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Jun 6, 2011

Scientists Boost Antitumor Effects of Dendritic Cell Therapy Using Inflammatory Virus

  • Scientists have found that infecting tumors in mice with an inflammatory virus prior to tumor-specific dendritic cell (DC) vaccination significantly boosts the immune system’s anticancer response. A group of researchers led by Florian Kühnel, M.D., at Hannover Medical School, claim this two-pronged attack leads to potent antitumoral CD8+ T-cell response, resulting in marked tumor regression and successful eradication of pre-established lung colonies in experimental mice, which represents essential prerequisite for potentially treating metastatic cancers.

    The researchers report on the approach, which they term oncolysis-assisted DC vaccination (ODC), in The Journal of Clinical Investigation. The paper is titled “Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice.”

    Vaccination using DCs carrying tumor-associated antigens (TAAs) has so far yielded limited clinical success in cancer treatment, primarily due to the low immunogenicity of tumor-associated antigens, Dr. Kühnel and colleagues point out. Conversely, and in contrast to the low immunogenicity of TAAs, viral infections stimulate evolutionarily conserved pathways that trigger strong innate and adaptive immune responses. The researchers investigated whether marrying the two approaches could boost the immune response to DC vacination and evaluated the role played by regulatory T cells in either enhancing or suppressing these effects.

    They established syngeneic, immunocompetent murine tumor models and first confirmed that intratumoral administration of a previously described tumor-selectively replicating adenovirus (hTERT-Ad) led to lysis of cancer cells and impaired integrity of tumor tissue. The DC vaccine was then prepared by loading dendritic cells with whole cell lysates from the relevant tumor cells.

    When the viral infection and DC vaccination were both administered to the mouse tumors, the degree of immune response depended on timing. Administering DC vaccination either before establishing tumor inflammation using  the hTERT-Ad virus or after the virus had been cleared elicited only weak antitumoral immune responses.

    However, when DC vaccination was carried out at the time of maximum inflammation of the tumor tissue after hTERT-Ad administration, a strongly enhanced antitumoral immune response resulted and led to complete tumor remission and long-term survival of the treated mice.  These effects were associated with a paradoxical inhibition of virus-specific Abs. The beneficial effects of ODC could not be replicated when animals were treated using either virotherapy or DC vaccination alone.

    Encouragingly, the results were also positive when the dendritic cells used for vaccination carried just a single tumor antigen rather than multiple TAAs, which will be more relevant to a clinical setting, the authors note. ODC therapy in addition resulted in the regression of well-established distal tumors that weren’t accessible to direct injection with the hTERT-Ad virus, suggesting the approach may be suitable for the treatment of metastases as well as accessible primary tumors.

    Interestingly, the beneficial effects of the dual ODC approach depended on the replication competence of the hTERT-Ad virus: Administration of a non-replicating construct of the virus resulted in significantly lower production of CD8 immune responses against the viral hexon protein.

    Moreover, it appeared to be the replication-competence of the virus that was important, rather than the production of infectious viral progeny, as ODC-mediated antitumoral immune responses were also induced in infected tumors in which the viral DNA was effectively replicating, but no infectious progeny were generated. Further studies confirmed that that the antigen used for DC vaccination must be associated with the inflamed tumor tissue for successful T-cell priming.

    The researchers investigated the roles of different subsets of immune cells that responded to ODC therapy by using antibodies to ablate myeloid cells as well as T-cell subpopulations. The antitumoral immune response was almost completely inhibited by antibodies targeting CD8+ T cells but only to a lesser degree by Gr1 and CD4 Abs , “which demonstrated that ODC depends on a complex immune response dominated by CD8+ T cells,”, the authors note.

    Previous work has suggested that CD25 Ab-mediated depletion of regulatory T cells (Tregs) enhances antiviral and antitumoral immune responses. The Hannover team’s research supported this finding, demonstrating that in their tumor-bearing mice, CD25 Ab-mediated depletion of Tregs boosted both antiviral and antitumoral immune responses after either  viral infection or DC vaccination.

    Conversely, in ODC-treated mice, eradication of Tregs using CD25 Ab resulted in significantly reduced antitumoral immune responses and restored virus-specific humoral responses. This finding also held true when they administered ODC to a lung cancer-bearing transgenic mouse model in which Tregs were selectively knocked out without impacting on other potential activated T-cell subsets that express CD25 after viral infection. In these animals, Treg depletion almost completely stopped the potent CD8 antitumoral cytotoxicity after ODC.  

    The authors admit their observation that depletion of Tregs significantly enhances antitumoral immune responses after virus injection or DC vaccination, but nearly abrogates the virus/tumor immune iresponse after ODC, is counterintuitive.

    When they investigated cytokine expression patterns of tumor-associated lymphocytes at the time point of DC applications during ODC, they found that depletion of Tregs did not markedly change the expression of cytokines in uninfected tumor tissue, whereas in tumors with viral infection, depletion of Tregs enhanced Th1-characteristic and IFN-γ–dependent chemokines, as well as TNF-α.

    In addition to these central inflammatory mediators, they observed enhanced expression of G-CSF, GM-CSF, M-CSF, and IL-6 in the Treg depletion group during viral replication. This observation prompted further investigation showing that in uninfected tumors and particularly in virus-infected tumors, depletion of Tregs resulted in significantly higher numbers of myeloid-derived suppressor cells.

    “Taken together, our present data suggest that the enhanced antitumoral immune response in ODC is dependent not only on the time point of vaccination and intratumoral viral DNA replication but also on physiologically balanced virus-induced tumor inflammation,” the authors conclude.

    “These results indicate that tumor-specific, replication-competent viruses are attractive tools to induce potent tumor inflammation as an essential precondition for effective tumor vaccination”.


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