Kinetics of Immune Responses and Tumor Burden in Patients with Indolent B Cell Lymphomas Receiving Recombinant Idiotype Vaccination as the Sole Treatment.

Abstract

Immunization of patients with B-cell non-Hodgkin's lymphoma with the individual idiotype expressed by the malignant clone can induce tumor-specific immune responses that correlate with improved remission duration and survival rates after cytoreductive chemotherapy. We have developed a production method for a recombinant idiotype vaccine based on expression of Fab fragments in E. coli. Intradermal administration of this vaccine mixed with lipid-based adjuvant and subcutaneous coadministration of GM-CSF has excellent immunogenicity as demonstrated by a high and idiotype-specific immune response rate in a phase I trial in advanced lymphoma patients with a severely impaired immune status (Bertinetti et al., Cancer Research 2006). Of a cohort of 15 patients with newly diagnosed or relapsed indolent B cell malignancies who had not been treated with conventional cytoreductive therapy and received 6 monthly immunizations of this idiotype vaccine, we observed 6 cases (40%) with objective quantitative evidence of tumor regression. 5 of these patients were in primary “watch and wait” situation for indolent NHL, and 1 follicular lymphoma patient had recurrence of nodal disease after a complete remission achieved in the phase I trial. At weeks 0, 8, 24, 36, and 52 after initiation of vaccination, staging examinations were performed including enumeration of circulating tumor cells by quantitative real-time PCR, and immune responses were assessed by ELISPOT and ELISA. Beginning with the 4th vaccination, evidence for reduction of nodal disase was noted in 5 cases, 4 of which achieved an objective partial response after all 6 scheduled immunizations according to standard staging criteria. These patients received continuing vaccinations in intervals of 1–3 months, and no progression has occurred after a follow-up of 9–32 months. Of 6 patients who had detectable lymphoma cells in the peripheral blood, 4 showed a continuous, at least 10fold decrease of the number of circulating lymphoma cells during the course of the vaccination. Two of the partial responders had never evidence for circulating tumor cells. A T cell response to the vaccine developed in 4/5 evaluated patients with evidence of tumor regression and in 3/6 patients without evidence for a clinical response. These cellular responses were maintained at stable levels during the vaccination and continued to be present 6 months after the last vaccination. Humoral immune responses were induced in 5/5 patients with declining tumor burden and in 2/6 non-responders. In 3 cases, the anti-idiotypic antibody titers declined after 6 months. In cases where anti-idiotype antibodies of IgM and IgG isotype occurred, IgM preceded the appearance of IgG. All objective clinical responders mounted a combined cellular and humoral immune response. The temporal association of immune responses with tumor regression provides support for the assumption that recombinant idiotype vaccination in the chosen format may play a causal role for a favorable disease course in previously untreated indolent lymphomas and may hence obviate the need for cytoreductive chemotherapy for extended time periods.