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Modified Carbohydrate Cancer Vaccines for Breaking Immune Self-Tolerance

  • Author(s): Miller, Isaac Andrew
  • Advisor(s): Bertozzi, Carolyn R
  • et al.
Abstract

The unusual glycosylation patterns on cancer cells, which harbor carbohydrate structures that are rarely seen on healthy tissue, provide a tempting target for the design of anti-cancer vaccines for immunotherapy. Unfortunately, carbohydrates tend to be poor immunogens. Much of the work in the carbohydrate-based cancer vaccine field is focused on boosting the immune system's response to these antigens. Scientists have had moderate success in this endeavor with strategies that include adding T-cell epitopes to the antigens, incorporating adjuvants in the vaccine injection mixture or directly conjugated to the vaccine, and priming immune cells outside of the body and re-injecting them, but no breakthrough strategy has emerged. Despite all this effort, to date no carbohydrate-based cancer vaccine has won approval from the Food and Drug Administration, and only one peptide-based cancer vaccine has been approved.

Chapter 1 describes some of the strategies that have been pursued in the quest to develop effective cancer immunotherapies, particularly those based on carbohydrate antigens. Later in the chapter, I introduce a new strategy to break immune self-tolerance based on vaccines built from modified carbohydrate antigens, and discuss some of the precedent established by our laboratory and others that suggests the new strategy is viable. In Chapter 2, I describe the synthesis of a panel of four vaccine constructs based on the disaccharide sialyl Tn. Then, I discuss the immune response elicited against the vaccines in rabbits based on ELISA analysis of their polyclonal antisera.

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