Immunological Mechanisms Of Oncolytic Adenoviral Therapy
Cancer is one of the most common causes of death in humans. The conventional cancer therapies include surgery, radiotherapy, chemotherapy, and targeting therapies, which are intended to directly destroy and eliminate tumor cells. These treatments often fail, resulting in tumor metastasis and recurrence. Therefore, there is a critical need for novel cancer therapies. In recent years, an increasing number of studies have revealed that immune responses play a critical role in conventional cancer therapies. Replication-selective oncolytic viruses are a rapidly expanding therapeutic platform for cancer. Professor Wang Shengdian and his group from the Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, have studied tumor immunity for several years, with a team focusing on oncolytic adenovirus. In this work, entitled “CD8+ T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model”, published in Chinese Science Bulletin 2012, Vol. 57(1), this team has demonstrated that the host anti-tumor immune responses, especially the CD8+ T cell responses, play a critical role in the therapeutic effects of oncolytic adenovirus. These studies might shed light on novel cancer therapies.
Researchers have identified several oncolytic viruses such as poliovirus, adenovirus, vesicular stomatitis virus, reovirus, and vaccinia virus, which can selectively infect or replicate in cancer cells, but spare normal cells. Among these, adenovirus has been the most commonly used oncolytic virus in the last decade, because of its efficacy, safety, and ease of manipulation. When administered to tumors, oncolytic adenovirus infects and kills cancer cells as a result of the normal viral life cycle, by replicating in cells and releasing progeny viruses. However, adenoviral infection is immunogenic and can induce strong anti-viral immune responses, which accelerate the clearance of virus and limit the therapeutic effects on cancer. Some studies have shown that suppressing the immune system could enhance the efficacy of oncolytic vectors. On the other hand, recent preclinical and clinical studies have suggested that the immune response plays an important role in mediating the antitumor efficacy. Therefore, the influence of immune responses on oncolytic therapy is complex. Because of the species specificity of adenoviral replication, it was widely assumed that adenoviral replication would not occur in mouse tumors. Consequently, oncolytic adenoviral vectors have been commonly evaluated in immunodeficient mouse-human tumor xenograft models, which do not accurately reflect what happens in humans treated with oncolytic adenovirus. A team led by Professor Yaohe Wang from the Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, previously screened a panel of mouse tumor cell lines and identified two cell lines–CMT 93 (a murine rectal cancer cell line) and CMT64 (a murine non-small-cell lung cancer cell line) with significant permissibility for adenoviral gene expression, cytopathic effects, and/or replication.
In this work, the team lead by Professor Wang Shengdian evaluated the roles of immune components in oncolytic adenoviral therapy with a murine tumor by subcutaneously inoculating CMT 93 cells into syngeneic C57BL/6 mice. They found that CD8+ T cells, but not CD4+ T cells or natural killer cells, are critical mediators of the antitumor efficacy of oncolytic adenovirus by deletion of the corresponding cell subsets with specific antibodies. Intratumoral injection of adenovirus serotype 5 (Ad5) could induce intensive infiltration of CD8+ T cells into the tumor, and increase tumor-specific interferon-Î³ production and cytotoxic T lymphocyte activity. The anti-tumor T cell responses induced by Ad5 therapy produced long-term tumor-specific memory immune responses that protected the cured mice well from tumor rechallenge. This anti-tumor immune memory is thought to play a major role in preventing tumor relapse. For larger tumors, Ad5 therapy alone controls tumor growth only transiently. However, Ad5 therapy followed by treatment with agonistic anti-4-1BB (cluster differentiation 137, CD137) antibody, a potent enhancer of the specific CD8+ T cell response, resulted in complete rejection of all transplanted tumors, demonstrating that promotion of T cell responses against tumors could enhance the therapeutic effects of oncolytic adenovirus.
In summary, this study provides insight into the antitumor mechanisms of oncolytic adenovirus, in addition to their direct oncolytic effect. Meanwhile, this study proposes a new and more effective therapeutic regime for cancer treatment using a combination therapy of oncolytic adenovirus and immunotherapy.
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