Gene-expression Profiling in Vaccine Therapy and Immunotherapy for Cancer

Davide Bedognetti; Ena Wang; Mario Roberto Sertoli; Francesco M Marincola

Disclosures

Expert Rev Vaccines. 2010;9(6):555-565. 

In This Article

Abstract and Introduction

Abstract

The identification of tumor antigens recognized by T cells led to the design of therapeutic strategies aimed at eliciting adaptive immune responses. The last decade of experience has shown that, although active immunization can induce enhancement of anticancer T-cell precursors (easily detectable in standard assays), most often they are unable to induce tumor regression and, consequently, have scarcely any impact on overall survival. Moreover, in the few occasions when tumor rejection occurs, the mechanisms determining this phenomenon remain poorly understood, and data derived from in vivo human observations are rare. The advent of high-throughput gene-expression analysis (microarrays) has cast new light on unrecognized mechanisms that are now deemed to be central for the development of efficient immune-mediated tumor rejection. The aim of this article is to review the data on the molecular signature associated with this process. We believe that the description of how the mechanism of immune-mediated tissue destruction occurs would contribute to our understanding of why it happens, thereby allowing us to develop more effective immune therapeutic strategies.

Introduction

The first observations about the role of the immune system in inducing tumor regression date back to the 1700s, with the description of sporadic tumor regression following infective episodes.[1]

In the 1890s, William Coley, influenced by such observations, injected bacterial products (also known as Coley's toxin or Coley's vaccine) directly into a tumor, achieving dramatic responses.[2,3] This is considered the first empiric evidence of the potential of the immunotherapy for inducing tumor rejection.[2–4] However, the broad acceptance of this phenomenon required several other studies and observations. In the 1980s, experimental and clinical data from studies investigating the role of exogenous proinflammatory cytokines (IL-2 and IFN-α) clearly demonstrated that the immune response contributed to tumor regression.[5–7] In the early 1990s, the identification and molecular characterization in humans of tumor antigens (TAs) recognized by autologous T cells gave the basis for modern vaccine anticancer therapy. In particular, van der Bruggen et al., with a landmark paper published in 1991, described melanoma antigen (MAGE)-1 as the first human TA.[8] This study, which was quickly followed by the description of the first human cancer-specific peptide epitope restricted by HLA-A1,[9] revolutionized the field of tumor immune biology by providing conclusive evidence that CD8+ T cells specifically recognize and kill autologous cancer cells overexpressing cancer-specific proteins. This important achievement gave molecular precision and novel distinction in this rather disregarded field and provided the opportunity to investigate with scientific accuracy the fascinating phenomenon of cancer rejection in physiologic conditions and/or in response to therapy. The subsequent identification of a myriad of TAs triggered the extensive utilization of TAs for the development of anticancer vaccines. For the first time, natural reagents (CD8+ T cells) that could selectively recognize only cancer cells were reliably generated, providing a powerful tool to analyze in molecular detail the dynamics of developing immune responses in the cancerbearing host.[10] This characteristic of high (almost absolute) specificity, confirmed also by the scarce toxicity (e.g., skin depigmentation), is an achievement that other anticancer therapies have rarely attained.[11] Nevertheless, although from a logical point of view TA-specific immunization reached its purpose, clinical results have been so far disappointing. Moreover, the biological explanations for this dichotomy between immunological and clinical end points remain elusive.[12,13]

Therefore, these data should encourage the optimization of immunization strategies by combining systemic immune stimulation, focusing particularly on the understanding of events downstream of TA-specific T-cell generation.[14,15]

Other immune-therapeutic modalities (monoclonal antibodies [mAbs]) have been effectively implemented in the last few years. For instance, targeting inhibitory molecules on the surface of activated T cells (e.g., cytotoxic T-lymphocyte-associated antigen-4) represents an emerging strategy to elicit (without specificity) the immune response against a tumor.[16] However, most mAbs are directed again surface molecules overexpressed in cancer cells (the majority of which are products of dominant oncogenes, e.g., growth factor receptors). Their mechanisms of action are represented by the inhibition of the targeted receptor but also by the induction of antibody-dependent cell-mediated cytotoxicity.[17] For these reasons, mAbs can be taken apart from the aforementioned forms of immune therapies; their in-depth analysis is beyond our purposes and will, therefore, not be covered here.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....