Vaccination Strategies in Follicular Lymphoma Shibichakravarthy Kannan, MBBS, PhD, and Sattva S. Neelapu, MD Corresponding author Sattva S. Neelapu, MD Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 903, Houston, TX 77030, USA. E-mail: sneelapu@mdanderson.org Current Hematologic Malignancy Reports 2009, 4: 189–195 Current Medicine Group LLC ISSN 1558-8211 Copyright © 2009 by Current Medicine Group LLC Follicular lymphoma is one of the most immune- responsive cancers. The clonal tumor immunoglobulin expressed on the surface of malignant B cells, termed idiotype, has been used as a tumor-speciic antigen in therapeutic vaccination strategies for follicular lym- phoma and other B-cell malignancies. A number of phase 1 and phase 2 clinical trials have established the safety and immunogenicity of idiotype vaccine in fol- licular lymphoma. Three randomized, double-blind, controlled phase 3 clinical trials have recently been completed to deinitively evaluate the clinical bene- it of idiotype vaccine in follicular lymphoma. This review focuses on the results of these idiotype vaccine trials and discusses potential strategies to enhance the eficacy of vaccines in the future. Introduction It is estimated that non-Hodgkin’s lymphoma (NHL) will be diagnosed in 65,980 patients in the United States in 2009, and an estimated 19,500 will die from NHL. Fol- licular lymphoma, the most common low-grade B-cell lymphoma, comprises 22% of all NHL cases worldwide. More than 85% of patients with follicular lymphoma have advanced-stage disease at the time of initial diagno- sis. Advanced-stage follicular lymphoma has a generally indolent course with a median survival of 8 to 10 years. Although it is highly responsive to various therapies such as chemotherapy, radiation therapy, and/or biologic therapy, advanced disease is characterized by repeated remissions and relapses and is considered incurable with the avail- able treatment options [1]. The recent use of rituximab in combination chemotherapy regimens has improved the response rates, progression-free survival (PFS), and overall survival of patients with follicular lymphoma. However, even these combinations do not appear to be curative, as no plateau in the survival curves has been demonstrated [2–4]. Therefore, novel treatment options are needed to improve clinical outcome in these lymphomas. The natural history of follicular lymphoma, char- acterized by stable disease or spontaneous remissions lasting months to years in a signi icant proportion of patients observed [5], suggests that the immune sys- tem may play a major role in the control of this tumor. This notion is now supported by several recent studies. First, the survival of patients with follicular lymphoma appears to correlate with the gene expression signatures of ini ltrating, nonmalignant immune cells in the tumor [6]. Second, high levels of CD8 + T-cell content in diag- nostic lymph nodes correlates with better prognosis [7]. Third, the presence of an immunosurveillance pattern (CD8 + T cells) correlates with good prognosis, whereas an immune-escape pattern (CD57 + T cells) correlates with poor prognosis [8]. Finally, tumor-speci ic T cells can be easily isolated from the peripheral blood and tumor microenvironment in follicular lymphoma [9,10]. Together, these results suggest that follicular lymphoma is particularly immune-sensitive and they support the development of immunotherapeutic strategies for the treatment of this disease. Idiotype as a Target for Active Immunotherapy As opposed to passive immunotherapy with monoclonal antibodies, active immunotherapy with therapeutic vac- cines has the potential to induce polyclonal humoral and cellular immune responses against one or more targets expressed by the tumor and therefore may minimize the emergence of tumor escape variants. Furthermore, active immunotherapy can generate immunologic memory, which in turn may lead to long-term control of the tumor. A therapeutic cancer vaccine usually comprises tumor- speci ic or tumor-associated antigen, a carrier, and an adjuvant. Follicular lymphoma is characterized by clonal proliferation of B cells expressing an identical immuno- globulin (Ig) on the cell surface. The clonal tumor Ig has unique amino acid sequences, termed idiotype or Id, within the complementarity determining regions (CDRs) of the variable sections of the heavy and light chains. Because of the clonal nature of B-cell malignancies, the