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Intratumoral and s.c. injection of inactivated hemagglutinating virus of Japan envelope (GEN0101) in metastatic castration-resistant prostate cancer.

ABSTRACT: Inactivated hemagglutinating virus of Japan envelope (HVJ-E) has an antitumor effect and tumor immunity. We undertook an open-label, phase I, dose-escalation study in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and s.c. injection of HVJ-E (GEN0101). Patients with CRPC, who were resistant to or unable to receive standard of care, were included. GEN0101 was injected directly into the prostate and s.c. in two 28-day treatment cycles. The primary end-points were to evaluate the safety and tolerability of GEN0101 and determine its recommended dose. The secondary end-points were to analyze the antitumor effect and tumor immunity. Three patients received 30 000 mNAU GEN0101 and 6 received 60 000 mNAU. There was no dose-limiting toxicity, and the recommended dose of GEN0101 was defined as 60 000 mNAU. Radiographically, 1 patient had stable disease and 2 had progressive disease in the low-dose group, whereas 5 patients had stable disease and 1 had progressive disease in the high-dose group. Three patients in the high-dose group showed reduction in lymph node metastasis. Prostate-specific antigen increase rates in the high-dose group were suppressed more than those in the low-dose group. Natural killer cell activity was enhanced in 2 patients of the low-dose group and in 5 patients in the high-dose group. In conclusion, intratumoral and s.c. injections of GEN0101 were well-tolerated and feasible to use. The study is registered with the UMIN Clinical Trials Registry (no. UMIN000017092).

SUBMITTER: Fujita K

PROVIDER: S-EPMC7226216 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Intratumoral and s.c. injection of inactivated hemagglutinating virus of Japan envelope (GEN0101) in metastatic castration-resistant prostate cancer.

Fujita Kazutoshi K Kato Taigo T Hatano Koji K Kawashima Atsunari A Ujike Takeshi T Uemura Motohide M Imamura Ryoichi R Okihara Koji K Ukimura Osamu O Miki Tsuneharu T Nakajima Toshihiro T Kaneda Yasufumi Y Nonomura Norio N

Cancer science 20200319 5

Inactivated hemagglutinating virus of Japan envelope (HVJ-E) has an antitumor effect and tumor immunity. We undertook an open-label, phase I, dose-escalation study in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and s.c. injection of HVJ-E (GEN0101). Patients with CRPC, who were resistant to or unable to receive standard of care, were included. GEN0101 was injected directly into the prostate and s.c. in two 28-day treatment cycles ...[more]

PMID: 32112659

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Project description:Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.

Project description:BackgroundWe aimed to evaluate cost-effectiveness of enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer patients in Japan.MethodsA Markov model was developed to capture time spent by patients in various health states: stable, progression and death. Abiraterone acetate and docetaxel were set as active comparators. Clinical outcomes were obtained from the PREVAIL, COU-AA-302 and TAX327 trials. Treatment sequence, concomitant drugs and therapies for adverse events were estimated from responses to a survey by 14 Japanese prostate cancer experts. The analytic perspective was public healthcare payer, with a 10-year time horizon. The incremental cost-effectiveness ratio was estimated from quality-adjusted life-years and Japanese public healthcare costs. Probabilistic sensitivity analysis was performed to assess the robustness of the findings.ResultsAccording to the survey, the most common treatment sequences were (i) enzalutamide → docetaxel → cabazitaxel (enzalutamide-first sequencing), (ii) abiraterone → enzalutamide → docetaxel (abiraterone-first sequencing) and (iii) docetaxel→ enzalutamide → cabazitaxel (docetaxel-first sequencing). In the base-case analysis, enzalutamide-first sequencing saved 1.74 million Japanese Yen versus abiraterone-first sequencing, with a 0.129 quality-adjusted life-year gain (dominant). Enzalutamide-first sequencing had a cost increase of 4.44 million Japanese Yen over docetaxel-first sequencing, with a 0.371 quality-adjusted life-years gain. The incremental cost-effectiveness ratio of enzalutamide-first sequencing versus docetaxel-first sequencing was estimated as 11.94 million Japanese Yen/quality-adjusted life-years. Probabilistic sensitivity analyses demonstrated that, compared with abiraterone-first sequencing, enzalutamide-first sequencing had an 87.4% probability of being dominant.ConclusionsResults modeled herein suggest that the enzalutamide-first sequencing is more cost-effective than the abiraterone-first sequencing, but less cost-effective than docetaxel-first sequencing for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

Project description:Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope (HVJ-E)) have a novel antitumor effect: HVJ-E fused to prostate cancer cells via cell surface receptor causes apoptosis of prostate cancer cells in vitro and in vivo. HVJ-E also induces antitumor immunity by activating natural killer (NK) cells and cytotoxic T cells and suppressing regulatory T cells in vivo. We conducted an open-label, single-arm, phase I/II clinical trial in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and subcutaneous injection of HVJ-E. Patients with CRPC who were docetaxel-resistant or could not receive docetaxel treatment were eligible. HVJ-E was injected directly into the prostate on day 1 and subcutaneously on days 5, 8 and 12 in two 28-day treatment cycles using a 3+3 dose-escalation design. The primary end points were to evaluate safety and tolerability of HVJ-E. The secondary end points were to analyze tumor immunity and antitumor effect. The study is registered at UMIN Clinical Trials Registry, number UMIN000006142. Seven patients were enrolled, and six patients received HVJ-E. Grade 2 or 3 adverse events (Common Terminology Criteria for Adverse Events Ver. 4.0) were urinary retention and lymphopenia from which the patients recovered spontaneously. No Grade 4 adverse events were observed. Radiographically, three patients had stable disease in the low-dose group, and one patient had stable disease and two had progressive disease in the high-dose group. The prostate-specific antigen (PSA) declined from 14 to 1.9 ng?ml-1 in one patient in the low-dose group after two cycles of HVJ-E treatment, and the PSA response rate was 16.6%. NK cell activity was elevated from day 12 to day 28 after HVJ-E administration, whereas serum interleukin-6, interferon (IFN)-?, IFN-? and IFN-? levels were not affected by HVJ-E treatment. Intratumoral and subcutaneous injections of HVJ-E are feasible and PSA response was observed in a subgroup of CRPC patients.

Dataset Information

Intratumoral and s.c. injection of inactivated hemagglutinating virus of Japan envelope (GEN0101) in metastatic castration-resistant prostate cancer.

Publications

Intratumoral and s.c. injection of inactivated hemagglutinating virus of Japan envelope (GEN0101) in metastatic castration-resistant prostate cancer.

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