Oncology
Abstract
Tuberous sclerosis complex (TSC) is an incurable multisystem disease characterized by mTORC1-hyperactive tumors. TSC1/2 mutations also occur in other neoplastic disorders, including lymphangioleiomyomatosis (LAM) and bladder cancer. Whether TSC-associated tumors will respond to immunotherapy is unknown. We report here that the programmed death 1 coinhibitory receptor (PD-1) is upregulated on T cells in renal angiomyolipomas (AML) and pulmonary lymphangioleiomyomatosis (LAM). In C57BL/6J mice injected with syngeneic TSC2-deficient cells, anti–PD-1 alone decreased 105K tumor growth by 67% (P < 0.0001); the combination of PD-1 and CTLA-4 blockade was even more effective in suppressing tumor growth. Anti–PD-1 induced complete rejection of TSC2-deficient 105K tumors in 37% of mice (P < 0.05). Double blockade of PD-1 and CTLA-4 induced rejection in 62% of mice (P < 0.01). TSC2 reexpression in TSC2-deficient TMKOC cells enhanced antitumor immunity by increasing T cell infiltration and production of IFN-γ/TNF-α by T cells, suggesting that TSC2 and mTORC1 play specific roles in the induction of antitumor immunity. Finally, 1 month of anti–PD-1 blockade reduced renal tumor burden by 53% (P < 0.01) in genetically engineered Tsc2+/– mice. Taken together, these data demonstrate for the first time to our knowledge that checkpoint blockade may have clinical efficacy for TSC and LAM, and possibly other benign tumor syndromes, potentially yielding complete and durable clinical responses.
Authors
Heng-Jia Liu, Patrick H. Lizotte, Heng Du, Maria C. Speranza, Hilaire C. Lam, Spencer Vaughan, Nicola Alesi, Kwok-Kin Wong, Gordon J. Freeman, Arlene H. Sharpe, Elizabeth P. Henske
Abstract
Colon cancer is a complex disease affected by a combination of genetic and epigenetic factors. Here we demonstrate that nardilysin (N-arginine dibasic convertase; NRDC), a metalloendopeptidase of the M16 family, regulates intestinal tumorigenesis via its nuclear functions. NRDC is highly expressed in human colorectal cancers. Deletion of the Nrdc gene in ApcMin mice crucially suppressed intestinal tumor development. In ApcMin mice, epithelial cell–specific deletion of Nrdc recapitulated the tumor suppression observed in Nrdc-null mice. Moreover, epithelial cell–specific overexpression of Nrdc significantly enhanced tumor formation in ApcMin mice. Notably, epithelial NRDC controlled cell apoptosis in a gene dosage–dependent manner. In human colon cancer cells, nuclear NRDC directly associated with HDAC1, and controlled both acetylation and stabilization of p53, with alterations of p53 target apoptotic factors. These findings demonstrate that NRDC is critically involved in intestinal tumorigenesis through its epigenetic regulatory function, and targeting NRDC may lead to a novel prevention or therapeutic strategy against colon cancer.
Authors
Keitaro Kanda, Jiro Sakamoto, Yoshihide Matsumoto, Kozo Ikuta, Norihiro Goto, Yusuke Morita, Mikiko Ohno, Kiyoto Nishi, Koji Eto, Yuto Kimura, Yuki Nakanishi, Kanako Ikegami, Takaaki Yoshikawa, Akihisa Fukuda, Kenji Kawada, Yoshiharu Sakai, Akihiro Ito, Minoru Yoshida, Takeshi Kimura, Tsutomu Chiba, Eiichiro Nishi, Hiroshi Seno
Abstract
Pleomorphic invasive lobular carcinoma (PILC) is an aggressive variant of invasive lobular breast cancer that is associated with poor clinical outcomes. Limited molecular data are available to explain the mechanistic basis for PILC behavior. To address this issue, targeted sequencing was performed to identify molecular alterations that define PILC. This sequencing analysis identified genes that distinguish PILC from classic ILC and invasive ductal carcinoma by the incidence of their genomic changes. In particular, insulin receptor substrate 2 (IRS2) is recurrently mutated in PILC, and pathway analysis reveals a role for the insulin receptor (IR)/insulin-like growth factor-1 receptor (IGF1R)/IRS2 signaling pathway in PILC. IRS2 mutations identified in PILC enhance invasion, revealing a role for this signaling adaptor in the aggressive nature of PILC.
Authors
Sha Zhu, B. Marie Ward, Jun Yu, Asia N. Matthew-Onabanjo, Jenny Janusis, Chung-Cheng Hsieh, Keith Tomaszewicz, Lloyd Hutchinson, Lihua Julie Zhu, Dina Kandil, Leslie M. Shaw
Abstract
Exosomes are extracellular vesicles produced by all cells with a remarkable ability to efficiently transfer genetic material, including exogenously loaded siRNA, to cancer cells. Here, we report on a bioreactor-based, large-scale production of clinical-grade exosomes employing good manufacturing practice (GMP) standards. A standard operating procedure was established to generate engineered exosomes with the ability to target oncogenic Kras (iExosomes). The clinical-grade GMP iExosomes were tested in multiple in vitro and in vivo studies to confirm suppression of oncogenic Kras and an increase in the survival of several mouse models with pancreatic cancer. We perform studies to determine the shelf life, biodistribution, toxicology profile, and efficacy in combination with chemotherapy to inform future clinical testing of GMP iExosomes. Collectively, this report illustrates the process and feasibility of generating clinical-grade exosomes for various therapies of human diseases.
Authors
Mayela Mendt, Sushrut Kamerkar, Hikaru Sugimoto, Kathleen M. McAndrews, Chia-Chin Wu, Mihai Gagea, Sujuan Yang, Elena V. Rodriges Blanko, Qian Peng, Xiaoyan Ma, Joseph R. Marszalek, Anirban Maitra, Cassian Yee, Katayoun Rezvani, Elizabeth Shpall, Valerie S. LeBleu, Raghu Kalluri
Abstract
BACKGROUND. Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019). METHODS. Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS). RESULTS. ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently. CONCLUSION. CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells. TRIAL REGISTRATION. Clinicaltrials.gov identifier NCT02135406. FUNDING. Novartis, NIH, Conquer Cancer Foundation.
Authors
Alfred L. Garfall, Edward A. Stadtmauer, Wei-Ting Hwang, Simon F. Lacey, Jan Joseph Melenhorst, Maria Krevvata, Martin P. Carroll, William H. Matsui, Qiuju Wang, Madhav V. Dhodapkar, Kavita Dhodapkar, Rituparna Das, Dan T. Vogl, Brendan M. Weiss, Adam D. Cohen, Patricia A. Mangan, Emily C. Ayers, Selene Nunez-Cruz, Irina Kulikovskaya, Megan M. Davis, Anne Lamontagne, Karen Dengel, Naseem D.S. Kerr, Regina M. Young, Donald L. Siegel, Bruce L. Levine, Michael C. Milone, Marcela V. Maus, Carl H. June
Abstract
Tumor-induced expansion of Tregs is a significant obstacle to cancer immunotherapy. However, traditional approaches to deplete Tregs are often inefficient, provoking autoimmunity. We show here that administration of IL-27–expressing recombinant adeno-associated virus (AAV–IL-27) significantly inhibits tumor growth and enhances T cell responses in tumors. Strikingly, we found that AAV–IL-27 treatment causes rapid depletion of Tregs in peripheral blood, lymphoid organs, and — most pronouncedly — tumor microenvironment. AAV–IL-27–mediated Treg depletion is dependent on IL-27 receptor and Stat1 in Tregs and is a combined result of CD25 downregulation in Tregs and inhibition of IL-2 production by T cells. In combination with a GM-CSF vaccine, AAV–IL-27 treatment not only induced nearly complete tumor rejection, but also resulted in amplified neoantigen-specific T cell responses. AAV–IL-27 also dramatically increased the efficacy of anti–PD-1 therapy, presumably due to induction of PD-L1 in T cells and depletion of Tregs. Importantly, AAV–IL-27 therapy did not induce significant adverse events, partially due to its induction of IL-10. In a plasmacytoma mouse model, we found that IL-10 was required for AAV–IL-27–mediated tumor rejection. Thus, our study demonstrates the potential of AAV–IL-27 as an independent cancer therapeutic and as an efficient adjuvant for cancer immunotherapy.
Authors
Jianmin Zhu, Jin-Qing Liu, Min Shi, Xinhua Cheng, Miao Ding, Jianchao C. Zhang, Jonathan P. Davis, Sanjay Varikuti, Abhay R. Satoskar, Lanchun Lu, Xueliang Pan, Pan Zheng, Yang Liu, Xue-Feng Bai
Abstract
We generated a comprehensive atlas of the immunologic cellular networks within human malignant pleural mesothelioma (MPM) using mass cytometry. Data-driven analyses of these high-resolution single-cell data identified 2 distinct immunologic subtypes of MPM with vastly different cellular composition, activation states, and immunologic function; mass spectrometry demonstrated differential abundance of MHC-I and -II neopeptides directly identified between these subtypes. The clinical relevance of this immunologic subtyping was investigated with a discriminatory molecular signature derived through comparison of the proteomes and transcriptomes of these 2 immunologic MPM subtypes. This molecular signature, representative of a favorable intratumoral cell network, was independently associated with improved survival in MPM and predicted response to immune checkpoint inhibitors in patients with MPM and melanoma. These data additionally suggest a potentially novel mechanism of response to checkpoint blockade: requirement for high measured abundance of neopeptides in the presence of high expression of MHC proteins specific for these neopeptides.
Authors
Hyun-Sung Lee, Hee-Jin Jang, Jong Min Choi, Jun Zhang, Veronica Lenge de Rosen, Thomas M. Wheeler, Ju-Seog Lee, Thuydung Tu, Peter T. Jindra, Ronald H. Kerman, Sung Yun Jung, Farrah Kheradmand, David J. Sugarbaker, Bryan M. Burt
Abstract
BACKGROUND. Myeloid-derived suppressor cells (MDSCs) are a population of immature immune cells with several protumorigenic functions. CD38 is a transmembrane receptor–ectoenzyme expressed by MDSCs in murine models of esophageal cancer. We hypothesized that CD38 could be expressed on MDSCs in human colorectal cancer (CRC), which might allow for a new perspective on therapeutic targeting of human MDSCs with anti-CD38 monoclonal antibodies in this cancer. METHODS. Blood samples were collected from 41 CRC patients and 8 healthy donors, followed by peripheral blood mononuclear cell (PBMC) separation. Polymorphonuclear (PMN-) and monocytic (M-) MDSCs and CD38 expression levels were quantified by flow cytometry. The immunosuppressive capacity of M-MDSCs from 10 CRC patients was validated in a mixed lymphocyte reaction (MLR) assay. RESULTS. A significant expansion of CD38+ M-MDSCs and a trend of expansion of CD38+ PMN-MDSCs (accompanied by a trend of increased CD38 expression on both M- and PMN-MDSCs) were observed in PBMCs of CRC patients when compared with healthy donors. The CD38+ M-MDSCs from CRC patients were found to be immunosuppressive when compared with mature monocytes. CD38+ M- and PMN-MDSC frequencies were significantly higher in CRC patients who previously received treatment when compared with treatment-naive patients. CONCLUSIONS. This study provides a rationale for an attempt to target M-MDSCs with an anti-CD38 monoclonal antibody in metastatic CRC patients. FUNDING. NCI P01-CA14305603, the American Cancer Society, Scott and Suzi Lustgarten Family Colon Cancer Research Fund, Hansen Foundation, and Janssen Research and Development.
Authors
Tatiana A. Karakasheva, George A. Dominguez, Ayumi Hashimoto, Eric W. Lin, Christopher Chiu, Kate Sasser, Jae W. Lee, Gregory L. Beatty, Dmitry I. Gabrilovich, Anil K. Rustgi
Abstract
Insulin resistance is associated with increased incidence and enhanced progression of cancers. However, little is known about strategies that can effectively ameliorate insulin resistance and consequently halt cancer progression. Herein, we propose that the transcription factor Nrf2 (also known as Nfe2l2) may be such a target, given its central role in disease prevention. To this end, we developed a mouse that overexpresses the Notch intracellular domain in adipocytes (AdNICD), leading to lipodystrophy-induced severe insulin resistance and subsequent development of sarcomas, as a model reflecting that Notch signaling is deregulated in cancers and shows positive associations with insulin resistance and fatty liver disease in humans. Nrf2 pathway activation was achieved by knocking down Keap1, a repressor of Nrf2, in the AdNICD background. Constitutively enhanced Nrf2 signaling in this setting led to prevention of hepatic steatosis, dyslipidemia, and insulin resistance by repressing hepatic lipogenic pathways and restoration of the hepatic fatty acid profile to control levels. This protective effect of Nrf2 against diabetes extended to significant reduction and delay in sarcoma incidence and latency. Our study highlights that the Nrf2 pathway, which has been induced by small molecules in clinical trials, is a potential therapeutic target against insulin resistance and subsequent risk of cancer.
Authors
Dionysios V. Chartoumpekis, Yoko Yagishita, Marco Fazzari, Dushani L. Palliyaguru, Uma N.M. Rao, Apostolos Zaravinos, Nicholas K.H. Khoo, Francisco J. Schopfer, Kurt R. Weiss, George K. Michalopoulos, Ian Sipula, Robert M. O’Doherty, Thomas W. Kensler, Nobunao Wakabayashi
Abstract
BACKGROUND. Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts. METHODS. We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed. RESULTS. MK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas. CONCLUSION. MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters. TRIAL REGISTRATION. ClinicalTrials.gov NCT01358331. FUNDING. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).
Authors
Stergios J. Moschos, Ryan J. Sullivan, Wen-Jen Hwu, Ramesh K. Ramanathan, Alex A. Adjei, Peter C. Fong, Ronnie Shapira-Frommer, Hussein A. Tawbi, Joseph Rubino, Thomas S. Rush III, Da Zhang, Nathan R. Miselis, Ahmed A. Samatar, Patrick Chun, Eric H. Rubin, James Schiller, Brian J. Long, Priya Dayananth, Donna Carr, Paul Kirschmeier, W. Robert Bishop, Yongqi Deng, Alan Cooper, Gerald W. Shipps, Blanca Homet Moreno, Lidia Robert, Antoni Ribas, Keith T. Flaherty
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