A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer

Hirooka, Yoshiki; Kasuya, Hideki; Ishikawa, Takuya; Kawashima, Hiroki; Ohno, Eizaburo; Villalobos, Itzel Bustos; Naoe, Yoshinori; Ichinose, Toru; Koyama, Nobuto; Tanaka, Maki; Kodera, Yasuhiro; Goto, Hidemi

doi:10.1186/s12885-018-4453-z

Cited by 113 publications

(57 citation statements)

References 39 publications

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“…Of the nine patients who completed treatment, three had PR, four had SD, and two had progressive disease. AEs recorded for this study were deemed unrelated to HF10 treatment . Similarly, tolerable toxicities and preliminary antitumor activity were seen in other early phase trials, warranting subsequent clinical investigation of HF10.…”

Section: Intratumoral Immunotherapiesmentioning

confidence: 74%

Intratumoral Immunotherapy—Update 2019

2019

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Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor‐derived antigens and subsequent activation of tumor‐specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV‐10 and toll‐like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa‐Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T‐VEC), a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T‐VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM‐CSF (16.3% vs. 2.1%; p < .001). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T‐VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T‐VEC in the treatment of advanced melanoma as a model for future solid tumor indications. Implications for Practice This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T‐VEC is the only U.S. Food and Drug Administration (FDA)‐approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T‐VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T‐VEC, the only U.S. FDA‐approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T‐VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

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Section: Intratumoral Immunotherapiesmentioning

confidence: 74%

Intratumoral Immunotherapy—Update 2019

2019

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“…[10][11][12][13] In patients treated with SEMS with flare to prevent migration, 14 the time to recurrent biliary obstruction (RBO) is significantly longer in those treated with PCSEMS than in those treated with UCSEMS. 15 However, the general survival time has been extended by advances in treatment, such as chemotherapy, [16][17][18][19] and patients requiring stent replacement as a reintervention have increased.…”

Section: Introduction E Ndoscopic Stent Placement In Patients Withmentioning

confidence: 99%

Comparison of 8‐ and 10‐mm diameter fully covered self‐expandable metal stents: A multicenter prospective study in patients with distal malignant biliary obstruction

Kawashima

Hashimoto

Ohno

et al. 2019

Digestive Endoscopy

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Objectives The time to recurrent biliary obstruction (TRBO) of unresectable distal malignant biliary obstruction is generally thought to be longer when a self‐expandable metal stent (SEMS) with a thicker inner diameter is used for drainage, but the dependence on the inner diameter using a fully covered SEMS (FCSEMS) is uncertain. The objective of this multicenter prospective study was to compare TRBO and adverse events, such as cholecystitis and pancreatitis, in treatment of patients with unresectable malignant biliary obstruction using 8‐ and 10‐mm diameter FCSEMS. Methods Eighteen tertiary‐care centers participated in the study. Patients were allocated to the 8‐ and 10‐mm diameter groups. TRBO, non‐inferiority of the 8‐mm FCSEMS, overall survival time, frequency and type of adverse events, and non‐recurrent biliary obstruction (RBO) rate at the time of death were compared between the two groups. Results Median TRBO did not differ significantly between the 8‐mm (n = 102) and 10‐mm (n = 100) groups (275 vs 293 days, P = 0.971). The hazard ratio of the 8‐ to 10‐mm groups was 0.90 (80% confidence interval, 0.77–1.04; upper limit lower than the acceptable hazard ratio [1.33] of the null hypothesis). Based on these findings, the 8‐mm diameter stent was determined to be non‐inferior to the 10‐mm diameter stent. Survival time, incidence of adverse events and non‐RBO rate at the time of death did not differ significantly between the two groups. Conclusions Time to RBO with an 8‐mm diameter FCSEMS was non‐inferior to that with a 10‐mm diameter FCSEMS. This finding is important for development of future SEMS.

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“…This suggests that the HSV LAT sequences we studied is of significance for HSV LAT transcription and oHSVs. Actually clinical studies on HF10 have been completed in breast, head and neck, and pancreatic cancers in Japan [59,60]. Meanwhile, in the United States, HF10 has completed phase I clinical trials for refractory superficial cancers and melanoma [59].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Latency-Associated Transcripts (LATs) of Herpes Simplex Viruses

Zhang

Xin

Zhang³

et al. 2020

J. Cancer

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Herpes simplex viruses (HSVs) cause cold sores and genital herpes and can establish lifelong latent infection in neurons. An engineered oncolytic HSV (oHSV) has recently been approved to treat tumors in clinics. HSV latency-associated transcripts (LATs) are associated with the latent infection, but LAT transcriptional regulation was seldom reported. For a better treatment of HSV infection and tumors, here we sequenced the LAT encoding DNA and LAT transcription regulatory region of our recently isolated new strain HSV-1-LXMW and did comparative analysis of the sequences together with those of other four HSV-1 and two HSV-2 strains. Phylogenetic analysis of LATs revealed that HSV-1-LXMW is evolutionarily close to HSV-1-17 from MRC University, Glasgow, UK. For the first time, Using a weight matrix-based program Match and multi-sequences alignment of the 6 HSV strains, we identified HSV LAT transcription regulatory sequences that bind to 9 transcription factors: AP-1, C-REL, Comp1, E2F, Hairy, HFH-3, Kr, TCF11/MAFG, v-Myb. Interestingly, these transcription regulatory sequences and factors are either conserved or unique among LATs of HSV-1 and HSV-2, suggesting they are potentially functional. Furthermore, literature analysis found that the transcription factors v-myb and AP-1 family member JunD are functional in regulating HSV gene transcription, including LAT transcription. For the first time, we discovered seven novel transcription factors and their corresponding transcription regulatory sequences of HSV LATs. Based on our findings and other reports, we proposed potential mechanisms of the initiation and maintenance of HSV latent infection. Our findings may have significant implication in our understanding of HSV latency and engineering of better oncolytic HSVs.

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A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer

Cited by 113 publications

References 39 publications

Intratumoral Immunotherapy—Update 2019

Intratumoral Immunotherapy—Update 2019

Comparison of 8‐ and 10‐mm diameter fully covered self‐expandable metal stents: A multicenter prospective study in patients with distal malignant biliary obstruction

Transcriptional Regulation of Latency-Associated Transcripts (LATs) of Herpes Simplex Viruses

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