GM-CSF plus rituximab immunotherapy: Translation of biologic mechanisms into therapy for indolent B-cell lymphomas

Abstract

Historically, patients with indolent non-Hodgkin lymphomas (NHL) have been treated with radiotherapy, chemotherapy or a combination of these therapies. The introduction of biologic agents, most notably rituximab, a monoclonal antibody targeting cell-surface CD20 present on B-cell NHL cells, has enhanced patient response rates; however, relapse continues to limit long-term disease-free survival. Recent advances in the treatment of patients with indolent B-cell NHL have taken two directions--combining rituximab with chemotherapy or enhancing rituximab-mediated mechanisms of action. The combination of rituximab with the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) takes the second approach and appears to lead to improved patient responses over rituximab monotherapy without compromising its tolerability profile. GM-CSF functions by increasing the numbers and cytotoxic activity of effector cells, perhaps in part by increasing the expression of some cell surface molecules (i.e., receptors, antigens). The combined biologic effects of GM-CSF and rituximab appear promising in that they might enhance a patient's inherent immune response against malignant cells. The biologic effects of these individual and combined immunotherapeutic agents, with or without chemotherapy, and their translation into patient outcomes are reviewed here.

Tumor-associated macrophages in diffuse large B-cell lymphoma

“…In addition, GM-CSF has pleiotropic effects, 14 and any clinical benefit can be explained by mechanisms other than an increase in macrophage function or number.…”

Prognostic influence of macrophages in patients with diffuse large B-cell lymphoma: a correlative study from a Nordic phase II trial

“…37,39 Administration of GM-CSF or M-CSF activates numerous immune cells, notably granulocytes and monocytes, which express FCγ receptors and are involved in rituximab-mediated antibody-dependent cellular cytotoxicity and phagocytosis. 39,41 Furthermore, GM-CSF can upregulate CD20 expression on lymphoma cells. 42 The concept of GM-CSF-induced immune priming has been successfully used in combination with rituximab monotherapy in patients with relapsed or progressive follicular lymphoma, 43 and recently also tested with R-CHOP in patients with primary DLBCL.…”

Biologic agent activity in chronic lymphocytic leukemia: a framework for future therapies

“…Granulocyte-macrophage colony stimulating factor (GM-CSF) increases the numbers and cytotoxic activity of effector cells by increasing the expression of relevant cell surface molecules such as CD20 [95]. The combined biologic effects of GM-CSF and rituximab appear promising, because GM-CSF increases surface expression of CD20 in CLL potentially rendering it a better target for rituximab [95].…”

“…The combined biologic effects of GM-CSF and rituximab appear promising, because GM-CSF increases surface expression of CD20 in CLL potentially rendering it a better target for rituximab [95]. The combination of GM-CSF and rituximab was evaluated as initial treatment in elderly patients with CLL who either required therapy or were at high risk of progression, based on elevated serum b 2microglobulin levels [96].…”