Prospective Randomized Trial of High-Dose Interleukin-2 Alone or in Conjunction With Lymphokine-Activated Killer Cells for the Treatment of Patients With Advanced Cancer

Rosenberg, Steven A.; Lotze, Michael T.; Yang, James Chih‐Hsin; Topalian, Suzanne L.; Chang, Alfred E.; Schwartzentruber, Douglas J.; Aebersold, Paul C.; Leitman, Susan F.; Linehan, W. Marston; Seipp, Claudia A.; White, Donald E.; Steinberg, Seth M.

doi:10.1093/jnci/85.8.622

Cited by 572 publications

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“…The cytokine/lymphokine IL-2, produced by activated T lymphocytes, is critical for immune responsiveness and has been extensively used in clinical trials. 2,4,8 Metastatic RCC can be treated with immunotherapy with interferons (IFN) and/or interleukin-2 (IL-2) with response rates of 15-27%. 2,4,8 High dose of recombinant IL-2 is approved for the treatment of metastatic RCC but is associated with significant toxicity limiting its use to selected patients.…”

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confidence: 99%

“…2,4,8 Metastatic RCC can be treated with immunotherapy with interferons (IFN) and/or interleukin-2 (IL-2) with response rates of 15-27%. 2,4,8 High dose of recombinant IL-2 is approved for the treatment of metastatic RCC but is associated with significant toxicity limiting its use to selected patients. 4,8 Using various models of the Renca murine renal adenocarcinoma, we have investigated the interaction between local tumor irradiation and systemic IL-2 immunotherapy.…”

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Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma

et al. 2003

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To circumvent the toxicity caused by systemic injection of cytokines, cytokine cDNA genes encoding the human interleukin IL-2 cDNA (Ad-IL-2) and murine interferon IFN-g gene (Ad-IFN-g) were inserted into adenoviral vectors. These constructs were used for intratumoral gene therapy of murine renal adenocarcinoma Renca tumors. Treatment with three doses of Ad-IL-2 or Ad-IFN-g, given a day apart, was more effective than single-dose gene therapy. We found that tumor irradiation enhanced the therapeutic efficacy of Ad-IL-2 and Ad-IFN-g intratumoral gene therapy. Tumor irradiation, administered 1 day prior to three doses of Ad-IL-2 treatment, was more effective than radiation or Ad-IL-2 alone, resulting in tumor growth arrest in all mice, increased survival and a consistent increase in complete tumor regression response rate. Complete responders rejected Renca tumor challenge and demonstrated specific cytotoxic T-cell activity, indicative of specific tumor immunity. The effect of radiation combined with three doses of Ad-IFN-g was less pronounced and did not lead to tumor immunity. Histological observations showed that irradiation of the tumor prior to gene therapy increased tumor destruction and inflammatory infiltrates in the tumor nodules. These findings demonstrate that tumor irradiation improves the efficacy of Ad-IL-2 gene therapy for induction of antitumor immune response. Cancer Gene Therapy (2004) 11, 61-72. doi:10.1038/sj.cgt.7700656Keywords: adenovirus; IL-2; IFN-c; radiation; renal carcinoma R enal cell carcinoma (RCC) incidence has increased in recent years with approximately 31, 200 new cases each year in the USA. 1 This increased RCC incidence may be linked to certain risk factors including smoking, obesity, high protein diets and hypertension. 2,3 The disease is responsible for an estimated 12, 000 deaths each year. 1 Nearly half of the patients present only with localized disease that can be treated by surgical removal. 2,4,5 However, one third of the patients also present with metastatic disease and half of the patients treated for localized carcinomas subsequently develop metastatic disease. 2,4 The median survival of patients with metastases is only 8 months, with a 5-year survival rate of less than 10%. 2,4 Patients with metastatic RCC frequently present with pulmonary metastases that are poorly responsive to conventional treatment including most chemotherapeutic drugs, hormones and radiation therapy. 2,4,5 The treatment of metastatic disease has been and remains a difficult clinical challenge. Immunotherapy is an alternate systemic approach for the treatment of metastatic cancers that is based on activation of a host immune response against the tumor cells using cytokines or activated immune cells. 6 Cytokines are used in immunotherapy to enhance immune mechanisms directed against tumors. 7 Cytokines are proteins produced following activation of lymphocytes, macrophages or other cells. Cytokines can induce a cascade of activation, proliferation and differentiation of immune cells and mount an anti...

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Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma

et al. 2003

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“…Overall, the toxicity was graded 0-2 according to the WHO toxicity scale in the majority of the patients. However, grade 3-4 toxicity was seen in a substantial amount of patients and was more common in the IL-2/IFN-atreated patients (Table 5) (Rosenberg et al, 1993;Besana et al, 1994;Oliver, 1994;Atzpodien et al, 1995;Facendola et al, 1995;Savage, 1995;Wagstaff et al, 1995;Hanninen et al, 1996). Recombinant cytokines, notably IL-2 and IFN-a, appear to have had encouraging results, and have led to approval by several national drug agencies in the management of RCC.…”

Section: Final Analysismentioning

confidence: 99%

“…In this context it is also of interest to emphasize that controlled randomized trials evaluating different approaches of immunotherapy on survival, for example IL-2 vs IL-2 plus lymphokine-activated killer cells or IFN-a vs IFN-a and vinblastin, displayed no significant differences (Fossa et al, 1992;Rosenberg et al, 1993;Kellokumpu-Lehtinen et al, 1995). Furthermore, the advantage of an increased response rate after immunological manipulation has not always been translated to a better chance of survival (Fossaet al, 1992;Facendola et al, 1995).…”

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confidence: 99%

“…RCC is one of the few tumours with a known propensity for spontaneous regression (Katz et al, 1982;Oliver et al, 1989 (Rosenberg et al, 1993;Oliver, 1994;Atzpodien et al, 1995;Facendola, 1995;Savage, 1995;Wagstaff et al, 1995;Hanninen et al, 1996). Although these treatment options can induce objective responses, they are associated with significant sideeffects and considerable expense (Oliver, 1994;Facendola et al, 1995;Savage, 1995;Wagstaff et al, 1995).…”

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Survival in renal cell carcinoma-a randomized evaluation of tamoxifen vs interleukin 2, α-interferon (leucocyte) and tamoxifen

Henriksson

Nilsson²,

Colleen³

et al. 1998

Br J Cancer

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Survival in renal cell carcinoma -a randomized evaluation of tamoxifen vs interleukin 2, a-interferon (leucocyte) and tamoxifen R Henriksson', S Nilsson2, S Colleen3, P WersaII4, M HeIsing5, R Zimmerman6 and K Engman7 'Department of Oncology, UmeA University Hospital; 2Department of Oncology, Uppsala University Hospital; 4Karolinska Institute, 6Sbdersjukhuset, Stockholm, 5Orebro Hospital; 3Department of Urology, Lund University Hospital, Sweden; and 7BioNative AB, Umec, Sweden Summary Metastatic renal cell carcinoma (RCC) has a poor prognosis. Conventional treatment strategies, including chemotherapy and hormonal therapy, have limited value. Although encouraging results have been achieved in terms of objective response using immunological manipulations, no conclusive studies yet exist with a controlled comparative evaluation of survival. Therefore, the present study was undertaken, which compared one of the present (and presumed best) treatments, interleukin 2/interferon-a (IL-2/IFN-a) and tamoxifen, with a control arm of tamoxifen only. Tamoxifen has been shown to potentiate in vivo anti-tumour activity of IL-2, and because of its non-toxic behaviour it was included in both groups. The study was open, randomized and included seven institutions in Sweden. The patients were stratified according to the different centres involved. An interim analysis was planned when a minimum of 100 patients were evaluable. The 128 patients finally included had a histologically documented metastatic RCC, with a life expectancy of more than 3 months, a performance status WHO 0-2 and no prior chemo-or immunotherapy. Informed consent was obtained from each patient. The patients randomized to the control arm (n = 63) received only tamoxifen 40 mg p.o. daily for at least 1 year or until progression. The patients (n = 65) randomized to biotherapy received subcutaneous recombinant IL-2, leucocyte IFN-a in a treatment cycle of 42 days, as well as tamoxifen p.o. In the absence of undue toxicity or disease progression, these patients received one additional treatment cycle of 42 days followed by maintenance treatment, consisting of 5 days therapy every 4 weeks, for 1 year, or until proven progression. Only two patients in the tamoxifen-only group received immunotherapy when the disease progressed, but without any beneficial effect. All patients received appropriate local treatment when indicated. The interim analysis demonstrated no survival advantage for either group, and therefore further inclusion of patients was stopped. The median follow-up was 11 months (range 0.4-48 months). The final survival analysis showed no significant differences between the two treatment arms in so far as comparison from the day of diagnosis of primary disease, from the day of first evidence of metastatic spread, or from the onset of treatment. This was valid both when the evaluation was performed with regard to intention to treat and when the analysis was directed only to patients that managed at least one treatment cycle (42 days) of IL-2/IFN-a. The adver...

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Adoptive Cellular Therapy of Malignancy

Chang

Geiger²,

Sondak

et al. 1993

Arch Surg

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The realization that human cancers can be responsive to the manipulation of the immune system has only recently been documented. The immune approaches to the treatment of malignancy can be broadly classified into either active or passive immunotherapies. With active immunotherapy, treatment relies on the in vivo stimulation of the endogenous host immune system to react against tumors with the administration of biological response-modifying agents (ie, bacterial adjuvants, cytokines, tumor vaccines). With passive immunotherapy, treatment involves the delivery of biologic reagents with established tumor-immune reactivity (ie, antibodies or cells) that can directly or indirectly mediate antitumor effects and does not necessarily depend on an intact host immune system. Cellular therapy of malignancy has become more feasible with increased understanding of the interactions between immune cells and tumors. This article will review our current understanding of the principles underlying these interactions.

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Prospective Randomized Trial of High-Dose Interleukin-2 Alone or in Conjunction With Lymphokine-Activated Killer Cells for the Treatment of Patients With Advanced Cancer

Abstract: As these studies continue, efforts are underway to develop improved immunotherapies using tumor-infiltrating lymphocytes (TIL) and gene-modified TIL.

Cited by 572 publications

References 0 publications

Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma

Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma

Survival in renal cell carcinoma-a randomized evaluation of tamoxifen vs interleukin 2, α-interferon (leucocyte) and tamoxifen

Adoptive Cellular Therapy of Malignancy

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