6<\/sup>BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.<\/p>\nMETHODS. We enrolled 7 newly diagnosed glioblastoma patients with MGMThi<\/sup> tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6<\/sup>BG\/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated.<\/p>\nRESULTS. Gene therapy permitted a significant increase in the mean number of tolerated O6<\/sup>BG\/TMZ cycles (4.4 cycles per patient, P<\/i> < 0.05) compared with historical controls without gene therapy (n<\/i> = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5\u201357+<\/sup>) months and OS of 20 (range 13\u201357+<\/sup>) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O6<\/sup>BG.<\/p>\nCONCLUSION. These data support further development of chemoprotective gene therapy in combination with O6<\/sup>BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT.<\/p>\nTRIAL REGISTRATION. Clinicaltrials.gov NCT00669669.<\/p>\n
FUNDING. R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.<\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"
https::\/\/www.jci.org\/articles\/view\/76739 Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients Jennifer E. Adair1,2, Sandra K. Johnston3, Maciej M. Mrugala4,5, Brian C. Beard1,2, Laura A. Guyman6,7, Anne L. Baldock6,7, Carly A. Bridge6,7, Andrea Hawkins-Daarud6,7, Jennifer L. Gori1, Donald E. Born8, Luis F. Gonzalez-Cuyar9, Daniel L. Silbergeld3,9, Russell C. Rockne6,7, Barry E. Storer1,10, Jason K. … <\/p>\n
Continue reading “Our new Journal of Clinical Investigation paper using patient-specific mathematical modeling to prove efficacy of a novel gene therapy of glioblastoma”<\/span><\/a><\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[4],"tags":[],"_links":{"self":[{"href":"https:\/\/mathematicalneurooncology.org\/index.php?rest_route=\/wp\/v2\/posts\/2010"}],"collection":[{"href":"https:\/\/mathematicalneurooncology.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/mathematicalneurooncology.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/mathematicalneurooncology.org\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/mathematicalneurooncology.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=2010"}],"version-history":[{"count":2,"href":"https:\/\/mathematicalneurooncology.org\/index.php?rest_route=\/wp\/v2\/posts\/2010\/revisions"}],"predecessor-version":[{"id":2012,"href":"https:\/\/mathematicalneurooncology.org\/index.php?rest_route=\/wp\/v2\/posts\/2010\/revisions\/2012"}],"wp:attachment":[{"href":"https:\/\/mathematicalneurooncology.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2010"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/mathematicalneurooncology.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2010"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/mathematicalneurooncology.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2010"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}