Combined immunotherapy with whole tumor lysate–pulsed interleukin-15–activated dendritic cells and cucurbitacin I promotes strong CD8+ T-cell responses and cures highly aggressive lymphoma

• Published in: Cytotherapy (Oxford, England) England), 2015-05, Vol.17 (5), p.647-664
• Main Authors: Hira, S. Kumar, Mondal, Indrani, Manna, Partha P
• Format: Article
• Language: English
• Subjects: adoptive cell therapy; Advanced Basic Science; Animals; antioxidant enzyme; Antioxidants - metabolism; Blood Glucose - metabolism; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Extracts - therapeutic use; Cell Proliferation - drug effects; Cytokines - metabolism; Cytotoxicity, Immunologic - drug effects; dendritic cell; Dendritic Cells - drug effects; Dendritic Cells - immunology; Immunotherapy; interleukin-15; Interleukin-15 - pharmacology; Interleukin-15 - therapeutic use; lymphoma; Lymphoma - immunology; Lymphoma - pathology; Lymphoma - therapy; Mice, Inbred AKR; Neoplasm Metastasis; Organ Specificity - drug effects; Other; Remission Induction; Survival Analysis; TNF-Related Apoptosis-Inducing Ligand - metabolism; Triterpenes - pharmacology; Triterpenes - therapeutic use; Tumor Necrosis Factor-alpha - metabolism; Vaccination
• ISSN: 1465-3249; 1477-2566
• DOI: 10.1016/j.jcyt.2015.01.006

Abstract Background aims Dendritic cell (DC)-based therapies could be important strategies for lymphoma treatment. Methods AKR/J mice with Dalton's lymphoma were treated with recombinant interleukin-15 (rIL-15)-activated autologous DCs and pulsed with whole tumor cell lysates in the presence or absence of suboptimal doses of the STAT3 inhibitor cucurbitacin I. One group of treated mice received an additional dose of rIL-15 to boost the DC-based adoptive cell therapy (ACT). Kaplan-Meier survival analysis and multiple immunologic and enzymatic parameters were assessed to demonstrate the efficacy of the vaccination protocol. Results Therapy with tumor lysate–pulsed, rIL-15–activated DCs plus cucurbitacin I significantly prolongs the survival of tumor-bearing mice but fails to provide a complete cure. Additional treatment of vaccinated mice with rIL-15 dramatically improves the therapeutic efficacy and provides a lifelong cure with no relapse. DCs derived from the surviving vaccinated mice regained their anti-tumor potential against the lymphoma cells with respect to growth inhibition and cytotoxicity. Both cluster of differentiation (CD)4+ and CD8+ T cells were mobilized in metastatic organs of successfully vaccinated mice in large numbers and demonstrated antigen-specific proliferation and tumor cell cytotoxicity. ACT also augments DC function by upregulating tumor necrosis factor-related apoptosis-inducing ligand and tumor necrosis factor-α expression. In addition, combinatorial immunotherapy restores the levels of antioxidant enzymes and liver function enzyme activities that are severely repressed in untreated tumor-bearing mice. Conclusions Effective vaccination for a complete cure against aggressive lymphoma requires DC-based ACT in combination with chemotherapy and cytokine therapy.