Successful cross-presentation of allogeneic myeloma cells by autologous alpha-type 1-polarized dendritic cells as an effective tumor antigen in myeloma patients with matched monoclonal immunoglobulins

Abstract

For wide application of a dendritic cell (DC) vaccination in myeloma patients, easily available tumor antigens should be developed. We investigated the feasibility of cellular immunotherapy using autologous alpha-type 1-polarized dendritic cells (αDC1s) loaded with apoptotic allogeneic myeloma cells, which could generate myeloma-specific cytotoxic T lymphocytes (CTLs) against autologous myeloma cells in myeloma patients. Monocyte-derived DCs were matured by adding the αDC1-polarizing cocktail (TNFα/IL-1β/IFN-α/IFN-γ/poly-I:C) and loaded with apoptotic allogeneic CD138(+) myeloma cells from other patients with matched monoclonal immunoglobulins as a tumor antigen. There were no differences in the phenotypic expression between αDC1s loaded with apoptotic autologous and allogeneic myeloma cells. Autologous αDC1s effectively took up apoptotic allogeneic myeloma cells from other patients with matched subtype. Myeloma-specific CTLs against autologous target cells were successfully induced by αDC1s loaded with allogeneic tumor antigen. The cross-presentation of apoptotic allogeneic myeloma cells to αDC1s could generate CTL responses between myeloma patients with individual matched monoclonal immunoglobulins. There was no difference in CTL responses between αDC1s loaded with autologous tumor antigen and allogeneic tumor antigen against targeting patient's myeloma cells. Our data indicate that autologous DCs loaded with allogeneic myeloma cells with matched immunoglobulin can generate potent myeloma-specific CTL responses against autologous myeloma cells and can be a highly feasible and effective method for cellular immunotherapy in myeloma patients.

Vaccination of multiple myeloma: Current strategies and future prospects

“…They investigated the possibility of DC therapy using autologous DCs loaded with apoptotic allogeneic myeloma cells from the matched monoclonal subtype of myeloma patients and showed that the CTL generated by these tumor antigens loaded DCs could generate myeloma-specific CTLs against autologous myeloma cells in patients with MM [109].…”

Cellular Immunotherapy Using Dendritic Cells Against Multiple Myeloma

“…The success of using an allogeneic myeloma cell line as tumor antigen led to the possibility that allogeneic myeloma cells could be also used as a viable source of tumor antigen in the context of appropriate major MHC alleles to autologous CTLs. We investigated the possibility of DC therapy using autologous DC loaded with apoptotic allogeneic myeloma cells from the matched monoclonal subtype of myeloma patients and showed that the CTL generated by these tumor antigens loaded-DCs could generate myeloma-specific CTLs against autologous myeloma cells in patients with MM (Yang et al, 2011). These findings suggested that the allogeneic matching monoclonal immunoglobulin subtype of myeloma is an effective tumor antigen capable of inducing functional CTLs against patients' own tumor cells.…”

“…In an attempt to increase DC potency using cytokine combinations, -type-1-polarized DCs (DC1s) that are induced to mature using the DC1-inducing cytokine cocktail IL-1, TNF-, IFN-, IFN-, and polyinosinic:polycytidylic acid [poly(I:C)]) has been developed to generate strong functional CTLs in several diseases, on average 20-fold higher compared to sDCs Mailliard et al, 2004). Recently, we successfully generated DC1s from a patient with MM with high expression of costimulatory molecules, significant production of IL-12p70, and potent generation of myeloma specific CTLs (Yang et al, 2010(Yang et al, , 2011. The potential of polarized DC1s to produce IL-12 has important implications for the use of DCs as cancer vaccines.…”

“…The selected antigen should possess the best characteristics to induce high cross presentation, be tumor specific, be easily available, but be unable to induce immune suppression. Whole tumor antigens is the best tumor antigen, which has been selected by many investigators including myeloma cell lysates (Kortylewski et al, 2005;Lee et al, 2007;Nefedova et al, 2005;Nefedova & Gabrilovich, 2007;, apoptotic bodies from myeloma cell line (Lee et al, 2007;Yang et al, 2010), and apoptotic allogeneic myeloma cells from other patients with matched subtype (Yang et al, 2011). In practical terms, there are a number of patients with MM, who have less than 50% of myeloma cells in the bone marrow at the time of diagnosis or during progression of the disease.…”

“…In contrast, DCs loaded with antigens derived from whole tumor cells can improve the antitumor response and that limits the risk for immunological escape. There have been increasing reports of these alternative approaches, such as DCs pulsed with myeloma lysates (Hayashi et al, 2003;Lee et al, 2007;Wen et al, 2002), DCs pulsed with myeloma apoptotic bodies (Nguyen- Yang et al, 2010;Yang et al, 2011), DCs transfected with myeloma-derived RNA , DCs pulsed with myeloma-derived HSP gp96 (Qian et al, 2005;Qian et al, 2009), or DC-myeloma cell hybrids (Gong et al, 2002;Hao et al, 2004;Vasir et al, 2005). These techniques have the advantage of allowing the presentation of multiple epitopes to MHC on DCs, therefore can induce polyclonal T cell response from many potentially unknown TAAs and reduce the probability of immune escape by single TAA.…”