This clinical trial design provided a unique opportunity to assess whether prior therapy with sorafenib might adversely affect IL-2-induced signal transduction within T cells. This correlative readout is of interest as prior in vitro studies from our group have indicated that a pretreatment with sorafenib may inhibit the subsequent cellular response to IL-2 stimulation ex vivo.17 For these studies, blood samples were available from 6 patients before and after sorafenib administration. The percentage of CD4+ and CD8+ T cells with pSTAT5 was assessed at baseline and 1 hour after IL-2 stimulation during series 1 and series 2. Consistent with prior studies by our group,19 the percentage of CD4+ and CD8+ T cells with pSTAT5 1 hour after IL-2 infusion was elevated as compared with baseline during both series 1 and 2. There was no significant difference in the percentage of pSTAT5-positive CD4+ or CD8+ T cells after IL-2 during series 1 versus series 2 (all P>0.4, Fig. 4). These data suggest that prior therapy with sorafenib may not adversely affect STAT5 signal transduction in T cells after subsequent IL-2 administration. We did not perform the same analysis in individuals who did not go on to receive a second series.
The biomarkers that account for clinical activity associated with HD IL-2 are likely multifactorial and involve changes in multiple immune effector cell compartments or the tumor microenvironment. The study design of the present trial allowed for a unique opportunity to evaluate the effect of prior sorafenib on IL-2-induced pSTAT5 in T cells at a number of prespecified timepoints. Prior preclinical studies from our group indicated that this canonical IL-2 signaling pathway might be inhibited by pretreatment of immune cells with sorafenib, and possibly compromise antitumor effects of exogenous IL-2.17 The data generated in this trial provided preliminary evidence that intracellular IL-2 signaling remained intact in patient T lymphocytes after a course of sorafenib treatment. The lack of an inhibitory effect of sorafenib on T-cell signaling is likely due to the schedule used, whereby the effects of sorafenib-mediated TK inhibition in T cells normalize before subsequent IL-2 therapy.
HD IL-2 remains relevant due to the remarkably durable CRs seen in a select few. In the nearly 20 years since HD IL-2 was approved by the FDA for the treatment of MM and RCC, several investigators have attempted clinical trials combining HD IL-2 with other agents.28–33 These studies demonstrated that the combination was feasible; however, the agents chosen to combine with HD IL-2 had very little single-agent activity. Sorafenib is one of the first in an expanding category of distinct but related agents. Its single-agent activity and nonoverlapping toxicity profile led us to perform this combination trial with HD IL-2. To the best of our knowledge, this is the first report of sorafenib or any other VEGF-TKI being combined with HD-IL-2. Sorafenib combined with lower dose subcutaneous IL-2 has been reported to be safe with no increase in efficacy compared with sorafenib alone.34 Given the safety of our treatment schedule, a phase II trial of this combination seems reasonable. We acknowledge that since this trial was initiated, there exists renewed enthusiasm for immune-based therapy based on new understanding and favorable clinical trial outcomes.35,36
1. Fisher RI, Rosenberg SA, Fyfe G.Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma
.Cancer J Sci Am.2000;6suppl 1S55–S57.
2. Fyfe G, Fisher RI, Rosenberg SA, et al..Results of treatment of 255 patients with metastatic renal cell carcinoma
who received high-dose recombinant interleukin-2 therapy.J Clin Oncol.1995;13:688–696.
3. Zou W.Immunosuppressive networks in the tumour environment and their therapeutic relevance.Nat Rev Cancer.2005;5:263–274.
4. Curiel TJ.Tregs and rethinking cancer immunotherapy.J Clin Invest.2007;117:1167–1174.
5. Sakaguchi S, Sakaguchi N, Shimizu J, et al..Immunologic tolerance maintained by CD25+
regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance.Immunol Rev.2001;182:18–32.
6. Schwartzentruber DJ.Guidelines for the safe administration of high-dose interleukin-2.J Immunother.2001;24:287–293.
7. Escudier B, Eisen T, Stadler WM, et al..Sorafenib
in advanced clear-cell renal-cell carcinoma.N Engl J Med.2007;356:125–134.
8. Llovet JM, Ricci S, Mazzaferro V, et al..Sorafenib
in advanced hepatocellular carcinoma.N Engl J Med.2008;359:378–390.
9. Gian V, Rubin M, Hainsworth JD, et al..Sorafenib
and continued erlotinib or sorafenib
alone in patients with advanced non-small cell lung cancer progressing on erlotinib. A randomized phase II study of the Sarah Cannon Research Institute.Proc Am Soc Clin Oncol.2012;30suppl30abstr 7587.
10. Lam ET, Ringel MD, Kloos RT, et al..Phase II clinical trial of sorafenib
in metastatic medullary thyroid cancer.J Clin Oncol.2010;28:2323–2330.
11. Sabatino M, Kim-Schulze S, Panelli MC, et al..Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy.J Clin Oncol.2009;27:2645–2652.
12. Busse A, Asemissen A, Nonnenmacher A, et al..Immunomodulatory effects of sorafenib
on peripheral immune effector cells in metastatic renal cell carcinoma
.Eur J Cancer.2011;47:690–696.
13. Nagai H, Mukozu T, Matsui D, et al..Sorafenib
prevents escape from host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma.Clin Dev Immunol.2012;2012:607851.
14. Desar IM, Jacobs JF, Hulsbergen-vandekaa CA, et al..Sorafenib
reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma
patients.Int J Cancer.2011;129:507–512.
15. Florcken A, Takvorian A, Van Lessen A, et al..Sorafenib
, but not sunitinib, induces regulatory T cells in the peripheral blood of patients with metastatic renal cell carcinoma
16. Hipp MM, Hif N, Walter S, et al..Sorafenib
, but not sunitinib, affects function of dendritic cells and induction of primary immune responses.Blood.2008;111:5610–5620.
17. Raig ET, Kondadasula SV, Olencki T, et al..The Raf Kinase Inhibitor Sorafenib
Inhibits Jak-STAT Signal Transduction in Human Immune Cells.2008.San Diego, CA:American Association for Cancer Research Annual MeetingAbstract # 6214.
18. Escudier B, Eisen T, Stadler WM, et al..Sorafenib
for treatment of renal cell carcinoma
: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial.J Clin Oncol.2009;27:3312–3318.
19. Varker KA, Kondadasula SV, Go MR, et al..Multiparametric flow cytometric analysis of signal transducer and activator of transcription 5 phosphorylation in immune cell subsets in vitro and following interleukin-2 immunotherapy.Clin Cancer Res.2006;12:5850–5858.
20. Motzer RJ, Mazumdar M, Bacik J, et al..Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma
.J Clin Oncol.1999;17:2530–2540.
21. Therasse P, Arbuck SG, Eisenhauer EA, et al..New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.J Natl Cancer Inst.2000;92:205–216.
22. Lesinski GB, Kondadasula SV, Crespin T, et al..Multiparametric flow cytometric analysis of inter-patient variation in STAT1 phosphorylation following interferon Alfa immunotherapy.J Natl Cancer Inst.2004;96:1331–1342.
23. Ko JS, Zea AH, Rini BI, et al..Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma
patients.Clin Cancer Res.2009;15:2148–2157.
24. Cho DC, Puzanov I, Regan MM, et al..Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted therapy in patients with advanced renal cell carcinoma
25. Flaherty KT, Schiller J, Schuchter LM, et al..A phase I trial of the oral, multikinase inhibitor sorafenib
in combination with carboplatin and paclitaxel.Clin Cancer Res.2008;14:4836–4842.
26. Flaherty KT, Lee SJ, Zhao F, et al..Phase III trial of carboplatin and paclitaxel with or without sorafenib
in metastatic melanoma
.J Clin Oncol.2013;31:373–379.
27. Pecuchet N, Lebbe C, Mir O, et al..Sorafenib
in advanced melanoma
: a critical role for pharmacokinetics?Br J Cancer.2012;107:455–461.
28. Demchak PA, Mier JW, Robert NJ, et al..Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma
: a pilot study.J Clin Oncol.1991;9:1821–1830.
29. Trehu EG, Mier JW, Dubois JS, et al..Phase I trial of interleukin 2 in combination with the soluble tumor necrosis factor receptor p75 IgG chimera.Clin Cancer Res.1996;2:1341–1351.
30. Atkins MB, Redman B, Mier J, et al..A phase I study of CNI-1493, an inhibitor of cytokine release, in combination with high-dose interleukin-2 in patients with renal cancer and melanoma
.Clin Cancer Res.2001;7:486–492.
31. Gollob JA, Sciambi CJ, Peterson BL, et al..Phase I trial of sequential low-dose 5-aza-2′-deoxycytidine plus high-dose intravenous bolus interleukin-2 in patients with melanoma
or renal cell carcinoma
.Clin Cancer Res.2006;12:4619–4627.
32. Schwartzentruber DJ, Lawson DH, Richards JM, et al..gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma
.N Engl J Med.2011;364:2119–2127.
33. Atchison E, Eklund J, Martone B, et al..A pilot study of denileukin diftitox (DD) in combination with high-dose interleukin-2 (IL-2) for patients with metastatic renal cell carcinoma
34. Procopio G, Verzoni E, Bracarda S, et al..Sorafenib
with interleukin-2 vs. sorafenib
alone in metastatic renal cell carcinoma
: the ROSORC trial.Br J Cancer.2011;104:1256–1261.
35. Brahmer JR, Tykodi SS, Chow LQ, et al..Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.N Engl J Med.2012;366:2455–2465.
36. Mellman I, Coukos G, Dranoff G.Cancer immunotherapy comes of age.Nature.2011;480:480–489.