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Overcoming Melanoma Immune Tolerance: Non-specific CTLA-4 Blockade/Interferon-alfa and Antigen Specific Immunization with TLR-9 Stimulation/Local GM-CSF as Components of a Melanoma Immunotherapeutic Strategy and Associated Biomarkers of Therapeutic Benefit

Tarhini, Ahmad Ali (2011) Overcoming Melanoma Immune Tolerance: Non-specific CTLA-4 Blockade/Interferon-alfa and Antigen Specific Immunization with TLR-9 Stimulation/Local GM-CSF as Components of a Melanoma Immunotherapeutic Strategy and Associated Biomarkers of Therapeutic Benefit. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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 regimen's 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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tarhini, Ahmad Alitarhiniaa@upmc.eduAAT8
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKirkwood, John M.kirkwoodjm@upmc.eduKIRKWOOD
Committee MemberSwitzer, Galen E.switzerge@upmc.eduGSWITZER
Committee MemberDavidson, Nancy E.davidsonne@upmc.eduNED23
Committee MemberKalinski, Pawelkalinskip@upmc.eduPAK5
Committee MemberBranch, Robert A.rab13@pitt.eduRAB13
Date: 11 July 2011
Date Type: Completion
Defense Date: 25 May 2011
Approval Date: 11 July 2011
Submission Date: 15 June 2011
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Clinical and Translational Science
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: CTLA4; immune tolerance; immunotherapy; interferon; Melanoma; vaccine
Other ID: http://etd.library.pitt.edu/ETD/available/etd-06152011-122145/, etd-06152011-122145
Date Deposited: 10 Nov 2011 19:47
Last Modified: 19 Dec 2016 14:36
URI: http://d-scholarship.pitt.edu/id/eprint/8120

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