Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial

Vermorken, Jan B.; Claessen, Anke M. E.; Tinteren, Harm van; Gall, Helen; Ezinga, Renate; Meijer, Sybren L.; Scheper, Rik J.; Meijer, Chris J.L.M.; Bloemena, Elisabeth; Ransom, Janet H.; Hanna, Michael G.; Pinedo, H.M.

doi:10.1016/s0140-6736(98)07186-4

Cited by 449 publications

(245 citation statements)

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“…Toxicity after the tumour cell vaccinations, consisting of ulcers after the first two injections and low grade fever in a minority of patients, was comparable to what we observed in our previous study, when no chemotherapy was used (Vermorken et al, 1999).…”

Section: -Fu+asi For Stage III Colon Cancer a Baars Et Alsupporting

confidence: 89%

“…Recently, we demonstrated in a randomised phase III study that adjuvant treatment with ASI, using autologous tumour cells and BCG, resulted in a significant reduction in the rate of recurrence in stages II and III colon cancer patients (Vermorken et al, 1999). Results were most pronounced in stage II patients, whereas in stage III colon cancer patients no clinically significant benefit was observed.…”

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confidence: 96%

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A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

et al. 2002

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Active specific immunotherapy, using vaccines with autologous tumour cells and BCG, significantly reduces the rate of tumour recurrence in stage II colon cancer patients, while no clinical benefit has yet been observed in stage III patients. Adjuvant treatment with 5-Fluorouracil/Leucovorin is now considered standard therapy for stage III colon carcinoma and results in an absolute survival benefit of approximately 10%. Yet, the 5-year overall survival rate of stage III colon cancer patients is only 40 -50%. Combining chemotherapy and immunotherapy might improve prognosis for stage III patients, especially when considering that active specific immunotherapy and chemotherapy have shown synergistic effects in pre-clinical tumour models. We performed a phase II study with 56 patients, using the combination of active specific immunotherapy and chemotherapy as an adjuvant therapy in stage III colon cancer patients to assess the influence of 5-Fluorouracil/Leucovorin on anti-tumour immunity induced by autologous tumour cell vaccinations. Anti-tumour immunity was measured before and after chemotherapy by means of delayed type hypersensitivity reactions, taken 48 h after the third and the fourth vaccination. We also investigated the toxicity of this combined immuno-chemotherapy treatment. Delayed type hypersensitivity reactions before chemotherapy had a median size of 20.3 mm, while after chemotherapy delayed type hypersensitivity size was 18.4 mm (P=0.01), indicating that chemotherapy hardly affected anti-tumour immunity. The severity of ulcers at the BCG vaccination sites was comparable to previous studies. In 30% of the patients grade III or grade IV chemotherapy related toxicity was seen; this is comparable to what is normally observed after adjuvant chemotherapy alone. This study shows that the active specific immunotherapy-induced anti-tumour immune response is only minimally impaired by consecutive chemotherapy and that the combined treatment of stage III colon cancer patients with active specific immunotherapy and 5-Fluorouracil/Leucovorin does not cause unexpected toxicity. Colon cancer is one of the most prevalent malignancies in the industrialised world, with approximately 240 000 new cases diagnosed each year in the USA and Western Europe. When colon cancer is detected early, in stages I or II (Dukes A or B), the 5 year survival rate with surgery alone is 60 -90%, depending on the depth of invasion of the tumour into the bowel wall. When the cancer has spread to the regional lymph nodes, or stage III (Dukes C), the 5 year survival rate is 25 -60%. Important prognostic factors in stage III colon carcinoma include the number of positive nodes, extra-nodal growth, invasion of adjacent organs, grade of histologic differentiation and post-operative CEA level. When distant metastases are diagnosed, stage IV (Dukes D), the 5 year survival rate is less than 5% (Cohen et al, 1997).Currently most patients with stage III colon carcinoma receive an adjuvant treatment with 5-Fluorouracil (5-FU) and Leucovorin. Several lar...

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Section: -Fu+asi For Stage III Colon Cancer a Baars Et Alsupporting

confidence: 89%

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confidence: 96%

A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

et al. 2002

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“…A greater understanding of the role of the host immune response in influencing the natural history of CRC might have important implications for risk stratification and the development of adjuvant immune-based therapies [13,37].…”

Section: Biology Of Infiltrating T Cells In Crcmentioning

confidence: 99%

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

Deschoolmeester

Baay

Lardon

et al. 2011

Cancer Microenvironment

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There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer (CRC) results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor-associated antigens possibly inducing a cellular antitumor immune response. It is well recognized that cytotoxic lymphocytes (CTLs) constitute one of the most important effector mechanisms of anti-tumor-immunity. However, their potential prognostic influence in CRC remains controversial. In addition, other key players like natural killer cells, tumor associated macrophages and regulatory T cells play an important role in the immune attack against CRC and need further investigation. This review will mainly focus on the role of the adaptive immune system in CRC and particularly in regard to microsatellite instability.

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“…2,3 The rationale behind a broadly applicable vaccination immunotherapy of human cancer disease with HLA-A2 binding p53 peptides is based on the high levels of wild-type p53 demonstrated in p53-mutated tumor cells 4,5 and the presence of peptide residues in the p53 protein that bind to the common HLA class I molecule HLA-A2. 6 A vaccination protocol based on wild-type peptides allows one to circumvent the limitations of strategies focused on the specific nonself peptides that arise through the variable p53 mutations found in single individuals.Recently, several clinical studies on cancer immunotherapy using different approaches to activate cytotoxic T cells in vivo [7][8][9] or ex vivo 10 recognizing individual tumor antigens have been highly successful. These results underscore the efficiency of the immune system in controlling tumor growth and emphasize the importance of characterizing CTL specific to general tumor antigens.…”

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confidence: 99%

Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

et al. 2001

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p53 is upregulated in the majority of spontaneous tumors and the HLA class I molecule HLA-A2 is expressed by approximately 50% of the caucasians. Potentially, these facts make HLA-A2-binding p53 peptides for CTL-inducing immunotherapy applicable to a broad range of cancer patients. In our study, we investigated the CTL-inducing capacity of autologous monocyte-derived dendritic cells (DC) maturated by exposure to CD40L and pulsed with a pool of 4 wild-type, HLA-A2-binding p53 peptides, and the p53-specific CD8 ؉ CTL lines established from healthy HLA-A2-positive donors were characterized. Reactivity to p53 65-73 and p53 [187][188][189][190][191][192][193][194][195][196][197] peptides was obtained in the T-cell lines. Interestingly, cold target inhibition experiments demonstrated that the simultaneous recognition of the 2 peptides was the result of crossreactivity, which was confirmed by killing experiments at the clonal CTL level. Furthermore, 4 HLA-A2 ؉ p53-mutated tumor cell lines were lysed by the CTL line, indicating that these peptides are endogenously processed and presented on HLA-A2 molecule. Thus, monocyte-derived DC pulsed with a pool of peptides are able to induce CTL reactivity to wildtype p53 peptides presented by several cancer cell lines. In addition, the recognition of 2 different p53 peptides by the same CTL clone suggests a promiscuous peptide recognition by the TCR involved. Taken together, these in vitro results suggest that vaccination with autologous DC pulsed with multiple p53 epitopes may induce an effective tumor-specific CTL response in vivo with the potential to eradicate p53-upregulated spontaneously occurring tumors. © 2001 Wiley-Liss, Inc. Key words: p53; cytotoxic T-lymphocytes; HLA-A2; dendritic cellsThe cell cycle regulating protein p53 binds to DNA with coincidental nucleotide misincorporations and leads to cell cycle arrest and DNA repair. 1 The involvement of p53 at this crucial checkpoint in the cell division is probably reflected by the fact that inactivating mutations in the p53 genome are found in the majority of human cancer diseases. 2,3 The rationale behind a broadly applicable vaccination immunotherapy of human cancer disease with HLA-A2 binding p53 peptides is based on the high levels of wild-type p53 demonstrated in p53-mutated tumor cells 4,5 and the presence of peptide residues in the p53 protein that bind to the common HLA class I molecule HLA-A2. 6 A vaccination protocol based on wild-type peptides allows one to circumvent the limitations of strategies focused on the specific nonself peptides that arise through the variable p53 mutations found in single individuals.Recently, several clinical studies on cancer immunotherapy using different approaches to activate cytotoxic T cells in vivo [7][8][9] or ex vivo 10 recognizing individual tumor antigens have been highly successful. These results underscore the efficiency of the immune system in controlling tumor growth and emphasize the importance of characterizing CTL specific to general tumor antigens. Four studies on...

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Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial

Cited by 449 publications

References 13 publications

A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

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