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Gemcitabine enhances antitumor efficacy of recombinant lipoimmunogen-based immunotherapy.

ABSTRACT: Although immunotherapy is an attractive approach for cancer treatment, increasing evidence has shown that the combination of immunotherapy with other treatment modalities may improve the outcome of advanced malignancy. We combined the anticancer drug gemcitabine (Gem) with recombinant lipoprotein-based immunotherapy (rlipo-E7m/CpG) to treat advanced cancer. Mice bearing huge solid tumors (? 12 mm in diameter) or orthotopic cervical cancer were treated with a therapeutic regimen consisting of rlipo-E7m/CpG and Gem. In addition, tumor-infiltrating immune cells were quantified by flow cytometry following the chemotherapy and/or immunotherapy. We observed the eradication of huge tumors following the administration of Gem on days 21, 24, and 27 or following rlipo-E7m/CpG therapy on day 30 post-tumor implantation. The combination therapy substantially reduced the number of immunosuppressive cells (CD11b⁺Gr-1⁺, CD11b⁺F4/80⁺, and CD4⁺CD25⁺FOXP3⁺) and increased the number of tumor-infiltrating antigen-specific CD8⁺ T cells compared to Gem or rlipo-E7m/CpG monotherapy. Interestingly, the administration of Gem and rlipo-E7m/CpG reduced the quantity of programmed cell death protein 1 (PD-1)-expressing antigen-specific cytotoxic T lymphocytes (CTLs) in the regressing tumors. These findings demonstrated that Gem enhances the eradication of huge tumors by inhibiting a broad range of immunosuppressive cells when combined with immunotherapy. Based on the promising results from this animal study, Gem chemotherapy combined with recombinant lipoimmunogen-based immunotherapy represents a feasible approach for cancer therapy.

SUBMITTER: Chang LS

PROVIDER: S-EPMC4839335 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Gemcitabine enhances antitumor efficacy of recombinant lipoimmunogen-based immunotherapy.

Chang Li-Sheng LS Yan Wan-Lun WL Chang Yu-Wen YW Yeh Yi-Chen YC Chen Hsin-Wei HW Leng Chih-Hsiang CH Liu Shih-Jen SJ

Oncoimmunology 20151029 3

Although immunotherapy is an attractive approach for cancer treatment, increasing evidence has shown that the combination of immunotherapy with other treatment modalities may improve the outcome of advanced malignancy. We combined the anticancer drug gemcitabine (Gem) with recombinant lipoprotein-based immunotherapy (rlipo-E7m/CpG) to treat advanced cancer. Mice bearing huge solid tumors (≧ 12 mm in diameter) or orthotopic cervical cancer were treated with a therapeutic regimen consisting of rli ...[more]

PMID: 27141356

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Project description:We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4+ and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment.Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations.We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4+ and CD8+ T cells along with a decrease of inhibitory cells.To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall efficacy of cancer immunotherapy.

Project description:BACKGROUND:BM32 is a grass pollen allergy vaccine based on recombinant fusion proteins consisting of nonallergenic peptides from the IgE-binding sites of the 4 major grass pollen allergens and the hepatitis B preS protein. OBJECTIVE:We sought to study the safety and clinical efficacy of immunotherapy (allergen immunotherapy) with BM32 in patients with grass pollen-induced rhinitis and controlled asthma. METHODS:A double-blind, placebo-controlled, multicenter allergen immunotherapy field study was conducted for 2 grass pollen seasons. After a baseline season, subjects (n = 181) were randomized and received 3 preseasonal injections of either placebo (n = 58) or a low dose (80 ?g, n = 60) or high dose (160 ?g, n = 63) of BM32 in year 1, respectively, followed by a booster injection in autumn. In the second year, all actively treated subjects received 3 preseasonal injections of the BM32 low dose, and placebo-treated subjects continued with placebo. Clinical efficacy was assessed by using combined symptom medication scores, visual analog scales, Rhinoconjunctivitis Quality of Life Questionnaires, and asthma symptom scores. Adverse events were graded according to the European Academy of Allergy and Clinical Immunology. Allergen-specific antibodies were determined by using ELISA, ImmunoCAP, and ImmunoCAP ISAC. RESULTS:Although statistical significance regarding the primary end point was not reached, BM32-treated subjects, when compared with placebo-treated subjects, showed an improvement regarding symptom medication, visual analog scale, Rhinoconjunctivitis Quality of Life Questionnaire, and asthma symptom scores in both treatment years. This was accompanied by an induction of allergen-specific IgG without induction of allergen-specific IgE and a reduction in the seasonally induced increase in allergen-specific IgE levels in year 2. In the first year, more grade 2 reactions were observed in the active (n = 6) versus placebo (n = 1) groups, whereas there was almost no difference in the second year. CONCLUSIONS:Injections of BM32 induced allergen-specific IgG, improved clinical symptoms of seasonal grass pollen allergy, and were well tolerated.

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Gemcitabine enhances antitumor efficacy of recombinant lipoimmunogen-based immunotherapy.

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Gemcitabine enhances antitumor efficacy of recombinant lipoimmunogen-based immunotherapy.

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