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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4542-4549 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.2136
Tumor Necrosis Factor
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAUTHORS' DISCLOSURES OF...AUTHOR CONTRIBUTIONSREFERENCES |
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(TNF-) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti–TNF- monoclonal antibody, in patients with immunotherapy-resistant or refractory RCC.
Patients and Methods Patients progressing after cytokine therapy were treated with intravenous infliximab as follows: study 1 (19 patients), 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks; study 2 (18 patients), 10 mg/kg at weeks 0, 2, and 6, and then every 4 weeks. Treatment continued until disease progression (PD). Response was assessed according to Response Evaluation Criteria in Solid Tumors. Plasma levels of TNF-, CCL2, and interleukin-6 (IL-6) were measured before and during treatment.
Results TNF- and its receptors were detected in malignant cells in RCC biopsies. In study 1, three patients (16%) achieved partial response (PR) and three patients (16%) achieved stable disease (SD). Median duration of response (PR + SD) was 7.7 months (range, 5.0 to 40.5+ months). In study 2, 11 patients (61%) achieved SD. Median duration of response was 6.2 months (range, 3.5 to 24+ months). One patient developed grade 3 hypersensitivity and another died as a result of pulmonary infection/sepsis. Enzyme-linked immunosorbent assay analysis of plasma revealed that higher levels of TNF- at baseline and higher levels of CCL2 during treatment were associated with PD. There were also correlations between higher levels of TNF-, IL-6, and CCL2 and poor survival (< 12 months).
Conclusion This is the first direct clinical evidence suggesting that TNF- may be a therapeutic target in RCC. Plasma levels of TNF-, IL-6, and CCL2 may have predictive and prognostic significance.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAUTHORS' DISCLOSURES OF...AUTHOR CONTRIBUTIONSREFERENCES |
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(TNF-) is considered to be a molecule with antitumor activity. In animals, high doses induce significant anticancer effects through stimulation of T-cell–mediated immunity and selective destruction of blood vessels.1-3 Conversely, physiologic and pathologic levels of TNF- may be involved in cancer promotion, tumor growth, and metastasis, directly or via a network of cytokines, chemokines, and matrix metalloproteinases.2-4 TNF- is secreted by a number of tumor cells, including renal cell carcinoma (RCC), and can act as an autocrine growth factor.3,5 Furthermore, the presence of TNF- in tumors is associated with poor prognosis, hormone resistance, and cachexia.3
In 2000, we published the results of a phase II trial documenting activity of thalidomide in patients with advanced RCC with 17% of patients achieving partial response (PR) and 72% of patients achieving stable disease (SD).6 In a second phase II study, we observed 9% PR and 32% SD.7 Other centers later reported response rates of 0% to 11%, with 25% to 64% of patients achieving SD.8-13 Thalidomide degrades TNF- mRNA,14 therefore we hypothesized that anti–TNF- therapies are a rational strategy for the treatment of RCC.
Infliximab (cA2, Remicade; Centocor Inc, Malvern, PA) is a chimeric human-mouse monoclonal antibody consisting of human immunoglobulin G1 (IgG1) Fc regions fused to the variable Fv region of a high-affinity neutralizing murine antihuman TNF- antibody.15 It prevents TNF- binding its receptors, TNF-R1 (p55 receptor) and TNF-R2 (p75 receptor), and causes cell death via complement-mediated lysis through interaction with membrane-bound TNF-.16
Infliximab is well tolerated, is licensed for use in Crohn's disease and rheumatoid arthritis at doses of 3 to 10 mg/kg, and has been used in more than 750,000 patients worldwide. We present the results of two sequential investigator-sponsored phase II studies, which show that infliximab is active in RCC and that TNF- may be an important target in this disease.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAUTHORS' DISCLOSURES OF...AUTHOR CONTRIBUTIONSREFERENCES |
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Patients
Entry criteria included histologically proven metastatic or locally advanced RCC, prior immunotherapy with interferon alfa (IFN ) and/or IL-2, the presence of at least one measurable or assessable progressing lesion, good performance status (Eastern Cooperative Oncology Group 0 to 2), and a life-expectancy more than 12 weeks. Patients had to be 18 years or older and those of child-bearing potential were required to use adequate birth-control measures for the duration of the study and for 6 months after receiving the last infusion. Female patients were required to have a negative serum or urinary β–human chorionic gonadotropin test at screening. All patients provided informed consent before any screening procedures that were not considered standard in this patient population.
Exclusion criteria included treatment with chemotherapy, immunotherapy, or an investigational drug within 4 weeks of study entry, treatment with any other TNF-–reducing agent within 3 months of screening, a history of receiving human-murine recombinant products, or a known allergy to murine products. Serious infection, active or latent tuberculosis (assessed by a positive Mantoux or Heaf test within 3 months of study entry), opportunistic infection, documented HIV infection, and active hepatitis B or C were also exclusion criteria, derived from the Warnings and Precautions in the approved labeling.17 Other exclusion criteria included cerebral metastases, autoimmune disorders, any demyelinating disease, or a history of congestive cardiac failure of any severity, or being a transplant recipient. Laboratory exclusion criteria included liver function tests more than 1.5x the upper limit of normal, serum creatinine more than 2.0x the upper limit of normal, hemoglobin less than 9 g/dL, total white cell count less than 1.5 x 109/L, and a platelet count less than 100 x 109/L.
The local scientific and ethics committees of the Royal Marsden Hospital approved these studies, and all patients provided written informed consent before study entry.
Treatment
Study 1.
Induction was administered with infliximab 5 mg/kg intravenously (IV) during 2 hours on weeks 0, 2, and 6. The maintenance regimen was 5 mg/kg IV during 2 hours, starting week 14, then once every 8 weeks.
Study 2. Induction was administered with infliximab 10 mg/kg IV during 4 hours on weeks 0, 2, and 6. The maintenance regimen was 10 mg/kg IV during 4 hours, starting week 10, then once every 4 weeks.
Patients were admitted overnight to the hospital for the first infusion and treated subsequently on an outpatient basis. Treatments continued until disease progression, significant toxicity, or withdrawal of consent.
Assessment
Tumor lesions were measured using Response Evaluation Criteria in Solid Tumors,18 with computed tomography (CT) scans at baseline, week 6, and then every 8 weeks. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria before each infusion. Plasma samples were taken at each visit.
Laboratory Procedures
Whole blood samples were collected 1 hour, 24 hours, 1 week, and 2 weeks after the first infusion of infliximab and before each subsequent infusion. Samples were collected in preservative-free heparin, spun at 1,500 rpm, and the supernatant was flash frozen and stored at –70°C. Biomarkers TNF-, IL-6, CCL2, vascular endothelial growth factor (VEGF), and CXCL12 were measured using enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems, Abingdon, United Kingdom). Assay sensitivity limits were 4.4, 0.7, 5.0, 9.0, and 18.0 pg/mL for TNF-, IL-6, CCL2, VEGF, and CXCL12, respectively.
Tumor specimens unrelated to this study were obtained from the Royal Marsden National Health Service Foundation Trust and the Tayside Tissue Bank. Indirect immunofluorescence staining of cryosections was used to detect TNF-, TNF- receptors 1 and 2, and IL-6. For detection of TNF- and TNF- receptors 1 and 2, cryosections were fixed for 10 minutes in 2% paraformaldehyde and permeabilized for 5 minutes with 0.2% Triton X-100. For IL-6 staining, cryosections were fixed for 10 minutes in acetone at –20°C. Slides were blocked with phosphate-buffered saline, 2% bovine serum albumin fraction V, 0.02% fish skin gelatin, and 10% fetal calf serum; primary antibodies were incubated overnight at 4°C followed by incubation with the fluorescent secondary antibody for 1 hour at room temperature. Prepared sections were mounted with Vectashield mount (Vector Laboratories, Burlingame, CA) containing 4,6-diamidino-2-phenylindole-2-HCl.
Antibodies used were TNF- (Mab610; R&D, Minneapolis, MN), TNF- receptor 1 (Ab19139; Abcam, Cambridge, United Kingdom), TNF- receptor 2 (Ab15563; Abcam), IL-6 (Mab206; R&D), mouse IgG (0102-01; Southern Biotechnologies, Birmingham, AL), rabbit IgG (AB-105-C; R&D), antirabbit Alexa488 (A11008
[GenBank]
; Molecular Probes Invitrogen, Paisley, United Kingdom), and antimouse Texas Red (6787; Abcam).
Statistics
These trials adopted a two-stage Gehan design with 19 patients in the first stage. The treatment would be rejected if there were no responses in this stage. The probability of this happening, assuming a true response rate of 15%, was less than 5%. If there were one to three responses in the first stage, no patients would be entered onto the second stage. If there were four, five, or six or more responses in the first stage, then three, five, or six patients, respectively, would be entered onto the second stage. This design ensured an SE of approximately 10% in the estimated response rate. PFS and OS were examined with the Kaplan-Meier product limit method.19
For biomarker analysis, data obtained from ELISA of plasma samples were transformed using natural logarithm before statistical analysis. The statistical analyses performed were the paired t test for samples from the same patient at different time points, and the unpaired t test for samples from different patients and comparisons between studies 1 and 2. Analyses were performed using Prism Version 4.0c for Macintosh (GraphPad Software Inc, San Diego, CA).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAUTHORS' DISCLOSURES OF...AUTHOR CONTRIBUTIONSREFERENCES |
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TNF- Expression in Tumor Samples
Twelve tumor samples were tested (seven clear cell, four papillary, and one chromophobe pathology). TNF- and TNF- receptors 1 and 2 were present in tumor cells in 12 of 12 specimens, and 10 of 12 specimens showed positive staining for IL-6 in the epithelial tumor cells (Fig 1). All 12 samples of normal kidney tissue stained positive for TNF- in renal tubules, with a higher intensity in the proximal tubules (Fig 2A). TNF receptor 1 was detected in normal proximal and distal tubules and TNF receptor 2 was detected in normal tubules, with high intensity in the glomeruli. In eight of 12 normal kidney samples, IL-6 was found in only a few stromal cells (Fig 2A).
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Median duration of disease control (PR + SD) was 7.7 months (range, 5.0 to 40+ months). Median PFS was 3.1 months, median OS was 10 months, and 1-year survival was 39% (95% CI, 18% to 60%).
Study 2. Eighteen patients were assessable for response. Median follow-up was 22 months. Eleven patients achieved SD (61%; 95% CI, 36% to 83%). Seven patients (39%) had documented PD. Median duration of disease control (PR + SD) was 6.2 months (range, 3.5 to 24+ months). Median PFS was 4.1 months, median OS was 13.1 months, and 1-year survival was 67% (95% CI, 40% to 83%).
Toxicity
Study 1.
One patient suffered a grade 3 allergic reaction on his fourth dose characterized by facial flushing, tachycardia, and chest tightness. He rapidly responded to hydrocortisone and chlorpheniramine, but on rechallenge had a similar reaction and was withdrawn from study. Otherwise, infliximab was extremely well tolerated, with no other drug-related toxicity observed. One patient on maintenance (8.4 months of therapy) died after an acute illness. The cause of death was reported as septicemia after pneumonia. The patient was admitted to the hospital within 24 hours of developing respiratory symptoms and died 48 hours later despite intravenous antibiotics and all supportive measures. There was no neutropenia and no positive blood cultures. No postmortem was performed.
Study 2. Toxicity was minimal. Grade 1 toxicity included infusion reaction with flushing (one patient), mucositis (two patients), fatigue (one patient), headache (one patient), myalgia (one patient), peripheral edema (one patient), and anemia (one patient). Grade 2 toxicity included infection (one patient) and anemia (one patient). No patient discontinued treatment or reduced dose due to toxicity.
Plasma Biomarkers
Comparison of baseline biomarkers between study 1 and 2 showed significantly higher TNF- levels in study 2 (P < .01, unpaired t test with Welch's correction; Fig 3A), but no differences in baseline levels of plasma IL-6 and CCL2 (data not shown).
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24 hours after infliximab infusion, which increased before the next dose, and afterward decreased again (Fig 3C). Combined data from both studies showed a significant decrease of plasma CCL2 levels 1 week after treatment (P < .001, paired t test; Fig 3D). There were no significant changes in plasma levels of IL-6, VEGF, or CXCL12 after treatment (data not shown).
Biomarker Changes: Response
We compared biomarker levels in PR and SD patients to those in PD patients. In PD patients, plasma TNF- levels at baseline were significantly higher in both studies combined (P < .05, unpaired t test; Fig 4A). Plasma CCL2 levels were significantly higher before doses 2 and 3 in study 2 (P < .05, unpaired t test; Fig 4B). In study 1 there was a similar pattern, but it was not statistically significant. Analysis of plasma IL-6 showed no difference between patients who did or did not experience disease progression (data not shown).
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12 v > 12 months). Higher plasma levels of TNF-, IL-6, and CCL2 were associated with survival less than 12 months. In both studies plasma TNF- levels were higher in patients with the poorer survival (Figs 5A and 5B). This was statistically significant in study 2 before dose 3 (P < .05, unpaired t test; Fig 5B). In study 1, higher levels of IL-6 were associated with a shorter survival at all time points, and were statistically significant at baseline (P < .05, unpaired t test; Fig 5C). No differences in IL-6 levels were seen between survival groups in study 2 (Fig 5D). Levels of CCL2 were higher in patients surviving less than 12 months (Figs 5E and 5F), and were statistically significant at week 1 and before dose 2 in study 2 (P < .01, unpaired t test; Fig 5F).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAUTHORS' DISCLOSURES OF...AUTHOR CONTRIBUTIONSREFERENCES |
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as a target in RCC in two phase II studies of the anti–TNF- antibody infliximab. In study 1, three PRs and three SDs were seen. Median duration of disease control in these six patients was 7.7 months, with one patient still receiving infliximab after 40+ months. In study 2, although there were no PRs, 11 of 18 patients achieved SD. Median duration of disease control in these 11 patients was 6.2 months, with two patients still receiving infliximab after 22+ and 24+ months. Overall, 46% of patients obtained a clinical benefit (PR + SD > 3 months); with higher doses, this clinical benefit increased to 61% of patients. The behavior of RCC is unpredictable and can be markedly indolent. Our results are likely to be clinically relevant because all patients had documented PD before study entry. For patients who achieved SD, 12 were available for review. Eight patients (67%) had PD according to Response Evaluation Criteria in Solid Tumors. In the other four patients, the degree of growth was 17%, 10%, 7%, and 5% when the baseline scan was compared with the preceding scan. Furthermore, Motzer et al20 described survival at 1 year as 76%, 49%, and 11% for those in favorable-, intermediate-, and poor-risk categories, respectively. In our two studies, the survival in the combined data set at 1 year was 90%, 42%, and 34% for the favorable-, intermediate-, and poor-risk categories, respectively. These results are encouraging and suggest that infliximab is active in RCC.
The clinical benefit must be assessed in the context of disease progression before study entry, especially given that there was minimal toxicity associated with this treatment. It is possible that anti–TNF- therapy may even help constitutional symptoms such as cachexia.3 The only note of caution is that one patient died as a result of non-neutropenic sepsis; infection is a complication of infliximab.
All of our patients who achieved a PR (including the patient who had a possible late response) previously experienced rapid disease progression after biochemotherapy. The combination of IFN , IL-2, and fluorouracil, like other IL-2–based therapies, induces high levels of TNF-,21 which can stimulate the growth of RCC cells22 through induction of nuclear factor-
B and MEK/ERK signaling pathways. Our responding patients may have had tumors with a mutation of von Hippel-Lindau (VHL) gene (present in 85% of RCC) and thus activated hypoxia-inducible factor and nuclear factor-B signaling. This explains their rapid growth on biochemotherapy and response to anti–TNF- therapy, similar to our thalidomide study in which two of three patients who had a PR to thalidomide had also experienced rapid progression while receiving IFN /IL-2 therapy.6
Plasma levels of TNF- decreased within 1 hour and increased after each infusion of infliximab. This is consistent with previous data and is believed to be due to the ELISA detecting biologically inactive infliximab–TNF- complexes.23 Alternatively, TNF- production may increase, compensating for depleted TNF-. We believe this is unlikely because plasma levels of the TNF-–inducible chemokine CCL2 decline during treatment.
Coexpression of TNF- and its receptors in RCC cells could result in autocrine- and/or paracrine-stimulated growth. Binding of TNF- to its receptors is known to induce the expression of genes such as CCL2,24 IL6,25 and VEGF.26 CCL2 is expressed by tumor and stromal cells; it facilitates tumor cell growth and survival,27 and recruits monocytes that secrete growth factors including VEGF.28 Although we and others29 have confirmed expression of IL-6 in RCC, plasma IL-6 was not reduced by infliximab, suggesting a TNF-–independent IL-6 regulation.
Higher levels of TNF- at baseline and of CCL2 during treatment were associated with PD. Higher levels of TNF-, IL-6, and CCL2 correlated with poor survival (< 12 months). A phase I study treating advanced cancer patients with infliximab also correlated higher baseline levels of TNF- and CCL2 with PD (Brown et al, submitted for publication). Thus, plasma levels of cytokines/chemokines may be both predictive and prognostic factors in cancer patients treated with anti–TNF-.
There are several possible mechanisms of action for infliximab. Neutralization of soluble and membrane-bound TNF- may inhibit tumor cell proliferation, survival, and/or induce apoptosis of TNF-–dependent cells through cytokine deprivation.30 This is supported by our observation that low circulating TNF- concentrations and administration of higher doses of infliximab both correlate with increased disease stabilization. In patients with higher circulating TNF-, all available infliximab might bind to circulating TNF-, resulting in less antibody reaching the cellular target. Infliximab may also kill TNF-–expressing cells by crosslinking transmembrane TNF-, leading to apoptosis by reverse signaling or antibody-facilitated cell death.30 We believe it more likely that infliximab modulates cytokine-dependent communication between cells rather than direct cytotoxicity. This is supported by slow response to treatment, stabilization of disease rather than rapid tumor shrinkage, and downregulation of circulating CCL2 1 week after TNF- is neutralized.
These clinical data are supported by recent results from our laboratory, where autocrine production of TNF- by ovarian cancer cells stimulated a constitutive network of other cytokines, angiogenic factors, and chemokines that promoted tumor growth.31
Finally, anti–TNF- agents such as infliximab may be effective in combination with other targeted agents, particularly given their low toxicity profile. Significant activity has been demonstrated for the tyrosine kinase inhibitors32,33 temsirolimus34 and bevacizumab35 in patients with advanced renal cancer. Dual inhibition of separate signaling pathways in tumor cells holds promise as a therapeutic strategy.
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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAUTHORS' DISCLOSURES OF...AUTHOR CONTRIBUTIONSREFERENCES |
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Employment: Robert Corringham, Centocor R&D Inc; Mark DeWitte, Centocor Inc/Johnson & Johnson Leadership: Robert Corringham, Centocor Inc; Mark DeWitte, Centocor Inc/Johnson & Johnson Consultant: Kate Hall, Centocor Inc; Tim Eisen, Centocor Inc; Frances Balkwill, Centocor Inc; Martin Gore, Centocor Inc Stock: Robert Corringham, Centocor Inc; Mark DeWitte, Centocor Inc/Johnson & Johnson Honoraria: Tim Eisen, Centocor Inc; Frances Balkwill, Centocor Inc/Johnson & Johnson Research Funds: Eva Obermueller, Centocor Inc; Susan Hoare, Centocor Inc; Kellie Charles, Centocor Inc; Tim Eisen, Centocor Inc; Frances Balkwill, Centocor Inc; Martin Gore, Centocor Inc Testimony: N/A Other: N/A
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AUTHOR CONTRIBUTIONS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAUTHORS' DISCLOSURES OF...AUTHOR CONTRIBUTIONSREFERENCES |
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Financial support: Robert Corringham, Mark DeWitte
Administrative support: Nick R. Maisey, Kim Edmonds, Kate Hall, Martin Gore
Provision of study materials or patients: Nick R. Maisey, David Chao, Eleni Timotheadou, Tim Eisen, Robert Corringham, Mark DeWitte, Martin Gore
Collection and assembly of data: Nick R. Maisey, Tim Eisen
Data analysis and interpretation: Michelle L. Harrison, Eva Obermueller, Nick R. Maisey, Susan Hoare, Kim Edmonds, Ningfeng F. Li, David Chao, Kate Hall, Kellie Charles, Roger Ahern, Tim Eisen, Robert Corringham, Mark DeWitte, Frances Balkwill, Martin Gore
Manuscript writing: Michelle L. Harrison, Eva Obermueller, Kim Edmonds, Kate Hall, Chooi Lee, Tim Eisen, Robert Corringham, Mark DeWitte, Frances Balkwill, Martin Gore
Final approval of manuscript: Michelle L. Harrison, Eva Obermueller, Nick R. Maisey, Susan Hoare, Kim Edmonds, Ningfeng F. Li, David Chao, Kate Hall, Chooi Lee, Eleni Timotheadou, Kellie Charles, Roger Ahern, D. Mike King, Tim Eisen, Robert Corringham, Mark DeWitte, Frances Balkwill, Martin Gore
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ACKNOWLEDGMENTS |
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NOTES |
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M.L.H. and E.O. contributed equally to this work.
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology Meeting, June 5-8, 2004, New Orleans, LA.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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REFERENCES |
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33. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115-124, 2007
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Submitted March 1, 2007; accepted July 16, 2007.
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T. Das, G. Sa, C. Hilston, D. Kudo, P. Rayman, K. Biswas, L. Molto, R. Bukowski, B. Rini, J. H. Finke, et al. GM1 and Tumor Necrosis Factor-{alpha}, Overexpressed in Renal Cell Carcinoma, Synergize to Induce T-Cell Apoptosis Cancer Res., March 15, 2008; 68(6): 2014 - 2023. [Abstract] [Full Text] [PDF]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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As a New Target for Renal Cell Carcinoma: Two Sequential Phase II Trials of Infliximab at Standard and High Dose
