Interleukin-2 (IL-2) augments host cellular immune reactivity in the perioperative period in patients with malignant disease

Deehan, David J.; Heys, Steven Darryll; Ashby, Julian; Eremin, O.

doi:10.1016/s0748-7983(05)80061-7

Cited by 27 publications

(19 citation statements)

References 23 publications

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“…There is strong evidence in the animal setting that numerous agents that broadly stimulate the immune system are effective in significantly reducing the incidence of metastatic disease after surgery. Perioperative administration of recombinant IL-2 and IFN-a has been explored in early-phase clinical trials showing their potential to prevent postoperative NK cell suppression and enhance progression-free survival (23)(24)(25)(26)(43)(44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

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Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

et al. 2013

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Natural killer (NK) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. Using a mouse model of surgical stress, we transferred surgically stressed NK cells into NK-deficient mice and observed enhanced lung metastases in tumor-bearing mice as compared with mice that received untreated NK cells. These results establish that NK cells play a crucial role in mediating tumor clearance following surgery. Surgery markedly reduced NK cell total numbers in the spleen and affected NK cell migration. Ex vivo and in vivo tumor cell killing by NK cells were significantly reduced in surgically stressed mice. Furthermore, secreted tissue signals and myeloid-derived suppressor cell populations were altered in surgically stressed mice. Significantly, perioperative administration of oncolytic parapoxvirus ovis (ORFV) and vaccinia virus can reverse NK cell suppression, which correlates with a reduction in the postoperative formation of metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity, and we show for the first time that oncolytic vaccinia virus markedly increases NK cell activity in patients with cancer. These data provide direct in vivo evidence that surgical stress impairs global NK cell function. Perioperative therapies aimed at enhancing NK cell function will reduce metastatic recurrence and improve survival in surgical cancer patients. Cancer Res; 73(1); 97-107. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

“…The perioperative administration of recombinant cytokines has been explored in early-phase clinical trials (23,24). These studies have shown that perioperative administration prevent the supression of NK cell activity that occurs following surgery (25,26).…”

Section: Introductionmentioning

confidence: 99%

Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

et al. 2013

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“…It appears that after preoperative administration of IL-2, the perioperative alterations of immunological parameters are most pronounced in the early post-operative period (Böhm et al, 2001). After the 10th post-operative day, these alterations are rather minor (Deehan et al, 1995) and can be biased by other factors. For these reasons, immunological parameters were measured during the first 10 days after surgery.…”

Section: Discussionmentioning

confidence: 99%

Perioperative immunomodulation with interleukin-2 in patients with renal cell carcinoma: results of a controlled phase II trial

Klatte

Ittenson

et al. 2006

Br J Cancer

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We conducted a non-randomised controlled phase II trial to investigate the role of preoperative administration of interleukin-2 (IL-2) in patients with renal cell carcinoma undergoing tumour nephrectomy. A total of 120 consecutive patients were allocated alternately to the two study groups: perioperative immunomodulation with IL-2 (IL-2 group; n ¼ 60) and perioperative immunomonitoring without immunomodulation (control group; n ¼ 60). Patients from the IL-2 group received four doses of 10 Â 10 6 IU m À2 twice daily subcutaneously a week before operation followed by a daily maintenance dose of 3 Â 10 6 IU m À2 subcutaneously until a day before the operation. Parameters of cellular and humoral immunity (leucocytes, T-cell markers CD3, CD4, and CD8, B-cell marker CD19, monocyte marker CD14, natural killer (NK) cell markers CD16, CD56, and CD57, activation markers CD6, CD25, CD28, and CD69, progenitor cell marker CD34, as well as IL-2, IL-6, IL-10, soluble IL-2 receptor, IL-1 receptor antagonist, transforming growth factorb1, and vascular endothelial growth factor) were measured in peripheral venous blood at various intervals. Interleukin-2-related toxicity was WHO grade 1 (24%), 2 (67%), and 3 (9%). In the postoperative period, T-cell markers, activation markers, and NK cell markers decreased, and IL-6 and IL-10 increased. However, all these alterations were significantly less accentuated in patients who had been pretreated with IL-2. Median follow-up was 40 months. Tumour-specific survival in the IL-2 group and the control group was 98 vs 81% after 1 year and 86 vs 73% after 5 years (P ¼ 0.04). A similar effect was found for progression-free survival. We conclude that IL-2 can be safely administered in the perioperative period and modulates immunological parameters. However, to validate the survival data, a larger randomised phase III trial is needed.

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“…Despite the large number of studies that have documented postoperative NK cell dysfunction, very few have attempted to reverse it to improve cancer outcomes (8,(17)(18)(19)(20)(21)(22). Current treatment regimens tend to ignore metastatic disease until after the recovery from the stress of surgery.…”

Section: Introductionmentioning

confidence: 99%

“…The perioperative administration of cytokine therapy has been explored in early-phase clinical trials showing their potential to prevent postoperative NK cell suppression and enhance progression-free survival (17)(18)(19)(20)(21)(22)(24)(25)(26). However, further development has been limited due to dose-limiting toxicity (27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Perioperative Influenza Vaccination Reduces Postoperative Metastatic Disease by Reversing Surgery-Induced Dysfunction in Natural Killer Cells

Tai

Zhang

Scott

et al. 2013

Clinical Cancer Research

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Purpose: Surgical removal of solid primary tumors is an essential component of cancer treatment. Surgery-induced dysfunction in natural killer (NK) cells has been linked to the development of metastases in animal models and patients with cancer. We investigated the activation of NK cells using influenza vaccine in the perioperative period to eradicate micrometastatic disease.Experimental Design: Both the B16lacZ and 4T1 tumor models in immunocompetent mice were used to assess the in vivo efficacy of perioperative influenza vaccine administration. In healthy human donors and cancer surgery patients, we assessed NK cell function pre-and post-influenza vaccination using both in vivo and ex vivo assays.Results: Using the TLR3 agonist poly(I:C), we showed as proof-of-principle that perioperative administration of a nonspecific innate immune stimulant can inhibit surgery-induced dysfunction in NK cells and attenuate metastases. Next, we assessed a panel of prophylactic vaccines for NK cell activation and determined that inactivated influenza vaccine was the best candidate for perioperative administration. Perioperative influenza vaccine significantly reduced tumor metastases and improved NK cytotoxicity in preclinical tumor models. Significantly, IFNa is the main cytokine mediator for the therapeutic effect of influenza vaccination. In human studies, influenza vaccine significantly enhanced NK cell activity in healthy human donors and cancer surgery patients.Conclusion: These results provide the preclinical rationale to pursue future clinical trials of perioperative NK cell activation, using vaccination in cancer surgery patients. Research into perioperative immune therapy is warranted to prevent immune dysfunction following surgery and eradicate metastatic disease.

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Interleukin-2 (IL-2) augments host cellular immune reactivity in the perioperative period in patients with malignant disease

Cited by 27 publications

References 23 publications

Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

Perioperative immunomodulation with interleukin-2 in patients with renal cell carcinoma: results of a controlled phase II trial

Perioperative Influenza Vaccination Reduces Postoperative Metastatic Disease by Reversing Surgery-Induced Dysfunction in Natural Killer Cells

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