Immunotherapy utilizing cytokines or immune regulatory check point blockade has consistently demonstrated superior clinical efficacy in melanoma when compared to tumor peptide immunization strategies reported to date. In this project, I conducted 2 model studies representing alternative immunotherapeutic approaches (non-antigen specific combination of interferon-á2b and an anti-CTLA4 monoclonal antibody, IFN-Treme compared to a tumor antigen specific multi-epitope vaccine given in adjuvant with the potent combination of a TLR-9 agonist and GM-CSF) designed to overcome tumor immune evasion and conducted separately in a similar patient population. In addition to evaluating safety and clinical efficacy, I tested the following hypotheses: (1) Clinical benefits are likely to be associated with markers of reversal of immune tolerance (autoimmunity). (2) Clinical benefits may be predicted by baseline peripheral biomarkers of immune tolerance/suppression (C-reactive protein, CRP and absolute lymphocyte count, ALC). (3) Superior antitumor efficacy is likely to be associated with more effective downregulation of the host suppressor immune response (circulating T regulatory cells, T-reg and myeloid derived suppressor cells, MDSC). My findings supported superior clinical efficacy that was associated with more significant modulation of immune tolerance by the combination of IFN-Treme. Autoimmunity correlated with improved clinical outcome among the recipients of IFN-Treme (but not the vaccine) and suggested more significant reversal of immune tolerance. Baseline CRP and ALC were significantly predictive of therapeutic benefit with the IFN-Treme combination and may serve as variables for stratification of future trials, as these are validated in larger studies. Finally, my findings supported more significant downregulation of the host suppressor immune response by the nonspecific IFN-á/Treme regimen as compared to the vaccine-TLR agonist/GM-CSF combination. There was apparent increase in CD4+CD25hi+ CD39+ Treg but this was associated with an increase in the overall CD4+ T cell population suggesting that direct inhibition of CTLA4 suppressive effects on T effector cells leading to their expansion and prolonged activation is likely more important than the regimens effect on T-reg. In addition, I saw parallel downregulation in several populations of MDSC following treatment with IFN-Treme which may have had a role in the reduction of immune suppression and superior clinical outcome observed.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-06152011-122145 |
| Date | 11 July 2011 |
| Creators | Tarhini, Ahmad Ali |
| Contributors | Galen E. Switzer, PhD, Robert A. Branch, MD, John M. Kirkwood, MD, Pawel Kalinski, MD, PhD, Nancy E. Davidson, MD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-06152011-122145/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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