Vaccines for colorectal cancer

doi:10.1016/S1471-4914(01)01992-X

Trends in Molecular Medicine

Volume 7, Issue 7, 1 July 2001, Pages 307-313

https://doi.org/10.1016/S1471-4914(01)01992-X Get rights and content

Abstract

Despite recent advances in the treatment of colorectal cancer, the overall survival rate for those patients with advanced locoregional disease remains less than 50%. Although adjuvant systemic chemotherapy has improved survival of these patients, more effective therapies are needed. Immunotherapy is an approach that could have a particular role in the adjuvant therapy of colorectal cancer. There is now convincing evidence that the immune system can specifically recognize and destroy malignant cells. Although both antibody- and T-cell-mediated anti-tumor responses have been documented, the cellular immune response with its direct cytotoxic mechanisms is felt to be the principal anti-tumor arm of the immune system. Analysis of the T cells that recognize tumors has led to the identification and characterization of many tumor-associated antigens including several colorectal antigens. Current approaches to developing a vaccine for colorectal cancer use our expanded understanding of these tumor-associated antigens and the conditions that allow development of an effective cellular immune response to them.

Section snippets

Advances in tumor immunology

The two most significant advances in the field of tumor immunology in the past ten years are (1) the isolation and molecular characterization of the TAAs that are recognized by T cells, and (2) the elucidation of the molecular events that lead to T-cell-activation. Our expanded understanding of the molecular structure and function of these two systems has ledtomore refined and directed cancer vaccine development.

Whole tumor cell vaccine

Until all of the TAAs for a particular cancer can be quickly isolated and characterized, many investigators believe that the best source of antigen is the tumor itself. The main advantage of this approach is that all of the antigens (unique, as well as shared) expressed by a particular cancer are presented to the immune system. However, a potential disadvantage of this technique is that the most immunologically-relevant antigens might be underexpressed on the tumor cell and thus

Antigen-specific strategies

The precise molecular identification of TAAs has allowed for the development of more refined vaccination strategies. Successful immunization to specific TAAs in pre-clinical models has been demonstrated through a variety of mechanisms (Table 3), including: (1) recombinant viral vectors 32, 33; (2) peptide vaccines 34, 35; (3) antigen loaded dendritic cell vaccines 36, 37; (4) anti-idiotypic antibody vaccination ³⁸;(5) DNA/RNA based vaccines ³⁹; and (6) Immunization with heat shock proteins ⁴⁰.

Anti-idiotypic antibodies to colorectal TAAs

Another approach for the development of both cellular and humoral immune responses to known TAAs is the use of anti-idiotypic antibodies. Based on the network hypothesis of Lindermann ⁵⁴ and Jerne ⁵⁵ any epitope could be converted into idiotypic determinants expressed on antibodies. Anti-idiotypic antibodies that share sequence homologies with nominal colorectal TAA could act as functional mimics of T-cell-antigens and stimulate cellular immune responses.

The best-characterized anti-idiotypic

Conclusions

Recent advances in the field of tumor immunology have expanded our understanding of the nature of tumor-associated antigens and mechanisms of T-cell activation. It is now clearly recognized that tumor cells express antigens that can be recognized by T cells. These antigens are derived from a variety of intracellular proteins. Successful activation of T-cell response to these antigens requires that they be presented in the context of the appropriate co-stimulatory signals. Current clinical

References (58)

A Lanzavecchia
From TCR engagement to T-cell activation: a kinetic view of T cell behavior
Cell
(1999)
C Somoza et al.
T-cell costimulation via CD28–CD80/CD86 and CD40–CD40 ligand interactions
Res. Immunol.
(1995)
P Matzinger
An innate sense of danger
Semin. Immunol.
(1998)
Vermorken
Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial
Lancet
(1999)
J.S Goydos
A phase I trial of a synthetic mucin peptide vaccine. Induction of specific immune reactivity in patients with adenocarcinoma
J. Surg. Res.
(1996)
R.T Greenlee
Cancer statistics
Cancer J. Clin.
(2000)
H.C Moore et al.
Adjuvant therapy of colon cancer
Semin.Oncol.
(1999)
O.J Finn et al.
Third Keystone Symposium on cellular immunology and the immunotherapy of cancer
J. Immunother.
(1998)
S.A Rosenberg
Development of cancer immunotherapies based on identification of the genes encoding cancer regression antigens
J.Natl Cancer Inst.
(1996)
M.J Maeurer et al.
Tumor recognition by the cellular immune system: new aspects of tumor immunology
Int. Rev. Immunol.
(1997)

J.C Solheim

Class I MHC molecules: assembly and antigen presentation

Immunol. Rev.

(1999)

N.L Harris et al.

The role of B7 costimulation in T-cell immunity

Immunol. Cell Biol.

(1999)

C van Kooten et al.

CD40–CD40 ligand

J. Leukoc. Biol.

(2000)

S Jacquot

CD27–CD70 interactions regulate T dependent B cell differentiation

Immunol. Res.

(2000)

L Fong et al.

Dendritic cells in cancer immunotherapy

Annu. Rev. Immunol.

(2000)

Lotze, M.T. et al. Dendritic cell based therapy of cancer. Adv. Exp. Med Biol. 417,...

S.R Clarke

The critical role of CD40/CD40L in the CD4-dependent generation of CD8⁺ T cell immunity

J. Leukoc. Biol.

(2000)

H.C.J Hoover

Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median follow-up of a phase III prospectively randomized trial

J. Clin. Oncol.

(1993)

J.E Harris

Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283

J.Clin. Oncol.

(2000)

H.C.J Hoover

Delayed cutaneous hypersensitivity to autologous tumor cells in colorectal cancer patients immunized with an autologous tumor cell: Bacillus Calmette–Guerin vaccine

Cancer Res.

(1984)

H.C.J Hoover

Prospectively randomized trial of adjuvant active-specific immunotherapy for human colorectal cancer

Cancer

(1985)

H.C.J Hoover

Meta analysis of threerandomized trials of active specific immunotherapy (ASI) of colon cancer

Proc. Am. Soc. Clin. Oncol.

(1993)

C Demangel et al.

Interaction of dendritic cells with mycobacteria: where the action starts

Immunol. Cell Biol.

(2000)

D.M Pardoll

Paracrine cytokine adjuvants in cancer immunotherapy

Annu. Rev. Immunol.

(1995)

G Dranoff

Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity

Proc. Natl. Acad. Sci. U. S. A.

(1993)

A.J Berns

Phase I study of non-replicating autologous tumor cell injections using cells prepared with or without GM–CSF gene transduction in patients with metastatic renal cell carcinoma

Hum. Gene Ther.

(1995)

E.M Jaffee

Novel allogeneic granulocyte–macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation

J. Clin. Oncol.

(2001)

E.M Jaffee

A phase I clinical trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene for the treatment of pancreatic adenocarcinoma

Hum. Gene Ther.

(1998)

K.W Suh

Treatment of liver metastases from colon carcinoma with autologous tumor vaccine expressing granulocyte-macrophage colony-stimulating factor

J. Surg. Oncol.

(1999)

Cited by (19)

Clinicopathological significance and prognostic implication of nuclear fatty acid-binding protein 4 expression in colorectal cancer
2023, Pathology Research and Practice
This study aimed to evaluate the clinicopathological significance and prognostic role of fatty acid-binding protein 4 (FABP4) expression in colorectal cancer (CRC). Nuclear expression of FABP4 was investigated by immunohistochemistry for FABP4 on 246 human CRC tissues. The correlations between FABP4 expression, and clinicopathological characteristics and survival, was evaluated in patients with CRC. FABP4 was expressed in 91 of the 246 CRC tissues (37.0%). FABP4 expression was significantly correlated with older age, right-sided colon cancer, perineural invasion, higher pT stage, lymph node metastasis, and higher pTNM stage. However, there was no significant correlation between FABP4 expression and sex, tumor size, tumor differentiation, vascular or lymphatic invasion, or distant metastasis. Nuclear FABP4 expression was not significantly correlated with cytoplasmic FABP4 expression (P = 0.412). FABP4 expression was significantly correlated with nuclear pNF-κB expression (P = 0.001), and was significantly higher in CRC with a low immunoscore than in CRC with a high immunoscore (P < 0.001). There were significant correlations between FABP4 expression and worse overall and recurrence-free survival rates (P < 0.001 and P = 0.007, respectively). FABP4 expression was significantly correlated with aggressive tumor behaviors and pathological characteristics. In addition, patients with CRC with FABP4 expression had worse survival rates.
Effects of tumor vaccine expressing Granulocyte–Macrophage Colony Stimulating Factor and interleukin-18 fusion on cancer cells and its possible application for cancer immunotherapy
2017, Cytokine
Citation Excerpt :
However, molecular expressions of most cancer cells targeted on the cell surface were yet similar with those of normal tissue cells. Theoretically, it is very difficult to induce an immune response against cancer by using a single tumor antigen only [4]. Therefore, tumor cell based anticancer vaccine has an advantage because it presents all antigens existing on the tumor cell surface, and trigger immune responses more effectively [5].
To access antitumor effects of a combined Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and interleukin-18 (IL-18), cDNA fusion of murine GM-CSF and mature IL-18 (GMIL-18) was constructed and transfected in mammalian cells. GMIL-18 fusion protein was highly secreted and displayed bifunctional activities, possessing immune response initiation and cytokine roles, including IFN-γ induction in mouse splenocytes and increased proliferation of GM-CSF-dependent cells, M-NSF-60. The GMIL-18 secreting tumor vaccine was generated and it strongly stimulated differentiation of dendrite cells (DCs) and effusive CD8⁺ and CD4⁺ cell infiltration into tumor mice. Moreover, growth of CT26 mouse colon cancer cells was significantly retarded by GMIL-18 (CT26GMIL-18), but not by CT26GM-CSF- or CT26IL-18. The efficiency of prophylactic vaccination was greater than that of therapeutic vaccination in terms of tumor size and its inhibitory role in proliferation. In micrometastasis analysis of tumor models, γ-ray irradiated GMIL-18 tumor vaccine showed a smaller number of liver-meta tumor nodules in mouse liver cells. We concluded that bifunctional GMIL-18 fusion protein could be applied as an immune therapy for cancer treatments.
Immunologic therapies for gastrointestinal cancers
2005, Clinical Colorectal Cancer
The treatment of solid tumors has shown a dramatic change in recent years. This revolution has come from an improved understanding of the mechanisms of tumor growth and the relationship of cancers to their microenvironments. As part of this revolutoin, we have had a dramatic increase in our understanding of the immune system and the role it could play in the management of cancers. This article reviews the current data supporting the use of cancer immunologic therapies for gastrointestinal tract cancers. The scope is focused on the variety of approaches that have been used, citing the clinical data that have been obtained and reviewing future trials.
Immunization of colorectal cancer patients with recombinant baculovirus-derived KSA (Ep-CAM) formulated with monophosphoryl lipid a in liposomal emulsion, with and without granulocyte-macrophage colony-stimulating factor
2004, Vaccine
Citation Excerpt :
Active specific immunotherapy is an area of intense investigation in the field of colorectal cancer, and several vaccine formulations are under investigation [1].
KSA (Ep-CAM) is highly expressed by colorectal cancers. The safety and immunologic effects of a vaccine consisting of recombinant baculovirus-derived KSA formulated with monophosphoryl lipid A (MPL) in liposomes and emulsified in mineral oil were evaluated, with and without co-administration of granulocyte-macrophage colony-stimulating factor (GM-CSF). Eleven patients with metastatic colorectal cancer received three subcutaneous (s.c.) injections of the vaccine at 4-week intervals. Six patients were randomized to also receive human recombinant GM-CSF (rGM-CSF) by subcutaneous injection daily for 4 days with each vaccination. Immunizations with and without rGM-CSF were well tolerated. Seven of the 11 patients developed significant KSA-specific cellular immune responses as assessed by lymphoproliferation and interferon-γ (IFN-γ) ELISPOT assays. All nine tested patients developed positive delayed type hypersensitivity reactions. Eight of the 11 patients developed KSA-specific antibody responses. The highest levels of cellular immune responses were observed in patients who received GM-CSF. Immunization with baculovirus-derived KSA formulated with monophosphoryl lipid A in liposomal emulsion is safe and can elicit KSA-specific immune responses. Co-administration of GM-CSF with this formulation is an effective method of generating KSA-specific T-helper (Th) 1-associated cellular immune responses.
Protective antitumor immunity induced by fixed tumor cells in combination with adjuvant in a murine hepatoma model
2003, Cancer Letters
We previously reported that fixed tumor sections induced autologous cytotoxic T lymphocytes (CTL) from human peripheral blood lymphocytes in vitro. Here, we examined whether fixed tumor cells could stimulate in vivo immunity using a murine hepatoma model. Vaccination of syngeneic mice with fixed Hepa 1-6 cells in combination with OK-432 and tuberculin as an adjuvant resulted in a significant increase in survival of mice against live Hepa 1-6 cell challenge. In addition, the splenocytes from vaccinated mice secreted CD4⁺ T cell-mediated interferon-γ (IFN-γ) and exhibited a specific CTL response. These findings suggest that fixed tumor cells combined with an appropriate adjuvant induce effective antitumor immunity in vivo.
Immunology and immunotherapy of colorectal cancer
2003, Critical Reviews in Oncology/Hematology
This review critically discusses data on immunology of colorectal cancer, starting from pathology and molecular biology, and then considering the molecular characterisation of colon cancer antigens and the clinical trials of immunotherapy. A careful evaluation of histopathological studies on intra-epithelial infiltration by T cells in primary tumours, together with the analysis of HLA expression by colorectal cancer cells, suggest that anti-tumour T cell immune responses may take place in vivo in those patients, influencing prognosis and shaping the tumour immunological profile. Moreover, the molecular characterisation of tumour antigens expressed by colorectal carcinomas, together with improved understanding of mechanisms of the immune response and more sensitive methods for the in vivo detection of T cell responses, are now allowing researchers to design new and more effective vaccination protocols, with encouraging preliminary results. By drawing together the experimental evidence from different research fields, this review provides support for the concept that colorectal carcinoma is immunogenic and may reasonably be considered as a target for immunotherapy, and attempts to address critical issues and envisage future developments in this challenging research field.

View all citing articles on Scopus

View full text

Trends in Molecular Medicine

ReviewVaccines for colorectal cancer

Abstract

Section snippets

Advances in tumor immunology

Whole tumor cell vaccine

Antigen-specific strategies

Anti-idiotypic antibodies to colorectal TAAs

Conclusions

Cell

Res. Immunol.

Semin. Immunol.

Lancet

J. Surg. Res.

Cancer statistics

Cancer J. Clin.

Adjuvant therapy of colon cancer

Semin.Oncol.

Third Keystone Symposium on cellular immunology and the immunotherapy of cancer

J. Immunother.

Development of cancer immunotherapies based on identification of the genes encoding cancer regression antigens

J.Natl Cancer Inst.

Tumor recognition by the cellular immune system: new aspects of tumor immunology

Int. Rev. Immunol.

Class I MHC molecules: assembly and antigen presentation

Immunol. Rev.

The role of B7 costimulation in T-cell immunity

Immunol. Cell Biol.

CD40–CD40 ligand

J. Leukoc. Biol.

CD27–CD70 interactions regulate T dependent B cell differentiation

Immunol. Res.

Dendritic cells in cancer immunotherapy

Annu. Rev. Immunol.

The critical role of CD40/CD40L in the CD4-dependent generation of CD8+ T cell immunity

J. Leukoc. Biol.

Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median follow-up of a phase III prospectively randomized trial

J. Clin. Oncol.

Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283

J.Clin. Oncol.

Delayed cutaneous hypersensitivity to autologous tumor cells in colorectal cancer patients immunized with an autologous tumor cell: Bacillus Calmette–Guerin vaccine

Cancer Res.

Prospectively randomized trial of adjuvant active-specific immunotherapy for human colorectal cancer

Cancer

Meta analysis of threerandomized trials of active specific immunotherapy (ASI) of colon cancer

Proc. Am. Soc. Clin. Oncol.

Interaction of dendritic cells with mycobacteria: where the action starts

Immunol. Cell Biol.

Paracrine cytokine adjuvants in cancer immunotherapy

Annu. Rev. Immunol.

Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity

Proc. Natl. Acad. Sci. U. S. A.

Phase I study of non-replicating autologous tumor cell injections using cells prepared with or without GM–CSF gene transduction in patients with metastatic renal cell carcinoma

Hum. Gene Ther.

Novel allogeneic granulocyte–macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation

J. Clin. Oncol.

A phase I clinical trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene for the treatment of pancreatic adenocarcinoma

Hum. Gene Ther.

Treatment of liver metastases from colon carcinoma with autologous tumor vaccine expressing granulocyte-macrophage colony-stimulating factor

J. Surg. Oncol.

Review
Vaccines for colorectal cancer

The critical role of CD40/CD40L in the CD4-dependent generation of CD8⁺ T cell immunity