Lymphocyte Activation Gene-3 Fusion Protein Increases the Potency of a Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Cell Immunotherapy

Abstract

Purpose: The purpose of the present study was to evaluate granulocyte macrophage colonystimulating factor (GM-CSF)-secreting tumor cell immunotherapy, which is known to stimulate a potent and long-lasting antigen-specific immune response in combination with lymphocyte activation gene-3 fusion protein (LAG-3Ig), which has been shown to act as an adjuvant for priming T helper type 1and cytotoxicT-cell responses. Experimental Design: Survival and immune monitoring studies were done in the B16 melanoma model. GM-CSF^secreting tumor cell immunotherapy was administered as a single s.c. injection and LAG-3Ig was administered s.c. at the immunotherapy site. Results: The studies reported here show that combining LAG-3Ig with GM-CSF^secreting tumor cell immunotherapy prolonged the survival of tumor-bearing animals compared with animals treated with either therapy alone. Prolonged survival correlated with increased numbers of systemic IFNg-secreting CD8 + Tcells and a significantly increased infiltration of activated effector CD8 + T cells into the tumor. Moreover, an increase in antigen-specific IgG1 humoral responses was detected in serum of animals injected with the combination therapy compared with animals injected with either therapy alone. Conclusion: LAG-3Ig combined with a GM-CSF^secreting tumor cell immunotherapy stimulated both cellular and humoral antitumor immune responses that correlated with prolonged survival in tumor-bearing animals.

Recent advances and hurdles in melanoma immunotherapy

“…Immunomonitoring of responding patients clearly suggests increased tumour specific immunity mediated by both antibodies and specific T cells (Hodi et al., 2008; Klein et al., 2009; Liakou et al., 2008; Yuan et al., 2008). Other potentially useful immunologically active compounds include cytokines (Davis et al., 2009; Kim‐Schulze et al., 2009; Li et al., 2009; Mueller et al., 2008; Shinozaki et al., 2009; Sikora et al., 2009), modulators of key signalling pathways such as STAT3 (Kong et al., 2009), chemotherapy (Nistico et al., 2009) or costimulatory agonists (Gray et al., 2008) such as 4‐1BB (Kim et al., 2008), LAG‐3 (Li et al., 2008), CD40 (Advani et al., 2009; Vonderheide et al., 2007) or chemokines (Loeffler et al., 2009). Reduction, depletion or induction of differentiation of various immunoregulatory cell types would also be synergistic with specific immunotherapy.…”

A Phase I Pharmacokinetic and Biological Correlative Study of IMP321, a Novel MHC Class II Agonist, in Patients with Advanced Renal Cell Carcinoma

“…The LAG-3Ig protein is efficacious as a vaccine adjuvant to inhibit tumor growth in mice grafted s.c. with different tumor cell lines (9,10) and spontaneous carcinogenesis in Her2/neu transgenic mice (11). In particular, the mere s.c. presence of LAG-3 leads to RCC tumor (RENCA) rejection in mice, due to boosted tumor-specific cytotoxic CD8 T-cell responses (9).…”

Novel Antibody-Based Proteins for Cancer Immunotherapy

“…A soluble form of LAG-3, termed LAG3Ig, was generated by genetically fusing DNA encoding the extracellular domain of human LAG-3 and the constant region of human Ig γ1 heavy chain spanning the hinge, C H 2, and C H 3 domains [70]. Binding of LAG3Ig to MHC class II molecules has been reported to act as an adjuvant, driving human immune responses toward a T-helper type 1 (Th1) phenotype [71], and to induce the activation of a large range of human effector cytotoxic cells [72]. In a Phase I clinical trial in metastatic breast carcinoma patients, the addition of LAG3Ig to the standard treatment (paclitaxel), did not induce clinically significant adverse effects, and no anti-LAG3Ig antibodies were detected (which is somewhat expected due to its human origin).…”