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Roberts N.J.,Howard Hughes Medical Institute | Zhang L.,Biomedical Valley Discoveries Inc. | Janku F.,University of Houston | Collins A.,Biomedical Valley Discoveries Inc. | And 36 more authors.
Science Translational Medicine | Year: 2014

Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted. © 2014, American Association for the Advancement of Science. All rights reserved.

Le D.T.,Sidney Kimmel Cancer Center | Le D.T.,Swim Across America Laboratory at Johns Hopkins | Lutz E.,Sidney Kimmel Cancer Center | Uram J.N.,Sidney Kimmel Cancer Center | And 9 more authors.
Journal of Immunotherapy | Year: 2013

Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg+GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P=0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS>4.3 months, there was an increase in the peak mesothelin-specific T cells (P=0.014) and enhancement of the T-cell repertoire (P=0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study. Copyright © 2013 by Lippincott Williams & Wilkins.

Bettegowda C.,Howard Hughes Medical Institute | Sausen M.,Howard Hughes Medical Institute | Sausen M.,Personal Genome Diagnostics (PGD) | Leary R.J.,Howard Hughes Medical Institute | And 70 more authors.
Science Translational Medicine | Year: 2014

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

Sausen M.,Personal Genome Diagnostics (PGD) | Parpart S.,Personal Genome Diagnostics (PGD) | Diaz Jr. L.A.,Howard Hughes Medical Institute | Diaz Jr. L.A.,Swim Across America Laboratory at Johns Hopkins
Genome Medicine | Year: 2014

Assessment of somatic genomic alterations from tumors can now be performed by sequencing circulating tumor DNA from the cell-free component of blood. This procedure, which identifies tumor-derived somatic mutations from a simple blood sample, circumvents the need for tumor tissue. A recent study highlights the promise of circulating tumor DNA to guide therapeutic decisions in a variety of solid tumors for both clinical and investigative purposes, as well as providing a tool for the early detection of cancer. © 2014 Sausen et al.; licensee BioMed Central Ltd.

Holdhoff M.,Howard Hughes Medical Institute | Schmidt K.,Howard Hughes Medical Institute | Diehl F.,Inostics GmbH | Aggrawal N.,Howard Hughes Medical Institute | And 9 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Defining an adequate resection margin of colorectal cancer liver metastases is essential for optimizing surgical technique. We have attempted to evaluate the resection margin through a combination of histopathologic and genetic analyses. Experimental Design: We evaluated 88 samples of tumor margins from 12 patients with metastatic colon cancer who each underwent partial hepatectomy of one to six liver metastases. Punch biopsies of surrounding liver tissue were obtained at 4, 8, 12, and 16 mm from the tumor border. DNA from these biopsies was analyzed by a sensitive PCR-based technique, called BEAMing, for mutations of KRAS, PIK3CA, APC, or TP53 identified in the corresponding tumor. Results: Mutations were identified in each patient's resected tumor and used to analyze the 88 samples circumscribing the tumor-normal border. Tumor-specific mutant DNA was detectable in surrounding liver tissue in 5 of these 88 samples, all within 4 mm of the tumor border. Biopsies that were 8, 12, and 16 mm from the macroscopic visible margin were devoid of detectable mutant tumor DNA and of microscopically visible cancer cells. Tumors with a significant radiologic response to chemotherapy were not associated with any increase in mutant tumor DNA in beyond 4 mm of the main tumor. Conclusions: Mutant tumor-specific DNA can be detected beyond the visible tumor margin, but never beyond 4 mm, even in patients whose tumors were larger prior to chemotherapy. These data provide a rational basis for determining the extent of surgical excision required in patients undergoing resection of liver metastases. ©2011 AACR.

Holdhoff M.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Holdhoff M.,Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins | Holdhoff M.,Swim Across America Laboratory at Johns Hopkins | Ye X.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | And 6 more authors.
Journal of Neuro-Oncology | Year: 2012

This study was conducted to assess the current pattern of use and the impact of available molecular predictive and prognostic biomarkers on clinical care in patients with glioblastoma (GBM). An online questionnaire consisting of 15 questions about the frequency of use and clinical utility of tissue-based molecular tests was distributed to 1,053 members of the Neuro-Oncology Community in the United States. A total of 320 responses (30.4 %) were collected. 73 respondents who did not see GBM patients were excluded from analysis. MGMT promoter methylation testing (MGMT-meth) was the most commonly requested (37.2; 95 % CI, 31-44), followed by EGFR amplification (22.7; 95 % CI, 18-28), co-deletion of 1p/19q (22.3 %), EGFR expression (21.5 %), P53 mutation (19.8 %), PTEN mutation or deletion (17.4 %), EGFRvIII mutation (12.1 %), IDH1/2 mutation (12.1 %), PDGFR (4.5 %), and PIK3CA (0.8 %). The perceived utility of these studies was variable between participants. A small percentage of respondents felt that any of the studies were always or almost always helpful in clinical decision making (MGMT-meth 10.9 %; range, 0-13.8 %), but more frequently never or almost never helpful (MGMT-meth 25.9 %; range, 25-54.7 %). 26.7 % reported not to routinely order any of these studies. Although molecular markers are frequently ordered for patients with GBM, only a minority of clinicians ordering these tests report that the results influence clinical decision-making. Molecular markers that are likely to affect patient care should be ordered with the goal to maximize benefit for patients and to avoid non-actionable results and additional costs. © 2012 Springer Science+Business Media, LLC.

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