Publication Date

2014-07-14

Availability

Open access

Embargo Period

2014-07-14

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2014-05-02

First Committee Member

Robert B. Levy

Second Committee Member

Krishna V. Komanduri

Third Committee Member

Eckhard R. Podack

Fourth Committee Member

Eli Gilboa

Abstract

Tumor relapse is the primary cause of mortality in patients with hematologic cancers following autologous hematopoietic stem cell transplantation (HSCT). Vaccination early post-HSCT can exploit both the state of lymphopenia and minimal residual disease for the generation of anti-tumor immunity. Here, multiple vaccinations utilizing lymphoma cells engineered to secrete the heat shock protein fusion gp96-Ig within two weeks of T cell replete syngeneic HSCT led to antigen cross-presentation and increased survival of lymphoma bearing mice. To enhance vaccine efficacy, IL-2 was directed to predominantly memory phenotype CD8+ T lymphocytes and natural killer cells via administration bound to anti-IL-2 monoclonal antibody clone S4B6 (IL-2/S4B6). Combination therapy with gp96-Ig vaccination and coordinated infusions of IL-2/S4B6 resulted in a marked prolongation of median survival time and overall survival, which directly correlated with a ~500% increase in effector CD8+ T cell numbers. Notably, this dual regimen elicited large increases in both donor CD8+ T lymphocytes and natural killer cells, but not CD4+ T lymphocytes, the former two populations essential for both vaccine efficacy and protection against opportunistic infections post-HSCT. Indeed, IL-2/S4B6 treated HSCT recipients infected with Listeria monocytogenes exhibited decreased bacterial levels. These pre-clinical studies validate a new strategy particularly well suited to the post-HSCT environment, which may rapidly augment adaptive and innate immune function in patients with malignant disease following autologous HSCT.

Keywords

autologous hematopoietic stem cell transplantation; heat shock protein gp96; interleukin-2; CD8+ T cells; vaccination; immunotherapy

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