Effect of Frequently Used Chemotherapeutic Drugs on Cytotoxic Activity of Human Cytotoxic T-lymphocytes

Márkász, László; Skribek, Henriette; Uhlin, Michael; Ötvös, Rita; Flaberg, Emilie; Eksborg, Staffan; Oláh, Éva; Stuber, György; Szekeres, L.

doi:10.1097/cji.0b013e3181628b76

Cited by 39 publications

(34 citation statements)

References 53 publications

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“…Rather, in combined treatment, the antitumor immunity benefits are produced by inducing lymphocytosis [44], increased CD4+ and LAK cell numbers and cytotoxicity with a marked reduction of Tregs, and a noteworthy infiltration of CD8+ T cells [45,46]. Efficient CTL and NK cell-mediated killing, even at concentrations comparable with the maximally achieved therapeutic concentrations in humans, were found [47,48]. We [49] and others [50] have also reported the synergistic activity between 5-FU and IL-2 in different types of cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

A new pharmacological approach to gastrointestinal cancer at high risk of relapse based on maintenance of the cytostatic effect

et al. 2010

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In metastatic colorectal and other locally advanced gastrointestinal cancers, the mechanisms of tumor growth and/or immune escape by residual cancer cells after curative resection often provoke tumor recurrence. Current adjuvant therapy is based on pharmacological administration up to 6-8 months after surgery. We hypothesized that the long-term, cytostatic action from repeated post-adjuvant administration of 5-fluorouracil (FU)-leucovorin (LV) cycles, as a result of the downregulation of the above-mentioned cellular mechanisms, could halt tumor progression. An active prospective cohort, including 19 patients (study group) at high risk of relapse, was considered. All patients received repeated post-adjuvant administration of 5-FU-LV cycles for up to 52-60 months following curative surgery (total cumulative dose of about 90 g and mean follow-up of 70.6 ± 49.7 months). The 5-year disease-free interval (DFS) and overall survival (OS) were 80.4 ± 10.2% and 87.1 ± 8.6%, respectively, which is very different from the recent literature that has reported 5-year DFS and OS values of 31.8% and 40.1%, respectively. These findings suggest that this new pharmacological approach based on the long-term maintenance of a cytostatic effect with 5-FU-LV can produce a relevant improvement in the outcome of this population.

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Section: Discussionmentioning

confidence: 99%

A new pharmacological approach to gastrointestinal cancer at high risk of relapse based on maintenance of the cytostatic effect

et al. 2010

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“…44 In contrast, 5-FU-mediated enhancement of cytotoxic T-lymphocyte activity and a shift of the cytokine secretion pattern from TH2 to TH1 has been described in vitro by other groups. 45,46 However, data from clinical cytokine studies in RCC are not sufficient to draw a final conclusion concerning immunologic effects of 5-FU in combined cytokine regimens. Although initial results with combination therapy consisting of IL-2, a-IFN, and 5-FU yielded clinical response rates up to 40%, 11,12 later large prospective randomized studies comparing overall survival could neither confirm advantages of combination therapy nor additional effects of 5-FU with respect to overall survival.…”

Section: Discussionmentioning

confidence: 99%

Granulocyte Macrophage-Colony Stimulating Factor Plus Interleukin-2 Plus α-interferon Plus 5-Fluorouracil in the Treatment of Metastatic Renal Cell Cancer

Westermann¹,

Hecker²,

Flörcken

et al. 2009

Journal of Immunotherapy

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Even in the era of multitargeted therapies, cytokines remain at least one of different treatment options in renal cell cancer (RCC), particularly for patients belonging to the good prognostic risk category according to Memorial Sloan Kettering Cancer Center criteria. Granulocyte macrophage-colony stimulating factor plays a central role in the differentiation and activation of antigen presenting cells. This clinical phase 1/2 chemoimmunotherapy trial in metastatic RCC used sequential application of alpha-interferon /5-fluorouracil followed by granulocyte macrophage-colony stimulating factor/interleukin-2. The study was performed before multikinase inhibitors were available for routine use. Twenty patients with metastatic RCC were enrolled into this phase 1/2 protocol. Sequential chemoimmunotherapy was feasible and safe on an outpatient basis. The regimen had only modest antitumor activity with 4 mixed responses and 4 stable diseases being documented after 4 treatment cycles. Enhanced proliferative and stimulatory capacity of peripheral blood mononuclear cells was only observed in patients with mixed responses/stable diseases whereas patients with progressive disease did not show any change. Most interestingly, there was a significant increase of T cells expressing the costimulatory molecules CD80/86 in patients with progressive disease. This finding is reported here for the first time under chemoimmunotherapy of RCC. In conclusion, clinical response rates of this cytokine-based regimen do not justify further clinical evaluation. However, the study suggests that CD80/86+ T cells might have negative regulatory function under cytokine treatment and are possibly useful as a negative predictive marker for clinical response.

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“…For example, cisplatin and 5-FU are known to induce lymphocytopenia, resulting in transient immunosuppression in cancer patients. These drugs are also reported to enhance or permit effi cient tumour cell killing in vitro at concentrations comparable with the maximally achieved therapeutic concentration in vivo in humans [26]. There is recent evidence indicating that some cytotoxic compounds and radiotherapy promote specifi c anticancer immune responses that contribute to the overall therapeutic effect [27,28].…”

Section: Discussionmentioning

confidence: 99%

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

et al. 2011

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Background Trifunctional antibodies, such as catumaxomab (anti-EpCAManti-CD3) and ertumaxomab (anti-HER-2/neuanti-CD3), transiently link immune effector cells to tumour cells, which results in cellular cytotoxicity towards the tumour cells. A functional immune system is therefore essential for effective anti-tumour activity. However, the commonly observed haematotoxicity of chemotherapeutics and radiation therapy may be associated with some degree of immunosuppression. Combining chemotherapy and trifunctional antibodies in cancer treatment requires understanding of the impact of chemotherapeutics on immune cell function and, thus, on the activity of trifunctional antibodies. Methods The effect of chemotherapeutic treatment on trifunctional antibody-mediated anti-tumour activity was assessed in vitro. Blood samples were collected from 12 head and neck squamous cell carcinoma patients after chemotherapy (5-fl uorouracil, cisplatin) and radiotherapy, and from one healthy control donor. The immune cell status was analysed and mononuclear cells (MNC) were isolated. The potency of catumaxomab and ertumaxomab was assessed in a cytotoxicity assay using MNC isolated from each patient sample in co-culture with a tumour target cell line. The release of infl ammatory cytokines was also monitored in the cell culture supernatant. Results Most patients included in this study had decreased immune cell counts during the course of chemotherapy. Nonetheless, an effective and concentration-dependent anti-tumour activity mediated by trifunctional antibodies was demonstrated using these patient immune effector cells. The immune response activity of the patient immune cells was not impaired one week after cisplatin administration or even three days after the last 5-fl uorouracil treatment. Conclusion This study shows for the fi rst time that immune effector cells from cancer patients undergoing standard chemotherapy and radiotherapy can be activated by trifunctional antibodies for effi cient killing of tumour cells.

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Effect of Frequently Used Chemotherapeutic Drugs on Cytotoxic Activity of Human Cytotoxic T-lymphocytes

Cited by 39 publications

References 53 publications

A new pharmacological approach to gastrointestinal cancer at high risk of relapse based on maintenance of the cytostatic effect

A new pharmacological approach to gastrointestinal cancer at high risk of relapse based on maintenance of the cytostatic effect

Granulocyte Macrophage-Colony Stimulating Factor Plus Interleukin-2 Plus α-interferon Plus 5-Fluorouracil in the Treatment of Metastatic Renal Cell Cancer

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

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