Biological therapy of colorectal cancer

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Abstract

In this review, the immunogenicity of colorectal cancer (CRC) and the results of clinical and recent preclinical studies are discussed. Evidence for immune reactivity has been found in several preclinical models and the prognostic value of some of these immune responses have been reported. The possible mechanisms are discussed. Treatment with monoclonal antibodies is still experimental; as previously described benefit of treatment with monoclonal antibodies could not be confirmed. Labelled monoclonal antibody therapy has produced mixed results and also need further investigation. Several antigens are used in active specific immunotherapy (ASI). Its targets and modifications are discussed, as are their use in clinical studies. Although some of the results are promising, the results still have to be confirmed in larger studies. Since there is sufficient evidence for immune reactivity in CRC, further research on immunotherapeutic strategies is justified and will be focused on the development of humanised antibodies, the search for other relevant T-cell epitopes and ways to induce a more effective T cell response.

Introduction

Although CRC has never been considered a very immunogenic tumour, there is evidence for immune reactivity, both in clinical and preclinical models. In the following paragraphs, we will review the immunogenicity of colorectal cancer (CRC) and discuss the results of clinical and some recent preclinical studies that may serve as a basis for future clinical immunotherapeutic research.

Section snippets

Immunogenicity and immune evasion in colorectal cancer

Several authors have reported on the prognostic value of T cell infiltrates (TIL) in CRC tissues 1, 2, 3. Specific cytotoxic T cell (CTL) responses against CRC epitopes may be induced both in vitro and in vivo, this has been reviewed in Ref. [4]. Furthermore, there is evidence of natural occurring cellular and humoral responses directed against tumour-associated antigens (TAAs) in patients with CRC 5, 6.

Several mechanisms have been identified that may explain why CRC can develop despite the

Non-specific immunotherapy

In non-specific immunotherapy, immunomodulating agents are administered with the aim of inducing a generalised immune response without attempting to direct the activity towards a specific antigen. Results of this treatment modality have been reviewed previously in Ref. [15].

In summary, many of these agents, mostly derived from microbial sources like Bacille Calmette Gúerin (BCG), OK432 or Corynebacterium parvum, have been tested in laboratory and clinical trials, usually in combinations with

Unlabelled monoclonal antibodies

The murine IgG2a monoclonal antibody (MoAb) 17–1A (Edrecolomab) binds to the cell surface glycoprotein CD17–1A antigen (GA733–2) that is preferentially expressed on adenocarcinomas, but also is found on normal epithelial cells. Naturally occurring autoantibodies to GA733–2 are found in a high incidence in patients with CRC, but do not appear to be correlated with the stage of disease and/or survival [6]. Clinical responses with edrecolomab therapy have been demonstrated. The exact mechanism of

Active specific immunotherapy

The goal of active specific immunotherapy (ASI) is to evoke a tumour-specific immune response resulting in the destruction of tumour cells, as well as a memory response against the relevant antigens. Initially, this was performed by using tumour cell preparations, but advances in molecular biology have led to the use of more sophisticated vaccine preparations such as gene-modified tumour cells, purified TAAs, DNA-encoding protein antigens and protein-derived peptides.

Conclusions

There is sufficient evidence for immune reactivity in CRC in order to justify further research on the development of immunotherapeutic strategies in this disease. Current research is focused on the development of humanised antibodies, the search for other relevant T-cell epitopes and more efficient ways to induce an effective T cell response.

As is probably true for immunotherapy in general, positive results, if any, are most likely to be expected in patients with limited tumour burden such as

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