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Vaccines for tumour prevention

Key Points

  • Numerous tumour-challenge experiments in immunized rodents and studies with cancer-prone genetically modified mice show that vaccines can prevent tumour onset and progression.

  • Effective prevention requires vaccination at an early stage of tumour formation. The ability of a vaccine to protect decreases when a precancerous lesion reaches a more advanced stage.

  • The main reason why vaccines are effective in tumour prevention is that the target is a small precancerous lesion. So, most of the difficulties that are encountered by vaccines in the therapy of established tumours do not apply to prevention.

  • The immune mechanisms leading to the blocking of carcinogenesis are not solely dependent on cytotoxic T cells — they mostly rest on the coordinated activation of multiple mechanisms. CD4+ T-helper cells, the release of interferon-γ and the production of antibodies are often the key features of a sustained prevention.

  • The extended time-frame that characterizes tumour prevention favours the immune selection of escaping tumour-cell clones that have lost expression of target antigens. When the vaccine-elicited immune response is directed against antigens that control the neoplastic process (oncoantigens), the likelihood of this kind of selection is markedly reduced.

  • Oncoantigens expressed on tumour cell membranes are accessible to antibody-mediated reactions. These reactions are not impaired by down-modulation of major histocompatability complex class I (MHC-I) glycoproteins on the surface of tumour cells, which is a frequent mechanism by which tumours escape immune surveillance.

  • Because oncoantigens are self-antigens, there is the risk of vaccine-elicited autoimmune reactions. Overexpression of oncoantigens by the tumour and elicitation of low-avidity reactions in tolerant hosts render the immune reaction selective and reduce this risk.

  • Preclinical results in transgenic mice provide a rationale for the use of vaccines in the prevention of human tumours in high-risk individuals with multifocal pre-neoplastic lesions, a genetic predisposition to cancer or following carcinogenic exposures. Translation of these results to the clinical setting requires sequential approaches, starting from the prevention of tumour relapse in cancer patients after successful conventional management.

Abstract

Despite tremendous progress in basic and epidemiological research, effective prevention of most types of cancer is still lacking. Vaccine use in cancer therapy remains a promising but difficult prospect. However, new mouse models that recapitulate significant features of human cancer progression show that vaccines can keep precancerous lesions under control and might eventually be the spearhead of effective and reliable ways to prevent cancer.

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Figure 1: Vaccine-activated immune reactions against membrane oncoantigens.
Figure 2: As a tumour progresses, a vaccine-induced reaction becomes less and less able to cope with tumour evasion mechanisms.
Figure 3: Mechanisms of action and side effects of cancer vaccines.

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Acknowledgements

Research of the authors is supported by the Italian Association for Cancer Research; Italian Ministries for the Universities and Health; University of Turin; University of Bologna; Compagnia di San Paolo and Fondazione Carlo Demegri, Turin; and the Nordic Centre of Excellence for the Development of Anti-Tumour Vaccine Concepts (NCEV), Stockholm.

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Correspondence to Guido Forni.

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DATABASES

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FURTHER INFORMATION

American Cancer Society Who is at Risk

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European Organization for the Research and Treatment of Cancer Protocols Database

BALB-neuT web page on the National Cancer Institute's Cancer Models

Your Disease Risk

Glossary

Primary cancer prevention

Prevention of tumour onset through the elimination of carcinogenic risk factors. Secondary cancer prevention is the prevention of tumour progression and growth to symptomatic size by means of early diagnosis, whereas tertiary cancer prevention is the prevention of metastatic development.

Immunization-tumour challenge experiments

Healthy experimental animals are first vaccinated against a tumour and then receive a transplant (challenge) of tumorigenic cells. The induced immunity is measured by the proportion of animals that remain tumour-free and/or by the increase in tumour latency time in comparison to mock-vaccinated controls.

Orthotopic challenge

Transplanting a tumour that originated in one animal into the same organ or tissue in another animal.

Regulatory T cells

A subpopulation of CD4+ T cells that constitutively express the α-chain of the interleukin-2 receptor (CD25+) and the transcription factor encoded by FOXP3. These cells suppress the immune response to self antigens.

Therapeutic vaccines

Therapeutic vaccines are given to patients to cure an existing disease, whereas prophylactic vaccines are given to healthy people to prevent a foreseeable disease.

Cytotoxic T lymphocytes

A subpopulation of CD8+ T cells that kill host cells expressing antigenic peptides associated with autologous major histoconpatability complex class I glycoproteins.

Microbial CpG sequences

Unmethylated cytosine–guanine sequences of microbial DNA are a hallmark of bacterial infection and stimulate the mammalian immune system through Toll-like receptor 9 (TLR9), which is expressed by dendritic cells and macrophages. CpG sequences function as adjuvants of vaccines.

Adjuvants

Vaccine components that non-specifically increase the immune response against antigens. Adjuvants are called the immunologists dirty little secret because the fact that all vaccines would be ineffective without adjuvants is something that few non-immunologists are aware of.

Natural killer cells

Population of lymphoid cells that release cytokines and kill host cells that do not express MHC-I glycoproteins.

Immune memory

The immune memory is an antigen-specific and long-lived feature of adaptative immunity. When an antigen is encountered more than once, immune memory means that the immune response to this antigen is speedier and more effective.

Avidity

Avidity is the sum total of the strength of the binding of two molecules or cells to one another at multiple sites. For instance, the overall strength of binding between a T cell and an antigen-presenting cell.

Central tolerance

The lack of self-responsiveness that occurs as lymphocytes develop. It is associated with the deletion of autoreactive clones. For T cells, this occurs in the thymus.

Adoptive transfer

A form of passive immunization in which previously sensitized immunological agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy.

Delayed-type hypersensitivity

Hypersensitivity (increased reaction by the body to a foreign substance such as an antigen or allergen) that does not appear until 24–48 hours after the body is exposed to the foreign substance.

Caretaker genes

Tumour-suppressor genes that control genome repair and stability.

Complement-mediated lysis

Killing (lysis) of a target cell owing to complement activation at the cell surface.

Antibody-dependent cellular cytotoxicity

Killing of antibody-coated target cells by cells with Fc receptors that recognize the constant region of the bound antibody.

Class I MHC glycoproteins

Polymorphic glyocoproteins encoded by genes of the major histocompatibility complex (MHC) that are expressed by the nucleated cells of the body. They present peptides that are derived from intracellular proteins to CD8+ T lymphocytes.

Vitiligo

A condition that is characterized by depigmented areas of skin due to the lack of melanocytes. Anti-melanoma vaccines can induce autoimmune vitiligo.

Flu-like syndrome

A collection of symptoms caused by cytokines such as IFNγ and TNFα that are released after vaccinations or other biological treatments of cancer. The symptoms include fever, headache, fatigue and musculoskeletal pain.

Alum

Generic name of aluminium-based (aluminium hydroxide or aluminium phosphate) gels that are used to adsorb vaccines. Alum is a weak, non-toxic adjuvant, and one of the few that are approved worldwide for use in human vaccines.

Freund's adjuvant

A powerful adjuvant consisting of water in a mineral oil emulsion containing killed mycobacteria. Incomplete Freunds adjuvant omits mycobacteria and is also used in human cancer vaccines, whereas the complete formulation is not used in humans because of unacceptable toxicity.

Electroporation

The use of an electric pulse to make cell membranes temporarily more permeable to molecules such as DNA. DNA electroporation is currently being tested in clinical trials.

Basal nevous syndrome

The basal (cell) nevous syndrome is an inherited group of multiple defects involving the skin, nervous system, eyes, endocrine glands and bones. The condition causes an unusual facial appearance and a predisposition to skin cancers.

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Lollini, PL., Cavallo, F., Nanni, P. et al. Vaccines for tumour prevention. Nat Rev Cancer 6, 204–216 (2006). https://doi.org/10.1038/nrc1815

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