Combination Immunotherapy of B-Cell Non-Hodgkin’s Lymphoma with Rituximab and Interleukin-2

Eisenbeis, Charles F.; Grainger, Andrew; Fischer, Beth; Baiocchi, Robert A.; Carrodeguas, Lester; Roychowdhury, Sameek; Chen, Lei; Banks, Amy; Davis, Thomas A.; Young, Donn C.; Kelbick, Nicole; Stephens, Julie; Byrd, John C.; Grever, Michael R.; Caligiuri, Michael A.; Porcu, Pierluigi

doi:10.1158/1078-0432.ccr-04-0525

Cited by 69 publications

(49 citation statements)

References 39 publications

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“…Currently, only phase II studies or preliminary data are available preventing any definitive conclusions (Davis et al, 2000b;Kimby, 2002). Phase I trials combining rituximab with other cytokines such as IL-2, IL-12, granulocyte-colony stimulating factor and granulocyte macrophage colonystimulating factor have shown promising preliminary results that need to be confirmed in phases II trials (van der Kolk et al, 2002;Eisenbeis et al, 2004).…”

Section: Rituximab In Combination With Cytokinesmentioning

confidence: 99%

Rituximab therapy in malignant lymphoma

2007

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Section: Rituximab In Combination With Cytokinesmentioning

confidence: 99%

Rituximab therapy in malignant lymphoma

2007

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“…The addition of human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) may enhance rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) because rIL-2 promotes natural killer (NK) cell expansion (9 -11) and enhances intrinsic NK cell cytotoxicity (11,12). NK cells are large granular lymphocytes that comprise 10% to 15% of peripheral blood lymphocytes (13,14) and mediate ADCC via expression of an activating receptor for the Fc portion of IgG antibodies (13,14).…”

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confidence: 99%

“…Rituximab is thought to exert its antitumor effect through ADCC (7, 8, 15 -17) in addition to complementdependent cytotoxicity (18) and direct induction of apoptosis (19). Indeed, this concept was previously shown in a preclinical mouse model of human B-cell NHL in which the efficacy of rituximab and rIL-2 was synergistic compared with either treatment alone (12).…”

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confidence: 99%

A Phase 2 Study of Rituximab in Combination with Recombinant Interleukin-2 for Rituximab-Refractory Indolent Non-Hodgkin's Lymphoma

Khan

Emmanouilides

Benson³

et al. 2006

Clinical Cancer Research

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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 FcgR 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.

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“…Interleukin-2 therapy has not been fully explored in hematologic malignancies, although there is ample evidence of activity against acute myeloid leukemia [13] and lymphoma [1][2][3][4][5], and evidence that it may be synergistic with rituximab and other agents against lymphoma in mouse [2,7] and man [14][15][16].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, some data suggest that the agent is synergistic with rituximab against human B-cell lymphoma [7]. Intrapleural interleukin-2 has been reported to resolve malignant pleural effusions in patients with mesothelioma [8] and lymphoma [9].…”

mentioning

confidence: 99%