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 Blood, 12 November 2009, Vol. 114, No. 20, pp. 4477-4485.
Prepublished online as a Blood First Edition Paper on September 17, 2009; DOI 10.1182/blood-2009-05-223263.

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LYMPHOID NEOPLASIA

Generation of CD8+ T cell–mediated immunity against idiotype-negative lymphoma escapees

Bindu Varghese1, Adam Widman1, James Do1, Behnaz Taidi1, Debra K. Czerwinski1, John Timmerman2, Shoshana Levy1, and Ronald Levy1

1 Division of Oncology, Department of Medicine, Stanford University School of Medicine, CA; and 2 Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles

We investigated the ability of CpG-oligodeoxynucleotide to generate an anti-tumor CD8+ T-cell immune response and to synergize with passive antibody therapy. For these studies, we generated an antibody against the idiotype on the A20 B-cell lymphoma line. This antibody caused the regression of established tumors, but ultimately the tumors relapsed. The escaping surface IgG-negative tumor cells were resistant to both antibody-dependent cellular cytotoxicity and signaling-induced cell death. Addition of intratumoral CpG to antibody therapy cured large established tumors and prevented the occurrence of tumor escapees. The failure of the combination therapy in mice deficient for CD8+ T cells demonstrates the critical role of CD8+ T cells in tumor eradication. When mice were inoculated with 2 tumors and treated systemically with antibody followed by intratumoral CpG in just one tumor, both tumors regressed, indicating that a systemic immune response was generated. Although antibody therapy can eliminate tumor cells bearing the target antigen, it frequently selects for antigen loss variants. However, when a poly-specific T-cell response was generated against the tumor by intratumoral CpG, even large established tumors were cured. Such an immune response can prevent the emergence of antibody selected tumor escapees and provide long-lasting tumor protection.


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