Improvement of Antitumor Effect of Intratumoral Injection of Immature Dendritic Cells Into Irradiated Tumor by Cyclophosphamide in Mouse Colon Cancer Model

Abstract

Recently, chemotherapy and radiotherapy are known to directly affect some immunosuppressive barriers within a tumor microenviroment. We used cyclophosphamide (CTX), which is known to enhance the immune response by suppressing CD4+CD25+ regulatory T cells (Treg cells) when used at a low dose, as a chemotherapeutic agent to provide a synergic effect in the irradiation and dendritic cells (DC) combination therapy. Some previous studies observed that a single-dose CTX treatment significantly reduced the number of Treg cells in 3-5 days, however, the reduced Treg cells increased rapidly after 5 days. To overcome the disadvantages of a single-dose CTX, we used 30 mg/kg dose of CTX, which was treated intraperitoneally to mice 3 days before every immature DC (iDC) injection (known as "metronomic schedule CTX"). Irradiation was applied at a dose of 10 Gy to the tumor on the right thigh by a linear accelerator. Then, iDC was intratumorally injected into the irradiated tumor site. Growth of a distant tumor on the right and left flank was suppressed by an injection of iDC into the irradiated tumor, and this effect was increased by the metronomic schedule CTX. Also, combinations treated with the metronomic schedule CTX and ionizing radiation (IR)/iDC, showed the longest survival time compared with other groups. This antitumor immune response of IR/iDC was improved by metronomic schedule CTX and this result was associated with decreasing the proportion of CD4+CD25+ Treg cells and increasing the number of tumor-specific interferon-γ-secreting T cells. Our results demonstrated that metronomic schedule CTX improves the antitumor effect of immunization with an injection of DC s into the irradiated tumor.

T‐cell modulation by cyclophosphamide for tumour therapy

“…Although administration of CY alone can significantly impair tumour growth in mice, there is also evidence from mouse models that the ability of CY to promote anti‐tumour immunity is markedly improved by combining the drug with other chemotherapeutic or immunotherapeutic agents. In the case of the latter, investigators have demonstrated increased immune responses and better control of tumour growth after combining low‐dose CY with recombinant virus vaccines, peptide‐based vaccines, exome‐based vaccines, whole‐cell vaccines, dendritic cell vaccines, Toll‐like receptor agonists, DNA vaccines, agonist antibodies specific for the co‐stimulatory molecules, e.g. OX‐40 and 4‐1BB, and anti‐PD‐1‐blocking antibodies .…”

Intratumoral gene therapy versus intravenous gene therapy for distant metastasis control with 2-Diethylaminoethyl-Dextran Methyl Methacrylate Copolymer Non-Viral Vector–p53

“…42,48,49,[73][74][75][76] Additional methods of enhancing the intratumoral gene therapy have been previously performed with the addition of radiotherapy, chemotherapy, thermal ablation, sorafenib, imatinib, use of ultrasound system, rituximab and dendritic cells to gene therapy administration alone. 34,[77][78][79][80][81][82] In our current study, we used the novel non-viral vector DDMC as the vehicle for the local intratumoral administration of pSicop53. The DDMC was synthesized by graft polymerization of methyl methacrylate (MMA) onto 2-Diethylaminoethyl-Dextran Methyl Methacrylate Copolymer (DAEX).…”

Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies

“…Immunotherapy as intratumoral therapy has also been investigated: (a) Propionibacterium acnes induces immunestimulation by increasing interleukin-12, tumor necrosis factor-α, and interferon-γ,77 (b) secondary lymphoid chemokine and unmethylated cytosine-phosphorothioate-guanine-oligodeoxynucleotide were used to mobilize lymphocytes and dendritic cells and increased the infiltration of CD4 + T-cells and CD11c + cells in the tumor mass with observed reduction in tumor mass,78 (c) hu14.18-interleukin-2 administration resulted in increased natural killer (NK) group 2, member D receptors on intratumoral NKG2A/C/E + NKp46 + NK cells,79 (d) OK-432 efficiently suppressed metastatic squamous cell carcinoma lesion by inducing interferon-γ and tumor necrosis factor-α,80 (e) pre-treatment with cyclophosphamide and oligodeoxynucleotides plus rituximab enhanced immune activation against tumor cells and reduced tumor evolution,81 (f) dendritic cells and dendritic cells plus cyclophosphamide or paclitaxel at low doses enhanced immune system activation,82,83 (g) anti-gal antibody injection 84. Furthermore, several biomarkers were used specifically in intratumoral therapies as independent predictive factors, such as T cells and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an inhibitor of lovastatin, as a formulation that blocks local metastasis after irradiation 85…”