason D. Christie, Nilam S. Mangalmurti
BACKGROUND Precise stratification of patients with non–small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODS We measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTS Nonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSION Combinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATION UMIN000019674.FUNDING This study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.
Hidetoshi Hayashi, Kenji Chamoto, Ryusuke Hatae, Takashi Kurosaki, Yosuke Togashi, Kazuya Fukuoka, Megumi Goto, Yasutaka Chiba, Shuta Tomida, Takayo Ota, Koji Haratani, Takayuki Takahama, Junko Tanizaki, Takeshi Yoshida, Tsutomu Iwasa, Kaoru Tanaka, Masayuki Takeda, Tomoko Hirano, Hironori Yoshida, Hiroaki Ozasa, Yuichi Sakamori, Kazuko Sakai, Keiko Higuchi, Hitoshi Uga, Chihiro Suminaka, Toyohiro Hirai, Kazuto Nishio, Kazuhiko Nakagawa, Tasuku Honjo
BACKGROUND. Weakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adult individuals harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGA in a general population are unknown as is the the penetrance of nAIGA in HLA-DRB1*15:02 or 16:02 individuals, and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs. METHODS. This study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM. RESULTS. We find that anti-IFN-γ autoantibodies detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype are not neutralizing. Moreover, we do not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02, including 71 individuals with detectable anti-IFN-g autoantibodies (27.6%). Additionally, nAIGA are absent in 1,063 patients with an autoimmune disease. Furthermore, we find only a few other autoantibodies in seven patients with nAIGAs tested. Finally, seven of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGA. Yet, nAIGA are absent in the remaining 41 patients who are HLA-DRB1*15:02 or 16:02, the 45 patients with IFN-g autoantibodies, and the five patients with HLA-DRB1*15:02 or 16:02 and IFN-g autoantibodies . CONCLUSION. These findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are causal of EM disease. FUNDING. The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), and partly by French National Research Agency (ANR).
Jessica N. Peel, Rui Yang, Tom Le Voyer, Adrian Gervais, Jérémie Rosain, Paul Bastard, Anish Behere, Axel Cederholm, Aaron Bodansky, Yoann Seeleuthner, Clément Conil, Jing-Ya Ding, Wei-Te Lei, Lucy Bizien, Camille Soudee, Mélanie Migaud, Masato Ogishi, Ahmad Yatim, Danyel Lee, Jonathan Bohlen, Thomas Perpoint, Laura Perez, Fernando Messina, Roxana Genet, Ludovic Karkowski, Mathieu Blot, Emmanuel Lafont, Laurie Toullec, Claire Goulvestre, Souad Mehlal-Sedkaoui, Jérôme Sallette, Fernando Martin, Anne Puel, Emmanuelle Jouanguy, Mark S. Anderson, Nils Landegren, Pierre Tiberghien, Laurent Abel, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Cheng-Lung Ku, Jean-Laurent Casanova
Background: Persistent controllers (PC) maintain antiretroviral-free HIV-1 control indefinitely over time while transient controllers (TC) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir of these phenotypes to identify the factors that lead to HIV progression and to open new avenues in HIV cure strategies. Methods: The characterization of HIV-1 reservoir, from peripheral blood mononuclear cells, was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-seq; MIP-seq). Results: PC and TC before losing virological control, presented significantly lower total, intact and defective proviruses compared to participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PC and TC. However, intact provirus levels were lower in PC compared to TC, being the intact/defective HIV-DNA ratio significantly higher in TC. Clonally expanded intact proviruses were found only in PC and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TC. Conclusions: These results suggest the need for, and can give guidance to the design of, future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART. Funding: Instituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057 PI18/01532, PI19/01127 and PI22/01796), Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía (PI20/1276), Gilead Fellowships (GLD22/00147) and I+D+iFEDER Andalucía 2014-2020 (US-1380938).
Carmen Gasca-Capote, Xiaodong Lian, Ce Gao, Isabelle C. Roseto, María Reyes Jiménez-León, Gregory Gladkov, María Inés Camacho-Sojo, Alberto Pérez-Gómez, Isabel Gallego, Luis E. Lopez-Cortes, Sara Bachiller, Joana Vitalle, Mohammed Rafii-El-Idrissi Benhnia, Francisco J. Ostos, Antonio R. Collado-Romacho, Jesús Santos, Rosario Palacios, Cristina Gomez-Ayerbe, Leopoldo Muñoz-Medina, Andrés Ruiz-Sancho, Mario Frias, Antonio Rivero-Juarez, Cristina Roca-Oporto, Carmen Hidalgo-Tenorio, Anna Rull, Julian Olalla, Miguel A. Lopez-Ruz, Francesc Vidal, Consuelo Viladés, Andrea Mastrangelo, Matthias Cavassini, Nuria Espinosa, Matthieu Perreau, Joaquin Peraire, Antonio Rivero, Luis F. López-Cortes, Mathias Lichterfeld, Xu G. Yu, Ezequiel Ruiz-Mateos
BACKGROUND. HER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance in part due to HER2 heterogeneity (HET) is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (T-DM1+P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR). METHODS. To investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing (RNA-seq) and ERBB2 FISH of 285 pre/post-treatment tumors from 129 patients in this T-DM1+P neoadjuvant trial. A subset of cases was also subject to Nanostring spatial digital profiling. RESULTS. Pre-treatment tumors from patients with pCR had the highest level of ERBB2 mRNA and ERBB signaling. HET was associated with no pCR, basal-like features, low ERBB2 expression yet high ERBB signaling sustained by activation of downstream pathway components. Residual tumors showed decreased HER2 protein levels and ERBB2 copy number heterogeneity and increased PI3K pathway enrichment and luminal features. HET tumors showed minimal treatment-induced transcriptomic changes compared to non-HET tumors. Immune infiltration correlated with pCR and HER2-HET status. CONCLUSION. Resistance mechanisms in HET and non-HET tumors are distinct. HER2-targeting antibodies have limited efficacy in HET tumors. Our results support the stratification of patients based on HET status and the use of agents that target downstream components of the ERBB signaling pathway in patients with HET tumors. TRIAL REGISTRATION. Clinicaltrials.gov NCT02326974. FUNDING. This study was funded by Roche and the National Cancer Institute.
Zheqi Li, Otto Metzger Filho, Giuseppe Viale, Patrizia dell'Orto, Leila Russo, Marie-Anne Goyette, Avni Kamat, Denise A. Yardley, Vandana Gupta Abramson, Carlos L. Arteaga, Laura M. Spring, Kami Chiotti, Carol Halsey, Adrienne G. Waks, Tari A. King, Susan C. Lester, Jennifer R. Bellon, Eric P. Winer, Paul T. Spellman, Ian E. Krop, Kornelia Polyak
BACKGROUND. Malaria transmission blocking vaccines aim to interrupt the transmission of malaria from one person to another. METHODS. The candidates, R0.6C and ProC6C, share the Plasmodium falciparum sexual stage antigen, Pfs48/45 “6C” domain. R0.6C utilizes the Glutamate Rich Protein (GLURP) as a carrier and ProC6C includes a second domain (Pfs230-Pro) and a short 36 amino acids CSP sequence. Healthy adults (n = 125) from a malaria endemic area of Burkina Faso were immunized with three intramuscular injections, four weeks apart, of 30 μg or 100 μg R0.6C or ProC6C each adsorbed to Alhydrogel adjuvant (AlOH) alone or in combination with Matrix-M (15 μg or 50 μg, respectively). The allocation was random and double blind for this Phase 1 trial. RESULTS. The vaccines were safe and well tolerated with no vaccine-related serious adverse events. A total of seven adverse events, mild to moderate in intensity and considered possibly related to the study vaccines were recorded. Vaccine-specific antibodies were highest in volunteers immunized with 100 μg ProC6C-AlOH with Matrix-M, and 13/20 (65%) subjects in the group showed greater than 80% transmission reducing activity (TRA) when evaluated in the standard membrane feeding assay at 15 mg/mL IgG. In contrast, R0.6C induced sporadic TRA. CONCLUSIONS. All formulations were safe and well tolerated in a malaria endemic area of Africa in healthy adults. The ProC6C-AlOH/Matrix-M vaccine elicited the highest levels of functional antibodies, meriting further investigation. TRIAL REGISTRATION. Pactr.org PACTR202201848463189. FUNDING. The study was funded by the European Union and Developing Countries Clinical Trials Partnership (Grant number RIA2018SV-2311).
B. Alfred Tiono, Jordan L. Plieskatt, Alphonse Ouedraogo, Ben Idriss Soulama, Kazutoyo Miura, Edith C. Bougouma, Mohammad Naghizadeh, Aissata Barry, Jean Baptiste B. Yaro, Sem Ezinmegnon, Noelie B. Henry, Ebenezer Ofori, Bright Adu, Susheel K. Singh, Augustin Konkobo, Karin Lövgren Bengtsson, Amidou Diarra, Cecilia Carnrot, Jenny M. Reimer, Amidou Z. Ouedraogo, Moussa Tienta, Carole A. Long, Issa N. Nebie, Issaka Sagara, Sodiomon B. Sirima, Michael Theisen
BACKGROUND. The tumor immune microenvironment can provide prognostic and therapeutic information. We aimed to develop noninvasive imaging biomarkers from computed tomography (CT) for comprehensive evaluation of immune context, and investigate their associations with prognosis and immunotherapy response in gastric cancer (GC). METHODS. This study involved 2,600 GC patients of nine independent cohorts. We developed and validated two CT imaging biomarkers [lymphoid radiomics score (LRS) and myeloid radiomics score (MRS)] for evaluating the immunohistochemistry (IHC)-derived lymphoid and myeloid immune context respectively, and then integrated them into a combined imaging biomarker [LRS/MRS: low(−) or high(+)] with four radiomics immune subtypes: 1(−/−), 2(+/−), 3(−/+), and 4(+/+). We further evaluated the imaging biomarkers' predictive values on prognosis and immunotherapy response. RESULTS. The developed imaging biomarkers (LRS and MRS) had a high accuracy in predicting lymphoid (AUC range: 0.765-0.773) and myeloid (AUC range: 0.736-0.750) immune context. Furthermore, same as IHC-derived immune context, two imaging biomarkers (HR range: 0.240-0.761 for LRS; 1.301-4.012 for MRS) and the combined biomarker were independent predictors for disease-free and overall survival in the training and all validation cohorts (all P<0.05). In addition, patient with high LRS or low MRS may benefit more from immunotherapy (P<0.001). Furthermore, a highly heterogeneous outcome on objective response rate was observed in four imaging subtypes: 1(−/−) with 27.3%, 2(+/−) with 53.3%, 3(−/+) with 10.2%, and 4(+/+) with 30.0% (P<0.0001). CONCLUSION. The noninvasive imaging biomarkers could accurately evaluate the immune context, and provide information regarding prognosis and immunotherapy for GC. FUNDING. None
Zepang Sun, Taojun Zhang, M. Usman Ahmad, Zixia Zhou, Liang Qiu, Kangneng Zhou, Wenjun Xiong, Jingjing Xie, Zhicheng Zhang, Chuanli Chen, Qingyu Yuan, Yan Chen, Wanying Feng, Yikai Xu, Lequan Yu, Wei Wang, Jiang Yu, Guoxin Li, Yuming Jiang
BACKGROUND. Vaccination is typically administered without regard to site of prior vaccination but this factor may substantially impact downstream immune responses. METHODS. We assessed serological responses to initial COVID-19 vaccination in baseline seronegative adults who received second–dose boosters in the ipsilateral or contralateral arm relative to initial vaccination. We measured serum SARS-CoV2 spike-specific Ig, RBD-specific IgG, SARS-CoV-2-nucleocapsid-specific IgG, and neutralizing antibody titers against SARS-CoV-2.D614G (early strain) and SARS-CoV-2.B.1.1.529 (Omicron) at approximately 0.6, 8, and 14 months after boosting. RESULTS. In 947 individuals, contralateral boosting was associated with higher spike-specific serum Ig, and this effect increased over time from a 1.1-fold to a 1.4-fold increase by 14 months (P < 0.001). A similar pattern was seen for RBD-specific IgG. Among 54 pairs matched for age, gender and relevant time intervals, arm groups had similar antibody levels at W2 but contralateral boosting resulted in significantly higher binding and neutralizing antibody titers at W3 and W4, with progressive increase over time, ranging from 1.3-fold (total Ig, P = 0.007) to 4.0-fold (pseudovirus neutralization to B.1.1.529 P < 0.001). CONCLUSIONS. In previously unexposed adults receiving an initial vaccine series with the BNT162b2 mRNA COVID-19 vaccine, contralateral boosting substantially increases antibody magnitude and breadth at times beyond 3 weeks after vaccination. This effect should be considered during arm selection in the context of multi-dose vaccine regimens.
Sedigheh Fazli, Archana Thomas, Abram E. Estrada, Hiro A.P. Ross, David Xthona Lee, Steven Kazmierczak, Mark K. Slifka, David Montefiori, William B. Messer, Marcel E. Curlin
BACKGROUND. Sanaria PfSPZ Vaccine, composed of attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against malaria. We conducted this clinical trial to assess the safety and efficacy of PfSPZ Vaccine in HIV positive (HIV+) individuals since the HIV infection status of participants in mass vaccination programs may be unknown. METHODS. This randomized, double blind, placebo-controlled trial enrolled 18-45-year-old HIV negative (HIV-) and well-controlled HIV+ Tanzanians (HIV viral load < 40 copies/mL, CD4 counts > 500 cells/µL). Participants received 5 doses of PfSPZ Vaccine or normal saline over 28 days followed by controlled human malaria infection (CHMI) 3 weeks later. RESULTS. There were no solicited adverse events in the 9 HIV- and 12 HIV+ participants. After CHMI, 6/6 normal saline (NS) controls, 1/5 HIV- vaccinees and 4/4 HIV+ vaccinees were Pf positive by qPCR. Post-immunization, anti-PfCSP (isotype and IgG subclass) and anti-PfSPZ antibodies, anti-PfSPZ CD4 T cell responses and Vδ2+ γδ CD3+ T cells were non-significantly higher in HIV- than HIV+ vaccinees. Sera from HIV- vaccinees had significantly higher inhibition of PfSPZ invasion of hepatocytes in vitro, and antibody-dependent complement deposition (ADCD) and Fcγ3B binding by anti-PfCSP and ADCD by anti-PfCelTOS antibodies. CONCLUSIONS. PfSPZ Vaccine was safe and well tolerated in HIV+ vaccinees, but not protective. Vaccine efficacy was 80% in HIV- vaccinees (P = 0.012), whose sera had significantly higher inhibition of PfSPZ invasion of hepatocytes and enrichment of multi-functional PfCSP antibodies. A more potent PfSPZ vaccine or regimen is needed to protect those living with HIV against Pf infection in Africa.
Said Jongo, L.W. Preston Church, Florence Milando, Munira Qassim, Tobias Schindler, Mohammed Rashid, Anneth Tumbo, Gloria Nyaulingo, Bakari M. Bakari, Thabit Athuman Mbaga, Latipha Mohamed, Kamaka Kassimu, Beatus S. Simon, Maxmillian Mpina, Irfan Zaidi, Patrick E. Duffy, Phillip A. Swanson II, Robert Seder, Jonathan D. Herman, Maanasa Mendu, Yonatan Zur, Galit Alter, Natasha KC, Pouria Riyahi, Yonas Abebe, Tooba Murshedkar, Eric R. James, Peter F. Billingsley, B. Kim Lee Sim, Thomas L. Richie, Claudia Daubenberger, Salim Abdulla, Stephen L. Hoffman
BACKGROUND. Improving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor-β receptor (TGF-βR) inhibitor that targets cancer associated fibroblasts (CAFs) is promising to enhance efficacy of immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy. METHODS. We measure CAFs in vivo using 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI)-04 for PET/CT imaging to guide combination of TGF-β inhibition and immunotherapy. 131 patients with metastatic colorectal cancer (CRC) underwent 68Ga-FAPI and 18F-fludeoxyglucose (18F-FDG) PET/CT imaging. Relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed in patients. Mouse cohorts of metastatic CRC were treated with TGF-βR inhibitor combined with KN046 which blocks PD-L1 and CTLA4, followed with 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses. RESULTS. Patients with metastatic CRC demonstrated high uptakes of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. TGF-βR inhibitor enhanced tumor infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamical changes of CAFs and tumor response to combined TGF-βR inhibitor with immunotherapy. CONCLUSION. 68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to guide CRC patients for precise TGF-β inhibition plus immunotherapy, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management. TRIAL REGISTRATION. CFFSTS Trial, ChiCTR2100053984, Chinese Clinical Trial Registry. FUNDING. National Natural Science Foundation of China (82072695, 32270767, 82272035,81972260).
Ke Li, Wei Liu, Hang Yu, Jiwei Chen, Wenxuan Tang, Jianpeng Wang, Ming Qi, Yuyun Sun, Xiaoping Xu, Ji Zhang, Xinxiang Li, Weijian Guo, Xiaoling Li, Shaoli Song, Shuang Tang
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