Again from the desk of CJ Gaddy:
Add MD-Anderson to our collaborators list. This 1-30-17 article was authored by 10 MDA researchers (LEAD: Jason B. Fleming), joined by UTSW’s Rolf Brekken (PPHM SAB). It’s preclin. results of a study of DNAtrix’s DNX2401 + MouseBAVI in Pancreatic, whereby the abstract states that the combo “further enhanced anticancer activity, possibly through inducing synergistic anticancer immune responses.”...
1-30-17 Mol Cancer Therapy: “Preclinical Evaluation of Sequential Combination of Oncolytic Adenovirus Delta-24-RGD and Phosphatidylserine-Targeting Antibody [1N11=MouseBAVI] in Pancreatic Ductal Adenocarcinoma”
Rec/8-5-16, Rev/12-1-16, Acc/12-15-16, PUB/1-30-17
Dai B 1, Roife D 1, Kang Y 1, Gumin J 2, Rios Perez MV 1, Li X 1, Pratt M 1, Rolf Brekken [PPHM SAB] 3, Fueyo-Margareto J 4, Lang FF 2, Jason B Fleming [MDA]***
1 Dept of Surgical Oncology, Univ. of Texas MDA CC
2 Dept of Neurosurgery, Univ. of Texas MDA CC
3 Hamon Ctr for Therapeutic Oncology Res., Depts Surgery/Pharmacology, UTSW-MC
4 Dept of Neuro-Oncology, Univ. of Texas MDA CC
5 Dept of Surgical Oncology, Univ. of Texas MDA CC
***Lead author: JASON B. FLEMING, “Dir. of the Tissue Acquisition & Biorepository Core for the Pancreas Cancer Res. Pgm at MDA” faculty.mdanderson.org
mct.aacrjournals.org
ABSTRACT
Delta-24-RGD (DNX-2401) [DNXtrix Co.**] is a conditional replication-competent oncolytic virus engineered to preferentially replicate in and lyse tumor cells with abnormality of p16/RB/E2F pathway. In a phase 1 clinical trial, Delta-24-RGD has shown favorable safety profile and promising clinical efficacy in brain tumor, which prompted us to evaluate its anticancer activity in pancreatic ductal adenocarcinoma (PDAC), which also has high frequency of homozygous deletion and promoter methylation of CDKN2A encoding the p16 protein. Our results demonstrate that Delta-24-RGD can induce dramatic cytotoxicity in a subset of PDAC cell lines with high Cyclin D1 expression. Induction of autophagy & apoptosis by Delta-24-RGD in sensitive PDAC cells was confirmed with LC3B-GFP autophagy reporter and Acridine Orange staining as well as Western blotting analysis of LC3B-II expression. Notably, we found that Delta-24-RGD induced phosphatidylserine (PS) exposure in infected cells independent of cells' sensitivity to Delta-24-RGD, which renders a rationale for combination of Delta-24-RGD viral therapy and PS targeting antibody for PDAC. In a mouse PDAC model derived from a liver metastatic pancreatic cancer cell line, Delta-24-RGD significantly inhibited tumor growth compared with control (p<0.001), and combination of PS targeting antibody 1N11 [mouse version of Bavituximab] further enhanced its anticancer activity (p<0.01) possibly through inducing synergistic anticancer immune responses. Given that these 2 agents are currently in clinical evaluation, our study warrants further clinical evaluation of this novel combination strategy in pancreatic cancer therapy.
**DNX-2401: DNAtrix Corp., Houston TX dnatrix.com (private company)
“DNAtrix’s lead product, DNX-2401 is a potent oncolytic adenovirus that targets & kills cancer cells, while leaving normal cells intact. Multiple clinical studies in patients with recurrent glioblastoma and gynecologic cancer have shown that DNX-2401 has a favorable safety profile, strong tumor-killing potential, and can trigger an anti-tumor immune response.”dnatrix.com
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I. Phase II Bavi+GEM vs. Front-Line Adv. PANCREATIC (randomized, unblinded, n=70)
Protocol: clinicaltrials.gov (15 U.S. + 4 Ukraine = 19 as of 6-7-2012)
…1-22-13: FTM's post of 13 Ph3 Gem+Treatment Pancreatic Trials ('02-'13) - Mean MOS: GEM=6.4mos., GEM+TR=7.3mos. tinyurl.com
......Another FTM Pancreatic Phase3 trials table showing HR's, P-Values, and ORR% stats: tinyurl.com
…6-3-13 ASCO’13/final data: n=70, Ctl=>Bavi MOS 5.2=>5.6mos, ORR 13%=>28% HR=.75 tinyurl.com
......Promising ‘immuno-indicative’ 1yr SURVIVAL results: GEM-Only(n=31): 0%, Bavi+GEM(n=32): 24.5% - see: tinyurl.com
...2-13-13 Topline Data: “Bavi+Gem resulted in more than a doubling of ORR” tinyurl.com
...6-25-12: Enrollment complete. tinyurl.com
...6-20-12: Early data (cutoff=6/6/12 bavi=15 ctl=17) presented at AACR Pancreatic Conf. tinyurl.com
...1-5-11: U.S. Ph.2 randomized trial initiated tinyurl.com "up to 70 front-line patients at ~10 clinical sites." |
