Abstract
The lymphotoxin-beta receptor (LT beta R) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LT beta R monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LT beta R caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LT beta R activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LT beta R with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers.
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / pathology
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Adenocarcinoma / therapy*
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal / therapeutic use*
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Camptothecin / analogs & derivatives
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Camptothecin / therapeutic use
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Cell Line, Tumor
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / pathology
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Colonic Neoplasms / therapy*
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Combined Modality Therapy
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Drug Synergism
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Immunoglobulin G / immunology
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Immunoglobulin G / therapeutic use
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Immunoglobulin M / immunology
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Immunoglobulin M / therapeutic use
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Irinotecan
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphotoxin beta Receptor / agonists*
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Lymphotoxin beta Receptor / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Random Allocation
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / therapeutic use
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Single-Blind Method
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Uterine Cervical Neoplasms / drug therapy
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Uterine Cervical Neoplasms / pathology
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Uterine Cervical Neoplasms / therapy*
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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Immunoglobulin G
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Immunoglobulin M
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Ltbr protein, mouse
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Lymphotoxin beta Receptor
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Recombinant Fusion Proteins
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Irinotecan
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Camptothecin