This long-term follow-up analysis evaluated overall survival (OS) and relapse-free survival (RFS) in a phase 2 study of the bispecific T-cell engager antibody construct blinatumomab in 36 adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). In the primary analysis, 25 (69%) patients with relapsed/refractory ALL achieved complete remission with full (CR) or partial (CRh) hematologic recovery of peripheral blood counts within the first 2 cycles. Twenty-five patients (69%) had a minimal residual disease (MRD) response (<10(-4) blasts), including 22 CR/CRh responders, 2 patients with hypocellular bone marrow, and 1 patient with normocellular bone marrow but low peripheral counts. Ten of the 36 patients (28%) were long-term survivors (OS ≥30 months). Median OS was 13.0 months (median follow-up, 32.6 months). MRD response was associated with significantly longer OS (Mantel-Byar P = .009). All 10 long-term survivors had an MRD response. Median RFS was 8.8 months (median follow-up, 28.9 months). A plateau for RFS was reached after ∼18 months. Six of the 10 long-term survivors remained relapse-free, including 4 who received allogeneic stem cell transplantation (allo-SCT) as consolidation for blinatumomab and 2 who received 3 additional cycles of blinatumomab instead of allo-SCT. Three long-term survivors had neurologic events or cytokine release syndrome, resulting in temporary blinatumomab discontinuation; all restarted blinatumomab successfully. Long-term survivors had more pronounced T-cell expansion than patients with OS <30 months.
© 2015 by The American Society of Hematology (ASH) (Free ASH Whitepaper).

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The most common congenital disorder of glycosylation, PMM2-CDG, is caused by mutations in phosphomannomutase 2 (PMM2) that limit availability of mannose precursors required for protein N-glycosylation. The disorder has no therapy and there are no models to test new treatments. We generated compound heterozygous mice with the R137H and F115L mutations inPmm2that correspond to the most prevalent alleles found in patients with PMM2-CDG. ManyPmm2(R137H/F115L)mice died prenatally, while survivors had significantly stunted growth. These animals and cells derived from them showed protein glycosylation deficiencies similar to those found in patients with PMM2-CDG. Growth-related glycoproteins insulin-like growth factor (IGF) 1, IGF binding protein-3, and acid-labile subunit, along with antithrombin III, were all deficient inPmm2(R137H/F115L)mice, but their levels in heterozygous mice were comparable to wild-type (WT) littermates. These imbalances, resulting from defective glycosylation, are likely the cause of the stunted growth seen both in our model and in PMM2-CDG patients. BothPmm2(R137H/F115L)mouse and PMM2-CDG patient-derived fibroblasts displayed reductions in PMM activity, GDP-mannose, lipid-linked oligosaccharide precursor, and total cellular protein glycosylation, along with hypoglycosylation of a new endogenous biomarker, glycoprotein 130 (gp130). Over-expression of WT-PMM2 in patient-derived fibroblasts rescued all these defects, showing that restoration of mutant PMM2 activity is a viable therapeutic strategy. This functional mouse model of PMM2-CDG,in vitroassays, and identification of the novel gp130 biomarker all shed light on the human disease, and moreover, provide the essential tools to test potential therapeutics for this untreatable disease.
© The Author 2016. Published by Oxford University Press.

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p53 tumor suppressor maintains genomic stability, typically acting through cell-cycle arrest, senescence, and apoptosis. We discovered a function of p53 in preventing conflicts between transcription and replication, independent of its canonical roles. p53 deficiency sensitizes cells to Topoisomerase (Topo) II inhibitors, resulting in DNA damage arising spontaneously during replication. Topoisomerase IIα (TOP2A)-DNA complexes preferentially accumulate in isogenic p53 mutant or knockout cells, reflecting an increased recruitment of TOP2A to regulate DNA topology. We propose that p53 acts to prevent DNA topological stress originating from transcription during the S phase and, therefore, promotes normal replication fork progression. Consequently, replication fork progression is impaired in the absence of p53, which is reversed by transcription inhibition. Pharmacologic inhibition of transcription also attenuates DNA damage and decreases Topo-II-DNA complexes, restoring cell viability in p53-deficient cells. Together, our results demonstrate a function of p53 that may underlie its role in tumor suppression.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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On April 7, 2016/ Evelo Biosciences and the University of Chicago reported that they have entered into an exclusive worldwide license agreement to develop and commercialize a microbiome-based cancer immunotherapy (Press release, Evelo Biosciences, APR 7, 2016, View Source [SID1234523301]). The cancer therapy, developed in the laboratories of UChicago researcher Thomas Gajewski, employs select gut microbes to boost the immune system’s attack on cancer cells and improve the efficacy of anti-cancer drugs.

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"This is the first license for the University in the area of microbiome immune-oncology, and one of the first of its kind nationwide," said Alan Thomas, associate vice president and director for UChicagoTech, the University’s Center for Technology Development and Ventures, which negotiated the license. "Immunotherapy is a rapidly growing field with huge potential and the University is at the forefront of oncobiome research."

The licensed technology adds to biotechnology company Evelo’s research into the power of the microbiome to disrupt and fight cancer.

"This exclusive license, in conjunction with our proprietary platform, solidifies Evelo’s leading position in the development of Oncobiotic therapeutics," said Simba Gill, Ph.D., chief executive officer of Evelo. "We are committed to working closely with the University of Chicago on this technology to rapidly develop novel therapies to help cancer patients worldwide."
Dr. Gajewski’s team showed that the introduction of a particular strain of bacteria into the digestive tracts of mice with melanoma boosted the ability of the animal’s immune systems to attack tumor cells. When combined with anti-PD-L1, an investigational anti-cancer antibody in the drug class known as checkpoint inhibitors, the therapy nearly eradicated tumors. Gajewski’s research was reported November 5, 2015, in the journal Science.

"This is a super exciting time in the field of cancer immunotherapy," Gajewski said. "Our recent work revealed a surprisingly potent role for the commensal microbiota in boosting the therapeutic efficacy of checkpoint blockade immunotherapy in mouse models. This relationship with Evelo will rapidly bring microbiota-based immunotherapy forward into clinical testing in cancer patients."