Idiotype Vaccination in Human Myeloma: Generation of Tumor-Specific Immune Responses After High-Dose Chemotherapy

Abstract

Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id-specific delayed-type hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH specificity was confirmed in 1 patient by investigating the reactivity to synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy chain. None of the patients generated soluble immune responses to Id, whereas the generation of soluble and cellular immune responses to KLH was observed in 100% and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient failed to finish owing to progression of disease. Freedom from disease progression (FFDP), measured from the date of first Id/KLH injection to the date of first treatment after vaccination or last follow-up, ranged from 9 to 36 months. These data indicate that the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation. It remains to be determined whether generation of Id-specific immune responses can reduce the relapse rate of patients with minimal residual disease.

Activated γδ T cells express the natural cytotoxicity receptor natural killer p44 and show cytotoxic activity against myeloma cells

“…This is of particular interest, as multiple myeloma is still an incurable disease for the vast majority of patients. Despite promising in vitro results, clinical investigations concerning potential immunotherapeutic strategies including idiotype and dendritic cells (DC) vaccination have been unsatisfying [25][26][27][28]. A study published recently investigated γδ T cells as effector cells in the treatment of myeloma and lymphoma, confirming the role of γδ T cells as potential effector cells in the immunotherapy of multiple myeloma [29].…”

Optimizing dendritic cell‐based immunotherapy in multiple myeloma

“…For the past decade, idiotype-based immunotherapy has been actively explored in B-cell malignancies such as follicular B-cell lymphoma and MM, for the purpose of developing an additional therapy that can be used to control or eradicate the minimal residual disease after high-dose chemotherapy in patients (Kwak et al, 1992;Bergenbrant et al, 1996;Hsu et al, 1997;Ö sterborg et al, 1998;Massaia et al, 1999;Bendandi et al, 1999). The results from these studies clearly demonstrated that idiotype-specific immunity can be generated in many patients, including those with smouldering disease (Bergenbrant et al, 1996;Ö sterborg et al, 1998) and also those with advanced disease after high-dose chemotherapy (Lim & Bailey-Wood, 1999;Massaia et al, 1999;Reichardt et al, 1999;Liso et al, 2000). However, despite the promising results obtained in B-cell lymphoma (Hsu et al, 1996(Hsu et al, , 1997Bendandi et al, 1999), a clinical antitumour response has only been anecdotally observed in vaccinated myeloma patients (Ö sterborg et al, 1998; this study).…”

Severe and long‐lasting disruption of T‐cell receptor diversity in human myeloma after high‐dose chemotherapy and autologous peripheral blood progenitor cell infusion

“…We have conducted a vaccination trial in MM patients in complete remission after high-dose chemotherapy and PBPC transplantation. The vaccines generated idiotype-specific and long-lasting T-cell immune responses in most patients (Massaia et al, 1999), but did not eliminate residual tumour cells. In contrast, idiotype vaccines produce regression in lymphoma patients (Kwak et al, 1992;Hsu et al, 1996Hsu et al, , 1997, even at the stage of minimal residual disease (Bendandi et al, 1999).…”

“…However, residual tumour cells are invariably detected in the remission phase (Corradini et al, 1995;Bakkus et al, 1996), and all patients ultimately relapse and die of their disease. Vaccine-based strategies are currently under investigation to induce a tumour-specific immune response during the remission phase and improve the clinical outcome (Massaia et al, 1999;Reichardt et al, 1999). The remission phase is regarded as the most appropriate setting for immune interventions, but a full recovery of immune function occurs very gradually and may take up to 1 year or more after autologous transplantation (Guillaume et al, 1998).…”