Anti-leukemic Activity of Anti-thymocyte Globulin

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dc.contributor.advisorStorek, Jan
dc.contributor.advisorKhan, Faisal Masood
dc.contributor.authorDabas, Rosy
dc.contributor.committeememberMorris, Don G.
dc.contributor.committeememberMahoney, Douglas J.
dc.date2018-11
dc.date.accessioned2018-09-20T15:18:48Z
dc.date.available2018-09-20T15:18:48Z
dc.date.issued2018-09-17
dc.description.abstractAllogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative therapy for hematologic malignancies. The most frequent indication is acute myeloid leukemia (AML). Relapse and graft-versus-host disease (GVHD) are the major causes of HCT failure. Most immunosuppressive drugs used for GVHD prophylaxis increase relapse, presumably due to inhibiting not only GVHD but also graft-versus-leukemia effect (GVL). Polyclonal rabbit anti-thymocyte globulin (ATG), now widely used for GVHD prophylaxis, is the only immunosuppressive drug reducing GVHD without increasing relapse. The reason for ATG not increasing relapse is not known. We hypothesized that this could be due to an anti-leukemic activity of ATG. I investigated the anti-leukemic activity both in vitro and in vivo (in patients). I first evaluated whether ATG at clinical concentrations kills leukemic blasts in vitro. I showed that ATG does kill leukemic blasts, via complement-dependent cytotoxicity (CDC) and direct induction of apoptosis. Next, I investigated whether ATG kills in vitro not only leukemic blasts but also leukemic stem cells (LSCs). I showed that ATG does kill LSCs, primarily via CDC, however, only at a higher concentration than needed for killing leukemic blasts. In spite of the anti-leukemic activity of ATG in vitro, in vivo ATG has so far been considered not to have an anti-leukemic activity as in 3/3 randomized studies ATG did not reduce relapse. We hypothesized that this could be due to differential effects of ATG pre- versus post-HCT. Specifically, we hypothesized that the direct anti-leukemic effect of ATG is countered by the anti-GVL effect of ATG post- but not pre-HCT. I evaluated associations between pre- versus post-HCT ATG area-under-the-curve (AUC) and relapse. I found that high pre-HCT AUC was associated with a low incidence of relapse. Conversely, there was a trend toward an association between high post-HCT AUC and a high incidence of relapse. The association between pre-HCT AUC and relapse is an indirect evidence for anti-leukemic activity of ATG in vivo. These findings are expected to lead to clinical studies harnessing the anti-leukemic effect of ATG, e.g., by dosing ATG so as to achieve a higher than conventional pre-HCT AUC and a conventional post-HCT AUC. This could lead to decreasing relapse without increasing GVHD which may lead to improved survival.en_US
dc.identifier.citationDabas, R. (2018). Anti-leukemic Activity of Anti-thymocyte Globulin (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/32956en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/32956
dc.identifier.urihttp://hdl.handle.net/1880/107793
dc.language.isoeng
dc.publisher.facultyCumming School of Medicine
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectAnti-thymocyte globulin
dc.subjectAllogeneic hematopoietic cell transplantation
dc.subjectAcute myeloid leukemia
dc.subjectGraft-versus-host disease
dc.subjectGraft-versus-leukemia effect
dc.subjectLeukemia relapse
dc.subjectLeukemic stem cells
dc.subjectHealthy hematopoietic stem cells
dc.subjectATG pharmacokinetics
dc.subject.classificationOncologyen_US
dc.titleAnti-leukemic Activity of Anti-thymocyte Globulin
dc.typedoctoral thesis
thesis.degree.disciplineMedical Science
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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