Date of Award

1-1-2013

Embargo Period

1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Michael I. Nishimura

Second Advisor

James S. Norris

Third Advisor

David J. Cole

Fourth Advisor

Soldano Ferrone

Fifth Advisor

Laura M. Kasman

Sixth Advisor

Mark P. Rubinstein

Abstract

Adoptive transfer of T cell receptor (TCR) gene transduced T cells can mediate dramatic tumor regressions in melanoma patients. However, improvements in these therapies are needed as most patients either fail to respond to the therapy or eventually experience recurrent disease. To evaluate the therapeutic potential of T cells expressing the high-affinity TIL 1383I TCR for treatment of human melanomas, we developed xenograft models for the malignancy. Human T cells transduced with the TIL 1383I TCR exhibited strong in vitro reactivity against HLA-A2+Tyrosinase+ targets but failed to impact tumor growth in vivo. In contrast, TIL 1383I TCR-expressing murine T cells exhibited strong reactivity against the same targets in vitro and in vivo, rejecting human HLA-A2+Tyrosinase+ melanomas established (30-150 mm^3) in SCID beige mice. The tumor rejection, mediated by TIL 1383I TCR-expressing mouse splenocytes, was HLA-A2-restricted and Tyrosinase368-376 specific and did not require adjuvant therapy. However, up to half the mice that initially cleared all measurable disease eventually recurred. In our model, the long-term disease-free survival was thus limited to 40-50%. The recurrent 634 MEL tumors evaded T cell recognition in vivo because they had lost expression of the restriction element HLA-A2. These recurrent tumors all shared an identical genetic signature, which was unique from those of 624 MEL and the previously described tumors derived from it, indicating the recurring tumors represent novel tumor variants that are preexisting in the parental tumor. Specifically, these recurring tumors seem to arise from an extremely low frequency (<0.04%) population of HLA-A2- cells present in the 624 MEL tumor line. With this work, we demonstrate that ACT based on TIL 1383I TCR-expressing T cells is a very potent treatment strategy that can reject established human melanomas in vivo. However, originally rare melanoma cell variants that are resistant to the effector cells frequently cause recurrent tumors. The recurrence of therapy-resistance tumors mimics what happens in some cancer patients. Understanding the mechanisms allowing human melanoma cell escape and defining novel strategies that tackle their recurrence, will allow for more efficient therapies that further improve the clinical prospects of ACT using TIL 1383I TCR-expressing T cells.

Rights

All rights reserved. All rights reserved. Copyright is held by the author.

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