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  • Review Article
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Vaccines

Spinning molecular immunology into successful immunotherapy

Nature Reviews Immunology volume 2, pages 227–238 (2002) Cite this article

Key Points

  • Tumour antigens that are potential targets for therapeutic immune responses are being identified. They can be divided into four categories: unique tumour-specific antigens that are the products of mutation; viral antigens in virus-associated cancers; tissue-specific differentiation antigens; and tumour-selective antigens.

  • As dendritic cells (DCs) are the crucial antigen-presenting cells that activate T-cell-dependent immune responses, enhancing their function is a central goal of new therapeutic vaccine strategies. The most common approach involves arming vaccines with genes that encode molecular signals for DC mitogenesis and/or activation.

  • Another important strategy for enhancing immunotherapy involves approaches to target antigen more effectively to DCs. Antigens can be targeted either extracellularly (by linking them to ligands that bind to DC surface receptors) or intracellularly (by linking them to intracellular sorting signals that target MHC processing pathways).

  • The modification of antigenic residues can enhance the potency of antigen-specific vaccines, through amino-acid substitutions that enhance the affinity of the antigen for either MHC or T-cell receptor.

  • Therapeutic vaccines can be enhanced by the incorporation of genes that encode co-stimulatory molecules. The growing list of both B7 and tumour-necrosis factor family co-stimulatory molecules offers a tremendous range of opportunities in vaccine design.

  • It is now clear that the quantitative response to antigen is the result of a balance between both positive (co-stimulatory) and negative (checkpoint) signalling pathways. Immunotherapies can be enhanced markedly through the blockade of negative regulatory pathways (so-called immunological checkpoints).

  • For all of the added value that recombinant DNA technology provides in engineering elements into vaccine constructs that enhance their potency, nature itself provides a virtually limitless array of delivery systems, in the form of diverse microbes with potent intrinsic immunological properties. Viruses, bacteria and fungi have all been engineered as vectors for therapeutic vaccination.

Abstract

Until recently, immunotherapies have been of limited success, particularly against cancer. However, recent insights into the cells, molecules and signalling pathways that regulate immune responsiveness are providing new approaches for immunotherapy. In this article, I review some of the most promising molecular and cellular targets for immunotherapy and discuss approaches that use these targets to amplify immune responses and potentially break antigen-specific tolerance. These strategies provide a blueprint for the development of successful immunotherapy over the next decade.

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Figure 1: Multi-step pathway for dendritic-cell differentiation and activation.
The alternative text for this image may have been generated using AI.
Figure 2: Approaches to enhance antigen targeting to antigen-presenting cells for improved immunization.
The alternative text for this image may have been generated using AI.

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Acknowledgements

We would like to thank D. Needle, the Topocer family and the Spires for their continued support of the Sidney Kimmel Cancer Center Immunology Program.

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Authors and Affiliations

  1. Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, 21231, Maryland, USA

    Drew M. Pardoll

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  1. Drew M. Pardoll
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DATABASES

CancerNet

melanoma

pancreatic cancer

renal-cell cancer

LocusLink

4-1BB

B7h/B7RP1

B7H1/PDL1

B7H3

Cabin

calreticulin

Cbl-b

CD14

CD27

CD28

CD30

CD36

CD45

CD80

CD86

CD91

CD40L

CDK4

CTLA4

Ctla4

Csk

DEC-205

FLT3 ligand

GM-CSF

gp96

gp70

gp100

HSP70

HSP90

HSP110

ICOS

IL-1

IL-2

IL-4

IL-10

IL-12

invariant chain

JAKs

LAMP1

MART1/melan-A

OX40

NFAT-c

PD1

Pd1

SHIP1

SHP1

SHP2

STAT

TARC

Toll

TNF-α

TNFR

TRP1

tyrosinase

Glossary

CYTOKINE

A protein released by one cell that affects the physiology of other cells in the vicinity in a particular fashion through binding to a specific receptor.

PROVIRUS

The latent form of a virus that exists within a cell without harming the cell or producing new virions.

CO-STIMULATORY SIGNAL

A signal to a T cell (in the form of a soluble or membrane-bound molecule) that has little or no effect on its own, but either enhances or modifies the physiological effect of the primary signal mediated by engagement of the T-cell receptor.

IDIOTYPE

The portion of either a T-cell receptor or immunoglobulin, defined by the hypervariable regions and involved in antigen recognition, that is completely unique.

T HELPER 1 (TH1)/TH2

Different phenotypes of helper T cells that are characterized by distinct patterns of cytokine release on activation.

TRANSCRIPTOME

The full complement of mRNA that is transcribed within a particular cell type.

CROSS-PRESENTATION

The presentation of exogenous antigen by MHC class I molecules.

IMMUNODOMINANT

Refers to the antigen(s) in a complex mixture (such as a whole virus or tumour cell) that are recognized preferentially during an immune response.

ADJUVANT

An agent mixed with an antigen that enhances the immune response to that antigen on immunization.

PRIME–BOOST

When a single application of a vaccine is insufficient, repeated immunizations are performed using the same vaccine preparation (homologous prime–boost) or using different vaccine preparations (heterologous prime–boost) to sequentially stimulate a better immune response.

CRYPTIC EPITOPE

An antigenic peptide that is generated at sub-threshold levels. When cryptic epitopes become visible to the immune system they can elicit an immune response that is responsible for autoimmune disease.

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Pardoll, D. Spinning molecular immunology into successful immunotherapy. Nat Rev Immunol 2, 227–238 (2002). https://doi.org/10.1038/nri774

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