Date of Completion

8-30-2019

Embargo Period

8-30-2020

Keywords

Breast Cancer, Cancer Immunotherapy, Cancer Vaccine Cancer Diagnosis, Cancer Antigens, Cancer Vaccine Adjuvants, Peptide Microarray, CD13 – Aminopeptidase N, MPLA (Monophosphoryl Lipid A), Proteomics, Cross-presentation, Dendritic Cells, Effector T cells, Immunoproteomics, Genomics, Putative Tumor Antigens, Cancer-Patient-Derived Antibody, Immunological Asessment

Major Advisor

Linda Shapiro

Associate Advisor

Kevin Claffey

Associate Advisor

David Han

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

Although very promising, current cancer treatments applications, including immunotherapy, fail to treat all cancer cases due to short comings such as a limited range of available therapeutic tools, patient antigenic profile, and the absence of strong, immune-boosting adjuvants.

In order to advance truly personalized cancer therapy, we report the generation of a new approach that combines genomic and immunoproteomic technologies. Utilization of this technology on cancer and normal tissue from 15 breast cancer patients resulted in the identification of 149 putative tumor antigens derived from single nucleotide variants (SNVs), insertions and deletions. Further utilization of this platform and histological evaluation of cancer tissue served as proof-of-principal for the generation of the first cancer patient-derived antibody. In this study we describe the isolation, expression and tumor-killing abilities of this antibody.

Additionally, in this study we aimed to investigate the adjuvant capability of CD13 in combination with the known adjuvant Monophosphoryl Lipid A (sMPLA), based on their previously shown immune-effecting properties through biased activation of the Interferon regulatory factor 3 (p-IRF-3) signaling.

We tested the ability of these two molecules to act synergistically in in-vitroand in-vivo conditions. Our results indicated a biased synergistic effect at the protein level of the p-IRF3 and no significant increase of pro-inflammatory signaling, like NF-kb. This effect of the combined molecules appeared to translate at the cytokine level, seeing that CD13 knock out (CD13KO) cells exhibited lower levels of pro-inflammatory cytokines. However, these effects did not seem to translate in the in-vivo settings when tested in the CD13KOC57B/6 mice. In order to fully explore the adjuvant potential of these two molecules further experimentation will be necessary with altered parameters and additional cohorts.

In conclusion, we report the generation of a new platform that can be utilized for rapid identification of cancer antigens, patient immunological assessment, and generation of potential therapeutic tools, like antibodies and vaccine antigens, within a short timeframe of approximately 22 days from primary tissue sampling. We also suggest further investigation on the adjuvant abilities of the CD13 molecule for application in cancer vaccines.

Available for download on Sunday, August 30, 2020

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