Pediatric cancer gone viral. Part II: potential clinical application of oncolytic herpes simplex virus-1 in children

摘要

Oncolytic engineered herpes simplex viruses (HSVs) possess many biologic and functional attributes that support their use in clinical trials in children with solid tumors. Tumor cells, in an effort to escape regulatory mechanisms that would impair their growth and progression, have removed many mechanisms that would have protected them from virus infection and eventual virus-mediated destruction. Viruses engineered to exploit this weakness, like mutant HSV, can be safely employed as tumor cell killers, since normal cells retain these antiviral strategies. Many preclinical studies and early phase trials in adults demonstrated that oncolytic HSV can be safely used and are highly effective in killing tumor cells that comprise pediatric malignancies, without generating the toxic side effects of nondiscriminatory chemotherapy or radiation therapy. A variety of engineered viruses have been developed and tested in numerous preclinical models of pediatric cancers and initial trials in patients are underway. In Part II of this review series, we examine the preclinical evidence to support the further advancement of oncolytic HSV in the pediatric population. We discuss clinical advances made to date in this emerging era of oncolytic virotherapy. prs.rt("abs_end"); Oncolytic herpes simplex viruses (oHSVs) retain their susceptibility to innate antiviral mechanisms in normal cells that quickly limit the ability of the virus to yield a productive infection. The pathogenesis of tumor cells has evolved to mutate or outright delete most of these mechanisms to select for the most replicative, invasive, and progressive cancer cell, creating a significant vulnerability to virus infection. The current wisdom holds that among the cells comprising a tumor, there resides a subpopulation resistant to radiation and chemotherapies and from which more aggressive malignancies arise. Strategies to target this tumor-initiating cell or tumor stem cell subpopulation are being developed and tested. However, as described below, preclinical evidence suggests that oHSV is an equal opportunity tumor killer that is not constrained by some of the limitations of chemotherapy or radiation, such as the requirement for cells to be dividing. As described in Part I of this review series, a number of unique challenges to the successful application of oHSV in children exist; however multiple lines of evidence in preclinical and clinical studies define most of the consequential barriers to a rational deployment of oHSV for cancer therapy. 1 In this Part II, we review the preclinical evidence to support the further advancement of oHSV in the pediatric population. We discuss clinical advances made to date in this emerging era of oncolytic virotherapy. Antitumor Efficacy by Disease Neuroblastoma Neuroblastoma is the most common non-central nervous system (CNS) solid tumor in children and contributes to 10–15% of all pediatric cancer mortality. Average age at diagnosis is 19 months and 90% are less than 5 years old. 2 Children with high-risk disease urgently require novel therapy as they continue to have poor outcomes despite intensive chemotherapy, surgery, radiation, immunotherapy, and retinoic acid. In fact, we are now finding that among those who survive this disease, about 30% of children develop secondary cancers as a result of the intensive treatments 10–15 years later. 3 Dr. Alice Moore is one of the earliest known physicians to study virotherapy for neuroblastoma in the early 1950s when she utilized a Russian Far East encephalitis virus to treat neuroblastoma with dramatic in vivo responses in mouse models, but with limited success overall as the mice died from the viral infection. 4 , 5 , 6 and 7 Neuroblastoma cells are moderately susceptible to G207 (see Table 1 for summary of viruses and Figure 1 for structural schematics for preclinical and therapeutic HSVs discussed in the text) in vitro but demonstrated tumor growth reduction and even cures in immunocompetent murine models. Additionally, intratumoral injections of G207 into subcutaneous N18 tumors demonstrated regression of a remote intracranial neuroblastoma. The enhanced antitumor effects in vivo are hypothesized to be secondary to stimulation of the host systemic antitumor response. Elevations of specific cytotoxic T-cell activity against neuroblastoma cells have been noted to persist for over 1 year. The increased specific cytotoxic T-cell activity is also theorized by Todo et al . 8 to further elicit systemic antitumor immunity as demonstrated by lack of tumor growth upon tumor rechallenge. The Cripe lab demonstrated the antitumor efficacy of NV1066 against human neuroblastoma xenograft models. 9 Because increased matrix metalloproteinase expression and activity correlates with poor prognosis in several human malignancies, including neuroblastoma, 10 they sought to create an oHSV, rQT3, which expressed human tis