Idiotype Based Protein Vaccines for Myeloma

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Our group at the Karolinska Institute, Stockholm, Sweden, was the first to introduce active immunization of myeloma patients with Id proteins (72,73). Having considered that immunotherapy may work better in immunocompetent patients with a low tumor burden, we targeted untreated patients with early disease. In our first pilot study, we recruited and immunized five previously untreated patients with stages I-III MM with the autologous Id protein precipitated in an aluminum phosphate suspension (72). In three patients, an anti-Id T-cell response, detected by enumeration of IFN-y- and IL-2-secret-ing cells by ELISPOT assay, was amplified 1.9- to fivefold during the immunization. The number of B cells secreting anti-Id antibodies also increased in these three patients, and two of the three patients had a gradual decrease of blood CD19+ B cells. However, the induced T-cell response was transient and was eliminated during repeated immunization. The disease was stable in all patients, and no side effects or clinical response were noted.

Number of cells

Fig. 2. Representative proliferative response (cpm) of a tumor lysate-specific CTL line from an MM patient in response to DCs pulsed with autologous tumor lysate (Auto-Lysate-DC) or Id protein (Auto-Id-DC), or autologous primary myeloma cells (Auto-PC). Controls include DCs alone (Auto-DC) and DCs pulsed in allogeneic tumor lysate from another patient (Allo-Lysate-DC).

Number of cells

Fig. 2. Representative proliferative response (cpm) of a tumor lysate-specific CTL line from an MM patient in response to DCs pulsed with autologous tumor lysate (Auto-Lysate-DC) or Id protein (Auto-Id-DC), or autologous primary myeloma cells (Auto-PC). Controls include DCs alone (Auto-DC) and DCs pulsed in allogeneic tumor lysate from another patient (Allo-Lysate-DC).

In our second series of the study, immunization was performed by subcutaneous or intradermal injection of Id protein and GM-CSF (73). Five patients with IgG myeloma were treated, and an Id-specific type-1 T-cell response developed in all of them. The response involved both CD8+ and CD4+ subsets and was mainly MHC class I restricted. There was a transient rise in B cells producing IgM anti-idiotypic antibodies in all patients. One patient had a clinical response, defined by a significant decrease in serum Id protein (from 20 g/L to 7 g/L) and normalization of serum Ig levels, which lasted for more than 1 yr after commencement of immunization. Although these studies involved a limited number of patients, the results clearly indicated that Id protein vaccination, especially in combination with GM-CSF, was able to induce specific anti-Id cellular and humoral immune responses, which were occasionally accompanied by a clinical response in treated patients.

Other clinical settings for immunotherapy could be minimal residual disease status achieved by high-dose chemotherapy and early host immunologic recovery following stem cell transplantation. These are supported by a study from Massaia and coworkers (74) showing that Id vaccination of myeloma patients with minimal residual disease was able to induce a strong Id-specific cellular immunity in many of the patients. In their study, 12 patients who had been treated with high-dose chemotherapy followed by stem-cell support received Id-KLH vaccines and a low dose of GM-CSF or IL-2. In most of the patients, the interval between the completion of prior high-dose therapy and vaccination was only 2-3 mo. Generation of Id-specific T-cell proliferative responses was documented in only two cases; however, a positive, Id-specific, delayed-type hypersensitivity (DTH) skin test reaction was observed in 8 of the 10 patients studied. The induction of humoral and cellular immune responses to KLH was observed in 100% and 80% of the patients, respectively, suggesting that the majority of patients shortly after high-dose therapy and stem-cell transplantation were already able to mount immune responses to KLH. Collectively, these results indicate that immunization of myeloma patients with the

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