Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Abstract

High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is a standard treatment for patients with multiple myeloma. However, lymphocyte reconstitution is impaired after HDM. Recent work has suggested that the lymphopenia period occurring after various immunosuppressive or chemotherapy treatments may provide an interesting opportunity for adoptive antitumor immunotherapy. The objective of this study was to determine an immunotherapy window after HDM and ASCT, evaluating T cell lymphopenia, and measuring circulating immune cytokine concentrations in patients with multiple myeloma. The counts of T cell subpopulations reached a nadir at day 8 post-ASCT (day 10 post-HDM) and recovered by day 30. IL-6, IL-7, and IL-15 plasma levels increased on a median day 8 post-ASCT, respectively, 35-fold, 8-fold, and 10-fold compared with pre-HDM levels (p ≤ 0.05). The increases in IL-7 and IL-15 levels were inversely correlated to the absolute lymphocyte count, unlike monocyte or myeloid counts. Furthermore, we have shown that CD3 T cells present in the ASC graft are activated, die rapidly when they are cultured without cytokine in vitro, and that addition of IL-7 or IL-15 could induce their survival and proliferation. In conclusion, the early lymphodepletion period, occurring 4–11 d post-HDM and ASCT, is associated with an increase of circulating immune cytokines and could be an optimal window to enhance the survival and proliferation of polyclonal T cells present in the ASC autograft and also of specific antimyeloma T cells previously expanded in vitro.

Alkylating Agent Melphalan Augments the Efficacy of Adoptive Immunotherapy Using Tumor-Specific CD4+ T Cells

“…Supporting this notion, Condomines et al indicated that the early lymphodepletion period after high-dose melphalan and ASCT in myeloma patients represents a window for adoptive immunotherapy (53). Along this line, it has been shown that post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells improved CD4 + and CD8 + T-cell counts and led to the induction of clinically relevant immunity in myeloma patients (54, 55).…”

Transfer of influenza vaccine–primed costimulated autologous T cells after stem cell transplantation for multiple myeloma leads to reconstitution of influenza immunity: results of a randomized clinical trial

“…30 Similarly, high levels of interleukin-6 could support B-cell recovery. 47 The global expansion of central memory CD8 T cells generically (Figure 3) may explain the previously observed increase in CMV responsiveness seen after autologous T-cell infusion but does not account for the enhanced response to the inactivated influenza vaccine seen exclusively in the primed patients. 29,48 The CD4 T cells were less tolerant of melphalan and, in the absence of a primed post-ASCT infusion, may not have been able to supply sufficient help for B-cell differentiation.…”

Immunostimulatory Effects of Melphalan and Usefulness in Adoptive Cell Therapy with Antitumor CD4+ T Cells

“…It has been shown that myeloma patients had increased plasma level of immune cytokines, including IL-6, IL-7 and IL-15, following HDM and ASCT, and the presence of IL-7 and IL-15 may contribute to the survival and activation of CD3 + T cells present in the SCT graft. 37 Along this line, the recent report by Dudek-Perić et al 39 showed that limb perfusion of melanoma patients with melphalan led to increased release of IL-1β, IL-6, and IL-8 in the locoregional sera of patients. In a prophylactic vaccination mouse model, the authors showed that melphalan administration in vivo could stimulate a CD8 + T-cell-dependent protective antitumor response.…”

“…35 Without ASCT, high-dose melphalan causes severe myelosuppression, which affects cells of the immune origin including T and B lymphocytes and NK cells. 36,37 …”