Regulators of apoptosis: suitable targets for immune therapy of cancer

KEY POINTS * The clinical application of immunotherapy against cancer is rapidly moving forward in multiple areas, including the adoptive transfer of antitumour-reactive T cells and the use

of 'therapeutic' vaccines. The latter aims at inducing cytotoxic T lymphocytes (CTLs) specific for tumour-associated antigens presented by cancer cells in the context of human

leukocyte antigen (HLA) molecules. * Surprisingly, until recently only limited attention has been focused on identifying the most suitable targets for the induction of clinically relevant

anticancer immune responses, the delineation of the most effective epitopes within these antigens and, finally, inclusion of sets of peptide epitopes best suited for targeting the disease in

question. * The vast majority of malignancies are characterized by defects in apoptosis signalling, which is mediated by two group of apoptosis regulators: the BCL2 family (for example,

BCL2, BCL-XL and MCL1) and the inhibitor of apoptosis proteins (IAP), such as survivin or melanoma IAP. * Such apoptosis regulators are therefore crucial cellular factors contributing to the

pathogenesis and progression of cancer. Consequently, they represent very attractive targets for the design of new anticancer drugs, such as antisense oligonucleotides and small-molecule

BCL2 inhibitors. * Notably, recently spontaneous cellular immune responses against these proteins have been identified as frequent features in cancer patients. Here, we summarize current

knowledge of IAP and BCL2 family proteins as T-cell antigens, report the results of the first exploratory trials using these antigens for immunotherapy and discuss future opportunities, such

as simultaneous targeting of several proteins or combination with conventional chemotherapy, because their expression in tumours is correlated with drug resistance and/or poor prognosis. *

Immunotherapy based on survivin, BCL2 or MCL1 might also compromise endothelial-cell viability and interfere with tumour angiogenesis. Targeting survivin or BCL2 family members in angiogenic

immunotherapy might therefore deliver two distinct and potentially synergistic treatment modalities using a common procedure. * In conclusion, a multi-epitope vaccine targeting regulators

of apoptosis seems to be a promising, universal antitumour vaccine, which addresses both the tumour and the tumour stroma. Moreover, it synergistically boosts the effects of conventional

cytotoxic therapies or radiation. ABSTRACT Harnessing the immune system in the battle against cancer has been the focus of tremendous research efforts during the past two decades. Several

means for achieving this goal, including adoptive transfer of tumour-reactive T cells, systemic or localized administration of immune modulating cytokines and the use of

'therapeutic' vaccines, have been explored. Anti-apoptotic molecules that enhance the survival of cancer cells and facilitate their escape from cytotoxic therapies represent prime

candidates as vaccination antigens. Notably, spontaneous cellular immune responses against these proteins have frequently been identified in cancer patients. Here, we summarize current

knowledge of IAP and BCL2 family proteins as T-cell antigens, report the results of the first explorative trial using these antigens in therapeutic vaccinations against cancer and discuss

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references ACKNOWLEDGEMENTS This work was funded in part by grants from the Danish Medical Research Council, The Danish Cancer Society and Danish Cancer Research Foundation. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Tumor Immunology Group, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, Dk-2100, Denmark Mads Hald Andersen, 

Jürgen C. Becker & Per thor Straten * Department of Dermatology, University of Würzburg, Josef-Schneider-Strasse 2, Würzburg, D-97080, Germany Mads Hald Andersen & Jürgen C. Becker

Authors * Mads Hald Andersen View author publications You can also search for this author inPubMed Google Scholar * Jürgen C. Becker View author publications You can also search for this

author inPubMed Google Scholar * Per thor Straten View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Mads Hald

Andersen. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS RELATED LINKS ENTREZ GENE Apollon BAD BAK BAX _BCL2_ BID c-IAP1 c-IAP2

IL-2 IL-7 IL-12 IL-15 IL-18 IL-21 ILP2 MCL1 ML-IAP NIAP survivin TLR4 XIAP NATIONAL CANCER INSTITUTE Chronic lymphocytic cancer melanoma myeloma non-small-lung cancer GLOSSARY * MAJOR

HISTOCOMPATIBILITY COMPLEX A complex of genetic loci in higher vertebrates that encodes a family of cellular antigens that allow the immune system to recognize self from non-self. * ADJUVANT

An agent mixed with an antigen that enhances the immune response to that antigen upon immunization. * CpG DINUCLEOTIDES Cytosine–guanosine pairs inDNA sequences. Oligodeoxynucleotide

sequences that include CpG dinucleotides and certain flanking nucleotides have been found to induce innate immune responses. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Andersen, M., Becker, J. & Straten, P. Regulators of apoptosis: suitable targets for immune therapy of cancer. _Nat Rev Drug Discov_ 4, 399–409 (2005).

https://doi.org/10.1038/nrd1717 Download citation * Issue Date: 01 May 2005 * DOI: https://doi.org/10.1038/nrd1717 SHARE THIS ARTICLE Anyone you share the following link with will be able to

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