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Valganciclovir As Add-On to Standard Therapy in Glioblastoma Patients

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Valganciclovir As Add-On to Standard Therapy in Glioblastoma Patients Published OnlineFirst May 18, 2020; DOI: 10.1158/1078-0432.CCR-20-0369 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY Valganciclovir as Add-on to Standard Therapy in Glioblastoma Patients Giuseppe Stragliotto1,2, Mattia Russel Pantalone1,2, Afsar Rahbar1,2, Jiri Bartek3,4, and Cecilia Soderberg-Naucler€ 1,2 ABSTRACT ◥ Purpose: Several groups have reported a prevalence of human Results: Patients with newly diagnosed glioblastoma receiving cytomegalovirus (CMV) in glioblastoma close to 100%. Previously, valganciclovir had longer median overall survival (OS 24.1 vs. we reported that treatment with the antiviral drug valganciclovir 13.3 months, P < 0.0001) and a 2-year survival rate (49.8% vs. as an add-on to standard therapy significantly prolonged survival 17.3%) than controls. Median time-to-tumor progression was in 50 patients with glioblastoma. Here, we present an updated also longer than in controls; 9.9 (0.7–67.5 months) versus retrospective analysis that includes an additional 52 patients. 7.3 (1.2–49 months), P ¼ 0.0003. Valganciclovir improved Patients and Methods: From December 2006 to November survival in patients with radical or partial resection and an 2019, 102 patients with newly diagnosed glioblastoma received unmethylated or methylated MGMT promoter gene. valganciclovir as an add-on to standard therapy. No additional Conclusions: Valganciclovir prolonged median OS of patients toxicity was observed. Contemporary controls were 231 patients with newly diagnosed glioblastoma (with methylated or unmethy- with glioblastoma who received similar baseline therapy. lated MGMT promoter gene) and was safe to use. Introduction to transform cells in vitro (19) and established tumors in immuno- deficient mice (19, 20). Despite increased understanding of their molecular phenotypes, In a case–control study, we found that patients with low-grade CMV glioblastomas remain incurable and have a dismal prognosis. Total infection had longer median overall survival (OS) than those with surgical resection provides better outcomes than partial resection (1). high-grade infection (33 vs. 13 months, P ¼ 0.036) and a higher 2-year With standard treatment, maximal surgical resection followed by survival rate (63.6% vs. 17.2%, P ¼ 0.003; refs. 21, 22). A low-grade concomitant chemoradiotherapy with temozolomide, median 2-year CMV infection was also associated with longer survival of patients with survival of up to 26% has been reported in controlled trials (2, 3), but breast (23, 24), colon (24), and ovarian cancer (12, 25). These seldom exceeds 15% to 20% in daily practice. Moreover, due to an observations suggest that CMV affects tumor progression and may unmethylated MGMT promoter gene in the tumor of the majority of . be a target of therapy, and support the hypothesis that antiviral therapy patients, they may not benefit from temozolomide therapy. They have for CMV may slow tumor progression. In an animal model, we showed an expected 2-year survival rate of only 13.8% (4). that anti-CMV treatment with valganciclovir and celecoxib reduced Human cytomegalovirus (CMV) nucleic acids and proteins are medulloblastoma growth by 72% (14). In a xenograft model, valgan- found in 90% to 100% of glioblastomas (5–8). CMV is also present ciclovir reduced neuroblastoma growth by 40% (15). The anti-CMV in solid cancers, including cancer of the breast (9), colon (10), drug cidofovir (18, 26) and nanobodies to the CMV protein US28 also prostate (11), and ovaries (12, 13), medulloblastoma (14), neuroblas- significantly reduced glioblastoma growth in mouse models (27). toma (15), and rhabdomyosarcoma (16). Present mainly in tumor To determine whether antiviral therapy for CMV improves the cells, the virus has oncomodulatory effects (5), can cause all the outcome of patients with glioblastoma, we enrolled 42 patients in a hallmarks of cancer (17), and promotes tumor growth in glioblastoma double-blind clinical phase I/II hypothesis generating trial to assess the mouse models (18). Some evidence suggests that certain CMV strains safety and potential efficacy of valganciclovir treatment in patients with can be oncogenic; two clinical strains were so far independently shown glioblastoma [the VIGAS study - Efficacy and Safety of Valcyte as an Add-on Therapy in Patients With Malignant Glioblastoma and Cyto- megalovirus (CMV) Infection,NCT00400322; ref. 28]. Patients received a full dose of valganciclovir (900 mg) or placebo twice daily for 3 weeks 1 Department of Medicine, Solna, Microbial Pathogenesis Unit, Karolinska Insti- followed by a maintenance dose of 450 mg twice daily for 21 weeks. The 2 tutet, Stockholm, Sweden. Division of Neurology, Karolinska University Hos- study was underpowered and failed its primary endpoint of reduced pital, Stockholm, Sweden. 3Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark. 4Department of Medical Biochemistry tumor growth by MRI at 6 months. However, in exploratory analyses of and Biophysics, Division of Genome Biology, Science for Life Laboratory, VIGAS patients with active valganciclovir intake, we observed that 50% Karolinska Institute, Stockholm, Sweden. of patients were alive at 2 years compared with 18% of contemporary G. Stragliotto and M.R. Pantalone contributed equally to this article. control patients receiving the same baseline therapy. The median OS was also longer in valganciclovir-treated patients than in controls Corresponding Author: Cecilia Soderberg-Naucler,€ Department of Medicine, (24.1 vs. 13.1 months; refs. 28, 29). CMV is also evaluated as target Karolinska Institutet, Bioclinicum J5:30, Stockholm 17164, Sweden. Phone: 468- 5177-9816; E-mail: [email protected] in immunotherapy approaches. Dendritic cells pulsed with pp65 mRNA have been used to vaccinate patients with glioblastoma (30, 31). A larger Clin Cancer Res 2020;XX:XX–XX clinical trial is currently ongoing to evaluate this therapeutic strategy. doi: 10.1158/1078-0432.CCR-20-0369 Adoptive transfer of CMV-specific T cells is also a promising Ó2020 American Association for Cancer Research. approach (32) and vaccination studies are ongoing. AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst May 18, 2020; DOI: 10.1158/1078-0432.CCR-20-0369 Stragliotto et al. Table 1. Demographic and clinical characteristic. Translational Relevance Cytomegalovirus presence in the majority of glioblastoma may Primary disease a represent a therapeutic target. We performed a retrospective Controls Valganciclovir n ¼ n ¼ analysis of survival data of 102 patients with glioblastoma receiving Characteristics ( 231) ( 102) the antiviral drug valganciclovir as an add-on to standard therapy Age, years and of 231 controls treated at our institution. Valganciclovir Median 63 59 improved survival of both newly diagnosed patients with glioblas- Range 24–85 22–76 toma who underwent complete or partial resection, with unmethy- Sex lated and methylated MGMT promoter status. Given the discour- Women, n 86 (37.2%) 30 (29.4%) n aging results from drug intervention studies for this patient group, Men, 145 (62.8%) 72 (70.6%) Race and an almost doubled life expectancy in valganciclovir-treated Caucasian 100% 100% patients with glioblastoma, our data suggest that this drug has a MGMT promoter status biological effect on glioblastoma rather than representing a random Methylated 50 (45.0%) 39 (44.3%) event or patient selection bias. This could open for a new under- Unmethylated 61 (55.0%) 49 (55.7%) standing of glioblastoma pathogenesis. A multicenter double-blind IDH status randomized trial to evaluate the treatment effect of valganciclovir Wild type 30 55 was recently initiated to confirm or dismiss these promising Mutated 2 1 treatment results. Tumor location Temporal 84 (36.4%) 42 (41.2%) Frontal 69 (29.9%) 31 (30.4%) Parietal 51 (22.1%) 19 (18.6%) Occipital 10 (4.3%) 5 (4.9%) For several years, we have tried to obtain funding for a randomized Other 17 (7.3%) 5 (4.9%) fi clinical trial to con rm or disprove the hypothesis that valganciclovir Treatment, n (%) as an add-on to standard therapy improves the prognosis of patients Surgery with glioblastoma. During this time, our cohort of patients with newly Radical resection 164 (71.0%) 79 (77.5%) diagnosed glioblastomas treated with valganciclovir has increased Partial resection or biopsy 67 (29.0%) 23 (22.5%) to 102 patients. In a letter to New England Journal of Medicine in Hypofractionated RT 11 5 2013, we reported an updated analysis of OS for 50 valganciclovir- and chemotherapy treated patients, who had a median OS of 25 months versus 13.5 in Chemotherapy only 60 12 Concomitant full dose controls (P < 0.001). Here, we present an updated, in-depth retro- RT and chemotherapy 157 77 spective analysis of this accrued patient cohort. KPS after surgery ≤80 141 40 Patients and Methods ≥80 83 58 Study design Abbreviation: RT, radiotherapy. This is a retrospective study of 102 patients with newly diagnosed aControls received standard-of-care treatment. glioblastoma that received valganciclovir as an add-on therapy to standard treatment between December 12, 2006, and November 10, Karolinska University Hospital is fractionated radiotherapy (60 Gy in 2019, at Karolinska University Hospital (Stockholm, Sweden). The 2-Gy fractions) with concomitant temozolomide. As patients over age diagnosis of primary glioblastoma was confirmed pathologically. The 70 are often not suitable candidates for full 60-Gy radiotherapy, some primary endpoint was OS. The study was conducted in accordance to elderly patients received hypofractionated radiotherapy (3.4 Gy  the declaration of Helsinki and approved by the regional ethics com- 10 days) in addition to chemotherapy (5 valganciclovir-treated and 11 mittee in Stockholm (Dnr: 2016/1426–31/1). We were not required to controls) or only chemotherapy (12 valganciclovir-treated patients take informed consent from the living patients or from relatives of received only temozolomide and among controls 3 received CCNU deceased patients for this study. Patient data are in a data file that can be and 57 received only temozolomide).
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