Long-term Idiotype Vaccination Combined with Interleukin-12 (IL-12), or IL-12 and Granulocyte Macrophage Colony-Stimulating Factor, in Early-Stage Multiple Myeloma Patients

Abstract

Purpose and Experimental Design: Twenty-eight patients with immunoglobulin G myeloma stages I to II were immunized i.d. over 110 weeks with autologous M protein combined with interleukin-12 (IL-12; n = 15) or with IL-12 and granulocyte macrophage colony-stimulating factor (GM-CSF; n = 13). Idiotype-specific T-cell responses were assessed by [ 3 H]thymidine incorporation, enzyme-linked immunospot assay, and delayed-type hypersensitivity reaction. Results: Based on these three assays, idiotype-specific immune responses were noted in 5 of 15 (33%) patients in the IL-12 group and in 11 of 13 (85%) patients in the GM-CSF/IL-12 group (P < 0.01). Immune response was seen only in patients with M-component concentration of <50 g/L. Three of 16 (19%) responders showed a gradually increasing idiotype-specific T-cell response, whereas 11 of 16 (69%) patients showed initial response, which then disappeared rapidly; the latter pattern was frequently associated with subsequent progressive disease. Immune nonresponse was associated with an increase in the numbers of CD4 + /CD25 + cells (regulatory T cells), which was absent in responding patients. Median time to progression for immune responders (n = 16) was 108 weeks compared with 26 weeks for nonresponders (n = 12; P = 0.03). Conclusions: These results indicate that idiotype immunization of myeloma patients with GM-CSF and IL-12 may induce specific T-cell response more frequently than with IL-12 alone and that immune response may correlate with time to progression and nonresponse with increased numbers of regulatory T cells.

Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry

“…idiotypic vaccination in MM). 26,27 Interestingly, our study showed that LTDC-MM patients have lower numbers of Treg cells than do symptomatic MM patients, particularly in the BM. Despite a large body of evidence that points to increased numbers and a functionally effective status of Treg cells in both hematologic and non-hematologic malignancies, 28 the results reported in MM are controversial, which is probably related to the different methodologies and techniques used to identify the cells.…”

The bone marrow of myeloma patients is steadily inhabited by a normal-sized pool of functional regulatory T cells irrespectiveof the disease status

“…Indeed, idiotype vaccination combined with IL-12 or IL-12 and GM-CSF 30 and the injection of cytokine-matured dendritic cells 31 have been reported to increase Tregs frequency in MM patients, providing further explanation as to why these strategies have fallen short of clinical expectations. More recently, thalidomide and lenalidomide have also been shown to increase the frequency and function of Tregs in MM, and lenalidomide, in association with dexamethasone, has been reported to increase Tregs and concurrently decrease the effector functions of T and NK cells.…”

Immunotherapy of cancer by IL-12-based cytokine combinations

“…GM-CSF/IL-12 has been used in multiple myeloma patients, where the combined actions of both cytokines led to a reduction in circulating tumor B cells [75][76][77]. Idiotype-specific immune responses were observed in the majority (75-85%) of patients treated with both GM-CSF and IL-12, as compared to 20-30% of the patients treated with IL-12 alone, and were inversely correlated with the frequency of CD4 + /CD25 + T regulatory cells.…”