Publication Date

2014-09-17

Availability

Embargoed

Embargo Period

2016-03-10

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2014-07-07

First Committee Member

Eli Gilboa

Second Committee Member

John Goldberg

Third Committee Member

Ralf Landgraf

Fourth Committee Member

Robert Levy

Fifth Committee Member

Geoffrey Stone

Abstract

Despite the recent successes of using immune modulatory antibodies in cancer patients, autoimmune pathologies resulting from the activation of self reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. Here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient, whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, vascular endothelial growth factor (VEGF). The approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma the T cells will be costimulated prior to their engagement of the MHC/peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to non-internalizing cell surface products expressed on the tumor cells. Underscoring the potency of stroma targeted costimulation and the broad spectrum of tumors secreting VEGF, systemic administration of the VEGF targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, post surgical metastasis, and carcinogen-induced tumor models, and exhibited a superior therapeutic index compared to non-targeted administration of an agonistic 4-1BB antibody.

Keywords

Tumor Immunotherapy; 4-1BB; Tumor Stroma; VEGF; RNA aptamers; RNA therapeutics

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