BACKGROUND. Studies assessing the efficacy of therapies for neovascular age-related macular degeneration (nvAMD) have demonstrated that aflibercept may have a longer treatment interval than its lesser-expensive alternative, bevacizumab. However, whether this benefit justifies the additional cost of aflibercept remains under debate. We have recently reported that a “treat-and-extend-pause/monitor” (TEP/M) approach can be used to successfully wean 31% of nvAMD patients off anti-VEGF therapy. Here we examine whether the choice of therapy influences the outcomes of this approach. METHODS. In this retrospective analysis, 122 eyes of 106 patients with nvAMD underwent 3 consecutive monthly injections with either aflibercept (n=70) or bevacizumab (n=52) followed by a treat-and-extend protocol in which the decision to extend the interval between treatments was based on visual acuity, clinical exam, and the presence or absence of fluid on optical coherence tomography (OCT). Eyes that remained stable 12 weeks from their prior treatment were given a 6-week trial of holding further treatment, followed by quarterly monitoring. Treatment was resumed for worsening vision, clinical exam, or OCT findings. RESULTS. At the end of one year, eyes receiving bevacizumab had similar vision but required more injections (8.7 ±0.3 vs. 7.2 ±0.3) compared to aflibercept. However, eyes treated with aflibercept were almost 3-times more likely to be weaned off treatment (43% vs. 15%) compared to eyes treated with bevacizumab at the end of one year. CONCLUSIONS. These observations expose a previously unappreciated advantage of aflibercept over bevacizumab and have important clinical implications for the selection of therapy for patients with nvAMD.
Xuan Cao, Jaron Castillo Sanchez, Tapan P. Patel, Zhiyong Yang, Chuanyu Guo, Danyal Malik, Anuoluwapo Sopeyin, Silvia Montaner, Akrit Sodhi
Mutational activation of KRAS is a common oncogenic event in lung cancer, yet effective therapies are still lacking. Here, we identify B cell lymphoma 6 (BCL6) as a lynchpin in KRAS-driven lung cancer. BCL6 expression was increased upon KRAS activation in lung tumor tissue in mice and was positively correlated with the expression of KRAS-GTP, the active form of KRAS, in various human cancer cell lines. Moreover, BCL6 was highly expressed in human KRAS-mutant lung adenocarcinomas and was associated with poor patient survival. Mechanistically, the MAPK/ERK/ELK1 signaling axis downstream of mutant KRAS directly regulated BCL6 expression. BCL6 maintained the global expression of prereplication complex components; therefore, BCL6 inhibition induced stalling of the replication fork, leading to DNA damage and growth arrest in KRAS-mutant lung cancer cells. Importantly, BCL6-specific knockout in lungs significantly reduced the tumor burden and mortality in the LSL-KrasG12D/+ lung cancer mouse model. Likewise, pharmacological inhibition of BCL6 significantly impeded the growth of KRAS-mutant lung cancer cells both in vitro and in vivo. In summary, our findings reveal a crucial role of BCL6 in promoting KRAS-addicted lung cancer and suggest BCL6 as a therapeutic target for the treatment of this intractable disease.
Kun Li, Yanan Liu, Yi Ding, Zhengwei Zhang, Juanjuan Feng, Jiaxin Hu, Jiwei Chen, Zhengke Lian, Yiliang Chen, Kewen Hu, Zhi Chen, Zhenyu Cai, Mingyao Liu, Xiufeng Pang
BACKGROUND. Results of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP. METHODS. Of 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP-donors (n=113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTS. The median follow-up of patients was 396 days, the estimated 1-year survival was 78.7% in the CCP and 60.2% in the control group (p=0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared to the control group (91.5% versus 60.2%; p=0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase of neutralizing antibodies after vaccination between CCP and the control group. CONCLUSION. The trial demonstrated a trend towards better outcome in the CCP group without reaching statistical significance. A pre-defined subgroup analysis showed a significant better outcome (long-term survival; time to discharge from ICU and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared to the control group. A substantial long-term disease burden remains after severe COVID-19. TRIAL REGISTRATION. EudraCT number 2020-001310-38 FUNDING. Bundesministerium für Gesundheit (German Federal Ministry of Health): ZMVI1-2520COR802/ZMI1-2521COR802
Sixten Körper, Beate Grüner, Daniel Zickler, Thomas Wiesmann, Patrick Wuchter, Rainer Blasczyk, Kai Zacharowski, Peter Spieth, Torsten Tonn, Peter Rosenberger, Gregor Paul, Jan Pilch, Joachim Schwäble, Tamam Bakchoul, Thomas Thiele, Julian Knoerlein, Matthias M. Dollinger, Joerg Krebs, Martin Bentz, Victor M. Corman, Dzenan Kilalic, Gerlinde Schmidtke-Schrezenmeier, Philipp M. Lepper, Lucas Ernst, Hinnerk Wulf, Alexandra Ulrich, Manfred Weiss, Jan Kruse, Thomas Burkhardt, Rebecca Müller, Harald Klüter, Michael Schmidt, Bernd Jahrsdörfer, Ramin Lotfi, Markus Rojewski, Thomas Appl, Benjamin Mayer, Philipp Schnecko, Erhard Seifried, Hubert Schrezenmeier
Fusion oncoproteins are the initiating event in the pathogenesis of many pediatric AML. The CBFA2T3-GLIS2 (C/G) fusion is a product of a cryptic translocation primarily seen in infants and early childhood and is associated with dismal outcome. Here, we demonstrate that the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem/progenitor cells (CB HSPCs) in an endothelial cell (EC) co-culture system, that recapitulates the transcriptome, morphology and immunophenotype of C/G AML and induces highly aggressive leukemia in xenograft models. Interrogating the transcriptome of C/G-CB cells and primary C/G AML identified a library of C/G fusion-specific genes that are potential targets for therapy. We developed chimeric antigen receptor (CAR) T cells directed against one of the targets, FOLR1, and demonstrated their pre-clinical efficacy against C/G AML using in vitro and xenograft models. FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Furthermore, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.
Quy Le, Brandon Hadland, Jenny L. Smith, Amanda Leonti, Benjamin J. Huang, Rhonda Ries, Tiffany A. Hylkema, Sommer Castro, Thao T. Tang, Cyd N. McKay, LaKeisha Perkins, Laura Pardo, Jay Sarthy, Amy K. Beckman, Robin Williams, Rhonda Idemmili, Scott Furlan, Takashi Ishida, Lindsey Call, Shivani Srivastava, Anisha M. Loeb, Filippo Milano, Suzan Imren, Shelli M. Morris, Fiona Pakiam, James M. Olson, Michael R. Loken, Lisa Eidenschink Brodersen, Stanley R. Riddell, Katherine Tarlock, Irwin D. Bernstein, Keith R. Loeb, Soheil Meshinchi
Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation leads to downregulation of the DNA repair pathways. This leads to enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG leads to accumulation of extrachromosomal DNA, which activates the cGAS-STING pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier permeable PARP inhibitor, pamiparib, and the cell cycle checkpoint CHK1/2 inhibitor, AZD7762), and these combinations resulted in approximately 50% long-term survivors. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induce immune-mediated therapeutic efficacy in G34-mutant pHGG.
Santiago Haase, Kaushik Banerjee, Anzar A. Mujeeb, Carson S. Hartlage, Fernando M. Nunez, Felipe J. Nuñez, Mahmoud S. Alghamri, Padma Kadiyala, Stephen Carney, Marcus Barissi, Ayman W. Taher, Emily K. Brumley, Sarah Thompson, Justin T. Dreyer, Caitlin T. Alindogan, Maria B. Garcia-Fabiani, Andrea Comba, Sriram Venneti, Visweswaran Ravikumar, Carl Koschmann, Angel M. Carcaboso, Maria Vinci, Arvind Rao, Jennifer S. Yu, Pedro R. Lowenstein, Maria G. Castro
In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53-dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule–based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.
Arnab Ghosh, Judith Michels, Riccardo Mezzadra, Divya Venkatesh, Lauren Dong, Ricardo Gomez, Fadi Samaan, Yu-Jui Ho, Luis Felipe Campesato, Levi Mangarin, John Fak, Nathan Suek, Aliya Holland, Cailian Liu, Mohsen Abu-Akeel, Yonina Bykov, Hong Zhong, Kelly Fitzgerald, Sadna Budhu, Andrew Chow, Roberta Zappasodi, Katherine S. Panageas, Olivier de Henau, Marcus Ruscetti, Scott W. Lowe, Taha Merghoub, Jedd D. Wolchok
CLN1 disease is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by delivering monthly infusions of recombinant human PPT1 (rhPPT1) in PPT1-deficient mice (Cln1−/−), and CLN1R151X sheep to assess scale up for translation. In Cln1−/− mice, intracerebroventricular rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1 treated-mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, intracerebroventricular infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural magnetic resonance imaging and neuropathology. These findings demonstrate the feasibility and therapeutic efficacy of intracerebroventricular rhPPT1 enzyme replacement therapy. This represents a key step towards clinical testing of ERT in children with CLN1 disease and highlights the importance of a cross-species approach to developing a successful treatment strategy.
Hemanth R. Nelvagal, Samantha L. Eaton, Sophie H. Wang, Elizabeth M. Eultgen, Keigo Takahashi, Steven Q. Le, Rachel Nesbitt, Joshua T. Dearborn, Nicholas Siano, Ana C. Puhl, Patricia I. Dickson, Gerard Thompson, Fraser Murdoch, Paul M. Brennan, Mark Gray, Stephen N. Greenhalgh, Peter Tennant, Rachael Gregson, Eddie Clutton, James Nixon, Chris Proudfoot, Stefano Guido, Simon G. Lillico, C. Bruce A. Whitelaw, Jui-Yun Lu, Sandra L. Hofmann, Sean Ekins, Mark S. Sands, Thomas M. Wishart, Jonathan D. Cooper
Vessel co-option has been demonstrated to mediate colorectal cancer liver metastasis (CRCLM) resistance to anti-angiogenic therapy. The current mechanisms underlying vessel co-option have mainly focused on the "hijacker" tumor cells, whereas the function of the “hijackee” sinusoidal blood vessels has not been explored. Here, we found that the occurrence of vessel co-option in bevacizumab-resistant CRCLM xenografts was associated with increased expression of fibroblast activation protein alpha (FAPα) in the co-opted hepatic stellate cells (HSCs), which was dramatically attenuated in HSC-specific conditional Fap-knockout mice bearing CRCLM allografts. Mechanistically, bevacizumab treatment induced hypoxia to upregulate the expression of fibroblast growth factor-binding protein 1 (FGFBP1) in tumor cells. Gain- or loss-of-function experiments revealed that the bevacizumab-resistant tumor cell-derived FGFBP1 induced FAPα expression by enhancing the paracrine FGF2-FGFR1-ERK1/2-EGR1 signaling pathway in HSCs. FAPα promoted CXCL5 secretion in HSCs, which activated CXCR2 to promote the epithelial-mesenchymal transition of tumor cells and the recruitment of myeloid-derived suppressor cells. These findings were further validated in CRCLM patient-derived tumor tissues. Targeting FAPα+ HSCs effectively disrupted the co-opted sinusoidal blood vessels and overcame bevacizumab resistance. Our study highlights the role of FAPα+ HSCs in vessel co-option and provides an effective strategy to overcome the vessel co-option-mediated bevacizumab resistance.
Ming Qi, Shuran Fan, Maohua Huang, Jinghua Pan, Yong Li, Qun Miao, Wenyu Lyu, Xiaobo Li, Lijuan Deng, Shenghui Qiu, Tongzheng Liu, Weiqing Deng, Xiaodong Chu, Chang Jiang, Wenzhuo He, Liangping Xia, Yunlong Yang, Jian Hong, Qi Qi, Wenqian Yin, Xiangning Liu, Changzheng Shi, Minfeng Chen, Wencai Ye, Dongmei Zhang
The vast majority of people with cystic fibrosis (CF) are now eligible for CF transmembrane regulator (CFTR) modulator therapy. Remaining individuals harbor premature termination codons (PTCs) or rare CFTR variants with limited treatment options. Although clinical modulator response can be reliably predicted using primary airway epithelial cells, primary cells carrying rare CFTR variants are scarce. To overcome this obstacle, cell lines can be created by overexpression of mouse Bmi-1 and human TERT (hTERT). Using this approach, we developed two non-CF and six CF airway epithelial cell lines, three of which are homozygous for the W1282X PTC variant. Bmi-1/hTERT cell lines recapitulated primary cell morphology and ion transport function. The two F508del-CFTR cell lines responded robustly to CFTR modulators, which was mirrored in the parent primary cells and in the cell donors’ clinical response. Cereblon E3 ligase modulators targeting eRF3a rescued W1282X-CFTR function to ~20% of wildtype levels and, when paired with G418, rescued G542X-CFTR function to ~50% of wildtype levels. Intriguingly, eRF3a degraders also diminished epithelial sodium channel (ENaC) function. These studies demonstrate that Bmi-1/hTERT cell lines faithfully mirror primary cell responses to CFTR modulators and illustrate a therapeutic approach to rescue CFTR nonsense mutations.
Rhianna E. Lee, Catherine A. Lewis, Lihua He, Emily C. Bulik-Sullivan, Samuel C. Gallant, Teresa M. Mascenik, Hong Dang, Deborah M. Cholon, Martina Gentzsch, Lisa C. Morton, John T. Minges, Jonathan W. Theile, Neil A. Castle, Michael R. Knowles, Adam J. Kimple, Scott H. Randell
Immune checkpoint blockade (ICB) has demonstrated clinical success in “inflamed” tumors with substantial T-cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the Polycomb-repressive complex 2 (PRC2) core components, EED or SUZ12, a prevalent genetic event in malignant peripheral nerve sheath tumor (MPNST) and sporadically in other cancers, drove a context-dependent immune-desert TME. PRC2 inactivation reprogramed the chromatin landscape that led to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., interferon γ) to PRC2-regulated development and cellular differentiation transcriptional programs. Further, PRC2 inactivation led to diminished tumor immune infiltrates through reduced chemokine production and impaired antigen presentation and T-cell priming, resulting in primary resistance to ICB. Intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) enhanced tumor immune infiltrates and sensitized PRC2-loss tumors to ICB. Our results provide molecular mechanisms of PRC2-inactivation-mediated context-dependent epigenetic reprogramming that underline the immune-desert phenotype in cancer. Our studies also point to intratumoral delivery of immunogenic viruses as an initial therapeutic strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.
Juan Yan, Yuedan Chen, Amish J. Patel, Sarah Warda, Cindy J. Lee, Briana G. Nixon, Elissa W.P. Wong, Miguel A. Miranda-Román, Ning Yang, Yi Wang, Mohini R. Pachai, Jessica Sher, Emily Giff, Fanying Tang, Ekta Khurana, Samuel Singer, Yang Liu, Phillip M. Galbo Jr., Jesper L.V. Maag, Richard P. Koche, Deyou Zheng, Cristina Antonescu, Liang Deng, Ming Li, Yu Chen, Ping Chi
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