PURPOSE: The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)-bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted. EXPERIMENTAL DESIGN: The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m(2) (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9). RESULTS: Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcgammaR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy. CONCLUSIONS: rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.
PURPOSE: The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)-bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted. EXPERIMENTAL DESIGN: The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m(2) (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9). RESULTS:Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcgammaR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy. CONCLUSIONS:rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.
Authors: Maximillian Rosario; Bai Liu; Lin Kong; Lynne I Collins; Stephanie E Schneider; Xiaoyue Chen; Kaiping Han; Emily K Jeng; Peter R Rhode; Jeffrey W Leong; Timothy Schappe; Brea A Jewell; Catherine R Keppel; Keval Shah; Brian Hess; Rizwan Romee; David R Piwnica-Worms; Amanda F Cashen; Nancy L Bartlett; Hing C Wong; Todd A Fehniger Journal: Clin Cancer Res Date: 2015-09-30 Impact factor: 12.531
Authors: Eric F Zhu; Shuning A Gai; Cary F Opel; Byron H Kwan; Rishi Surana; Martin C Mihm; Monique J Kauke; Kelly D Moynihan; Alessandro Angelini; Robert T Williams; Matthias T Stephan; Jacob S Kim; Michael B Yaffe; Darrell J Irvine; Louis M Weiner; Glenn Dranoff; K Dane Wittrup Journal: Cancer Cell Date: 2015-04-13 Impact factor: 31.743
Authors: Alice L Yu; Andrew L Gilman; M Fevzi Ozkaynak; Wendy B London; Susan G Kreissman; Helen X Chen; Malcolm Smith; Barry Anderson; Judith G Villablanca; Katherine K Matthay; Hiro Shimada; Stephan A Grupp; Robert Seeger; C Patrick Reynolds; Allen Buxton; Ralph A Reisfeld; Steven D Gillies; Susan L Cohn; John M Maris; Paul M Sondel Journal: N Engl J Med Date: 2010-09-30 Impact factor: 91.245
Authors: Evdoxia Hatjiharissi; Lian Xu; Daniel Ditzel Santos; Zachary R Hunter; Bryan T Ciccarelli; Sigitas Verselis; Michael Modica; Yang Cao; Robert J Manning; Xavier Leleu; Elizabeth A Dimmock; Alexandros Kortsaris; Constantine Mitsiades; Kenneth C Anderson; Edward A Fox; Steven P Treon Journal: Blood Date: 2007-05-02 Impact factor: 22.113