Granulocyte-macrophage-colony stimulating factor in combination immunotherapy for patients with metastatic renal cell carcinoma

Ryan, Christopher W.; Vogelzang, Nicholas J.; Dumas, Clément; Kuzel, Timothy M.; Stadler, Walter M.

doi:10.1002/(sici)1097-0142(20000315)88:6<1317::aid-cncr7>3.0.co;2-x

Cited by 27 publications

(2 citation statements)

References 22 publications

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“…The aim for EBRT was, for some patients, pain palliation; for others, we hoped to obtain a synergy with the immunotherapy by increasing the antigenicity of the radiated tumor cells. 20 Although our study was not carried out in a randomized fashion, by reviewing retrospectively our results from a heterogeneous sample of patients, our data confirm the absence of efficacy of EBRT as an adjuvant treatment to IL-2 immunotherapy in MRCC and are in agreement with those of Redman et al 41 and Ryan et al, 42 though others have reported encouraging results. 43 Following our first observation, 10 some phase I studies with intralymphatic rIL-2 have been initiated.…”

Section: Discussionsupporting

confidence: 88%

Immunotherapy of metastatic kidney cancer

et al. 2001

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, 122 MRCC patients were treated by monthly intralymphatic injections (containing a mean of 573 IL-2 U and 26 ؋ 10 6 LAK cells) and i.m. administration of IFN and TF; 71 patients also received a 3-day cycle of monthly IL-2 inhalations with a mean of 998 daily U. MRCC cases not treated by immunotherapy (n ‫؍‬ 89) represent our historical controls. Adverse clinical side effects related to treatment were negligible. CR (n ‫؍‬ 11) and PR (n ‫؍‬ 13) were noticed in 24/122 patients. Of 24 responding patients, 17 resumed progression, whereas 7 remain in remission 11-69 months later. The overall median survival of treated patients (28 months) was 3.5-fold higher than the median survival of historical controls (7.5 months), and a Kaplan-Meier curve showed 25% survival 11 years after the beginning of immunotherapy. Apparently, the addition of IL-2 by inhalation improved survival. The present immunotherapy protocol appears to be efficacious, safe, devoid of adverse side effects, far less costly than others and able to offer a good quality of life to MRCC patients; if confirmed in a multicenter trial, it could set the basis for developing lowdose immunomodulatory treatments. © 2001 Wiley-Liss, Inc. Key words: immunotherapy; IL-2; lymphokine-activated killer cells; metastasis; transfer factor; interferon; renal cancerThe most promising systemic therapy for MRCC is immunotherapy with IL-2. 1 The original observations by Rosenberg et al., 2 using i.v. administration of high-dose rIL-2 and LAK in MRCC patients showed encouraging clinical response rates and longlasting remissions. These results have prompted many clinical trials using various administration routes: i.v. both in bolus and continuous or s.c. in combination or not with IFN and/or chemotherapeutic agents. In 1,411 MRCC patients, the overall rate of response was 20%. 3,4 Nonetheless, despite the lowering of the IL-2 dosage and the decrease of the 4% fatal outcome of the initial studies, thanks to the improved selection of patients and the clinical experience acquired, 5,6 the persistence of more often than not severely adverse clinical side effects remains the most important hindrance for the wide use of IL-2.Hence, being aware of the risk from a high IL-2 dose and of its ability to activate, at low doses, tumor mass rejection, 7-9 we attempted to develop alternative protocols. An observation made in 1 MRCC patient, in whom injection of a metastasis with IL-2 and LAK cells was followed by regression not only of the treated tumor but also of several other abdominal lymph node metastases, prompted us to further investigate the low-dose effect using the intralymphatic route. Following intratumor low-dose injections of IL-2 into infiltrating bladder cancers or lymph node metastases of MRCC patients, both the injected and the non-injected distant metastases often disappeared. 7,8 Thus, by administering very low doses of IL-2 and LAK cells into the lymphatic vessels of the foot, we observed encouraging clinical results with minimal side effects. 10,11 To boost the overall ...

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Section: Discussionsupporting

confidence: 88%

Immunotherapy of metastatic kidney cancer

et al. 2001

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“…Granulocyte macrophage colony-stimulating factor (GM-CSF) is known as a potent hematopoietic growth factor for granulocyte and macrophage expansion and is considered to play a critical role in anti-tumor responses by dendritic cells (DCs) maturation and T cell proliferation and activation [ 8 ]. However, clinical trials in metastatic RCC (mRCC) using GM-CSF as single-agent or combined with either interleukine-2 (IL-2) or interferon-α (IFN-α) have failed to show anti-tumor effect [ 9 – 11 ]. Although RCC vaccination studies using GM-CSF as immune adjuvant have shown promising results, it is not clear whether this cytokine is indispensable for the clinical improvement [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Granulocyte macrophage colony-stimulating factor predicts postoperative recurrence of clear-cell renal cell carcinoma

Chang

Zhou

et al. 2016

Oncotarget

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BackgroundGranulocyte macrophage colony-stimulating factor (GM-CSF) is currently widely used as an adjuvant in cancer immunotherapy. However, recent studies have shown that GM-CSF can impair anti-tumor immune responses. Thus the role of GM-CSF in clear-cell renal cell carcinoma (ccRCC) remains unraveled. Our present study aims to investigate the prognostic significance of intratumoral GM-CSF in patients with clinically localized ccRCC.ResultsA high intratumoral GM-CSF expression was significantly associated with lymph node metastases (P = 0.009), high TNM stage (P = 0.031), high Fuhrman grade (P < 0.001), presence of tumor necrosis (P = 0.005), and high Leibovich scores (P < 0.001). In addition, the prognostic significance of intratumoral GM-CSF expression was restricted to patients with Leibovich intermediate/high-risk (P = 0.001). Furthermore, a high intratumoral GM-CSF expression was demonstrated as an independent prognostic factor of reduced RFS (P = 0.018). Incorporation of the intratumoral GM-CSF expression into a prognostic model including TNM stage, Fuhrman grade, tumor necrosis and lymphovascular invasion generated a nomogram, which predicted accurately 3- and 5-year survival for ccRCC patients.Materials and MethodsThis study comprised 233 clinically localized (T1-3N0-1M0) ccRCC patients undergoing nephrectomy in 2008 at a single centre. Intratumoral GM-CSF expression was assessed by immunohistochemical staining and its associations with clinicopathologic features and recurrence-free survival (RFS) were evaluated.ConclusionsThe intratumoral GM-CSF expression, as a potentially independent prognostic biomarker for recurrence, might improve conventional clinical and pathologic analysis to refine outcome prediction for clinically localized ccRCC patients after surgery.

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A Phase II trial of intravenous gemcitabine and 5‐fluorouracil with subcutaneous interleukin‐2 and interferon‐α in patients with metastatic renal cell carcinoma

Ryan¹,

Vogelzang²,

Stadler³

2002

Cancer

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BACKGROUND The objective of this study was to determine the response rate and toxicity of gemcitabine and continuous‐infusion 5‐fluorouracil (5‐FU) in combination with subcutaneous interleukin‐2 (IL2) and interferon‐α (IFNA) in patients with metastatic renal cell carcinoma. METHODS Forty‐one patients were treated with gemcitabine 600 mg/m2 on Days 1, 8, and 15 and continuous‐infusion 5‐FU on Days 1–21. The dose of 5‐FU was 200 mg/m2 per day for the initial 8 patients but was reduced to 150 mg/m2 per day for all remaining patients due to toxicity. Starting on Day 15, IL2 and IFNA were administered for 4 weeks. IL2 was administered at a dose of 11 × 106 IU subcutaneously (sc) 4 days per week and IFNA was administered at a dose of 10.0 × 106 IU sc 2 days per week. RESULTS Of 41 patients enrolled in the study, there was 1 complete response (CR), and there were 5 partial responses (PR), for an overall response rate of 14.6% (90% confidence interval [90%CI], 6.6–26.9%). The median time to disease progression was 6.6 months (90%CI, 3.9–7.5 months), and the median overall survival was 20.6 months (90%CI, 9.6–23.3 months). Toxicity was moderate to severe, with fatigue, fever, anorexia, or nausea experienced by 75–90% of patients. Mucositis and neutropenia, likely due to the gemcitabine and 5‐FU, were experienced by a majority of patients. CONCLUSIONS The addition of gemcitabine and 5‐FU to subcutaneous IL2 and IFNA results in a similar response rate to what was observed in previous studies of IL2‐based therapy. The toxicity of this four‐drug combination is significant, and the regimen is not recommended for further development. Cancer 2002;94:2602–9. © 2002 American Cancer Society. DOI 10.1002/cncr.10528

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Granulocyte-macrophage-colony stimulating factor in combination immunotherapy for patients with metastatic renal cell carcinoma

Cited by 27 publications

References 22 publications

Immunotherapy of metastatic kidney cancer

Immunotherapy of metastatic kidney cancer

Granulocyte macrophage colony-stimulating factor predicts postoperative recurrence of clear-cell renal cell carcinoma

A Phase II trial of intravenous gemcitabine and 5‐fluorouracil with subcutaneous interleukin‐2 and interferon‐α in patients with metastatic renal cell carcinoma

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