Chemoimmunotherapy Reduces the Progression of Multiple Myeloma in a Mouse Model

Abstract

Multiple myeloma (MM) is a B-cell malignancy characterized by clonal proliferation of malignant plasma cells in the bone marrow. Recently, we showed a correlation between increased ratios of functional regulatory T cells (Treg) and disease progression in a unique mouse model that mimics the human disease. Cyclophosphamide (CYC) is a cytotoxic alkylating agent widely used in chemotherapeutic regimens. Low-dose CYC was previously reported to selectively reduce Treg levels and to contribute to immunostimulation. Our objectives were (a) to determine whether treatment using a low-dose CYC could reduce MM progression and (b) to further characterize the modes of action underlying these effects. We found that both low-and high-dose CYC given to sick mice with hind limb paralysis resulted in the disappearance of the paralysis, the replacement of plasma tumor cells in the bone marrow by normal cell populations, and a significant prolongation of survival. However, only low-dose CYC treatment decreased the incidence of MM. Low-dose CYC rendered Tregs susceptible to apoptosis because of the downregulation of Bcl-xL and CTLA-4 in these cells, and a decreased production of interleukin 2 by effector CD4 cells. Moreover, using this treatment, we noted the recovery of IFN-γ-producing natural killer T cells and maturation of dendritic cells. Treatment of tumor-bearing mice with repeated administrations of low-dose CYC at longer time intervals (coinciding with the blocked renewal of Tregs) resulted in reduced tumor load, and the prevention or delay of disease recurrence, thereby breaking immune tolerance against MM tumor cells. Cancer Prev Res; 3(10); 1265-76. ©2010 AACR.

Anti‐PD‐1 synergizes with cyclophosphamide to induce potent anti‐tumor vaccine effects through novel mechanisms

“…Spots were counted using CTL Immunospot Analyzer (Cellular Technology), and the results were examined for differences between E7 restimulated and irrelevant peptide (hgp100 [25][26][27][28][29][30][31][32][33] -KVPRNQDWLCelltek Bioscience) re-stimulated splenocyte cultures.…”

“…Use of other cell markers, such as CTLA-4, may also be insufficient since it was previously demonstrated that Treg cells from CTLA-4 knockout mice maintain their suppressive function [26,27]. Cyclophosphamide (CPM) has been used as a standard alkylating chemotherapeutic agent against certain solid tumors and lymphomas because of its direct cytotoxic effect and its inhibitory activity against actively dividing cells [28]. While high doses of CPM may lead to the depletion of immune cells, low doses of CPM have been shown to enhance immune responses and induce anti-tumor immune-mediated effects by reducing the number and function of Treg cells [27,[29][30][31][32][33].…”

Cytosine Arabinoside Promotes Cytotoxic Effect of T Cells on Leukemia Cells Mediated by Bispecific Antibody

“…Moreover, some studies have shown that chemotherapeutic drugs might also enhance the immune response of the host against the tumor. For example, administration of cyclophosphamide at low doses has shown to restore an efficient immune response against tumor cells in the tumor-bearing mice (Sharabi et al, 2010). In rats, low-dose combretastatin A4 phosphate has shown to enhance the immune response of tumor hosts against experimental colon carcinomas (Badn et al, 2006).…”

In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway

“…Paclitaxel also reduced the number of regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), and led to the augmentation of the functions of CD4 and CD8 T cells (16,17). In other cases, DNA alkylating agents, such as cyclophosphamide and mafosfamide, in low doses selectively depleted Treg cells (18,19), caused an increase in effector T cells (Teff)/Treg cell ratios via up-regulation of the T helper (Th) 17 pathway (20), and improved the outcome of tumor vaccinations against cancer (21)(22)(23). Furthermore, doxorubicin, mitomycin C, vinblastine, and methotrexate in low doses have been found to up-regulate DC maturation, antigen processing, and antigen presentation, which led to synergistic antitumor effects of low-dose chemotherapy combined with a DC vaccine (24)(25)(26).…”