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Immunomodulation Within a Single Tumor Site to Induce Systemic Antitumor Immunity: In Situ Vaccination for Cancer

  • Linda Hammerich
  • Joshua D. Brody
Chapter

Abstract

Prophylactic vaccinations have been one of the greatest advances in modern medicine, both eradicating disease and reducing mortality. The translation of this advance into cancer therapy has been challenging and dates back to the turn of the twentieth century (Currie, Br J Cancer 26: 141–153, 1972). Cancer cells, derived from an aberrant clone, bear predominantly self-antigens and thus avoid alerting the immune system. In addition, the tumor microenvironment can be severely immunosuppressive; adding an extra layer of protection against the host immune response. Tumor cells can actively suppress immune responses through the downregulation of antigen presentation and the production of membrane-bound and secreted immuneregulatory molecules (Upadhyay et al, Cancers (Basel), 7: 736-62, 2015). To overcome such obstacles, a successful cancer vaccine must be able to induce a powerful immune response against tumor-associated antigens (TAAs) while avoiding normal host cells. This strategy has proven difficult because TAAs are highly variable in their immunogenicity and undergo immune editing to escape recognition. In addition, they can differ between tumor types and more importantly between individuals (Escors, New J Sci, 2014: 25, 2014). The presence of antigen-presenting cells (APCs) is generally low in the tumor microenvironment. Some efficacy in the treatment of cancer has been demonstrated by the use of autologous dendritic cells (DCs) pulsed with tumor cell lysates containing a whole array of antigens as well as single TAAs (Reichardt et al, Blood Rev: 18, 235-43, 2004). DC can be differentiated and expanded from peripheral blood ex vivo, and a resected tumor mass can be used to subsequently load the DC with TAAs. These strategies, while successful in developing a patient-specific vaccine, are labor and time intensive limiting the ability to experiment with numerous iterations to optimize the approach.

Keywords

Cancer vaccine Cancer immunotherapy Toll-like receptors Dendritic cells GM-CSF FLT3L Oncolytic virus Anti-CD40 antibody Interleukin-2 Interleukin-12 

Abbreviations

APC

Antigen-presenting cell

CNS

Central nervous system

CTL

Cytotoxic T-lymphocyte

CTLA-4

Cytotoxic T-lymphocyte-associated protein 4

DC

Dendritic cell

ECM

Extracellular matrix

EGFR

Epidermal growth factor receptor

FLT3L

Fms-like tyrosine kinase 3 ligand

GM-CSF

Granulocyte-macrophage colony-stimulating factor

HSPs

Heat shock proteins

IFN

Interferon

IL

Interleukin

LPS

Lipopolysaccharide

PD-1

Programmed death 1

Rb

Retinoblastoma

TAA

Tumor-associated antigen

TLR

Toll-like receptor

TNF

Tumor necrosis factor

VEGF

Vascular endothelial growth factor

VSV

Vesicular stomatitis virus

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Hematology and Medical OncologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Lymphoma Immunotherapy ProgramDivision of Hematology and Medical OncologyIcahn School of Medicine at Mount SinaiNew YorkUSA

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