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IMSUT Hospital

Department of Surgical Neuro-Oncology
脳腫瘍外科

Professor
Project Professor
Assistant Professor
Assistant Professor
Assistant Professor(Thoracic surgeon)

Tomoki Todo, M.D., Ph.D.
Minoru Tanaka, M.D., Ph.D.
Hirotaka Ito, M.D., Ph.D.
Seisaku Kanayama, M.D.
Yoshinori Sakata, M.D., Ph.D.

教 授
特任教授助 教助 教助 教博士（医学）
博士（医学）
博士（医学）

藤田伊金博士（医学）（呼吸器外科医）  坂堂
中藤山田具博政義紀実
崇作
詞

All kinds of brain tumors, especially malignant glioma, are treated at ourdepartment. Malignant glioma is incurable by standard therapy alone, therefore
refined, personalized treatment regimens utilizing non-standard radiation therapy
and chemotherapy are considered. In addition, G47∆, the first oncolytic virus
therapy drug for malignant glioma in the world, developed by this department, iscommercially available and used for treatment since November 2021. Based on
scientific evidence and findings from basic research, we conduct advanced medical
practices in addition to standard therapy.

Introduction
Department of Surgical Neuro-Oncology was established in 2011. Our department started treating
out-patients in October 2011 and in-patients in April
2012. Our department focuses on malignant tumorsof the brain, such as gliomas or metastatic brain tumors. Glioblastoma is one of the most aggressive andmalignant cancers of the central nervous system. The
standard upfront treatment includes resection to remove as much of the tumor as possible while preserving function, followed by radiation of 60Gy and temozolomide. Established good prognostic factors arelimited but include young age, high Karnofsky Performance Status (KPS), high mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation, and resection of > 98%of the tumor. Nevertheless, glioblastoma is refractory
to conventional therapies and has a poor prognosis
with a 5-year survival rate of less than 5%. Therefore,
we should consider refined and personalized treatment approaches for selected patients: high dose radiation therapy of 80Gy for newly diagnosed glioblastoma or extended field stereotactic radiosurgery forrecurrent gliomas. We also conduct translational research based on scientific evidence. We are developing recombinant herpes simplex virus type I (HSV-1),
which has genetic modifications in the viral genome
so that the viruses replicate selectively in cancer cells
while eliciting an immune response against tumor-associated proteins. Clinical trials using a third-generation, triple-mutated oncolytic herpes simplex virus
type 1 (HSV-1), G47Δ, were performed in patientswith glioblastoma from 2015 to 2020 and malignant
pleural mesothelioma from 2018 to 2021. The clinical
trial is ongoing in patients with olfactory neuroblastoma. We also started a new investigator-initiated clinical trial using T-hIL12 for malignant melanoma jointly with Shinshu University since January 2020.
A phase II clinical trial of a replication-competent,HSV-1, G47Δ in patients with glioblastoma
Genetically engineered, conditionally replicating
HSV-1is promising therapeutic agents for solid carcinomas. We developed G47∆ by introducing an additional genetic mutation to a second generation, double-mutated oncolytic HSV-1, G207, used in the phase275
I clinical trial for glioblastoma in the United States in1998. We conducted a phase II clinical trial of G47∆ inpatients with glioblastoma since December 2014 toJune 2020. The main inclusion criteria were a recurrent or residual glioblastoma with a single lesion(≥1cm) after initial radiation therapy concomitantwith temozolomide chemotherapy, age 18 or older,
life expectancy of at least 3 months, a performance-status according to Karnofsky Performance Scale of ≥60% and adequate organ function. The eligible patients received repeated stereotactic injections withG47Δ every 4 weeks, 6 injections being the maximum
total. The efficacy of G47Δ evaluates using a one-year
survival rate as the primary endpoint. The plannedinterim analysis showed significant efficacy with limited side effects of G47∆, so the trial was terminatedearly. In the final analysis, the 1-year survival rate after initiation of G47∆ treatment (primary endpoint)
was 84%, and the most common side effect of G47∆
was fever followed by vomiting, nausea, lymphopenia, and leukopenia. A new drug application (NDA)
for G47∆ for malignant glioma has been submitted to
the Ministry of Health, Labour and Welfare in December 2020. In June 2021, G47Δ was approved as theworld’s first oncolytic virus drug for malignant glioma. The oncolytic virus therapy using G47Δ for thepatient with malignant gliomas started at this department in November 2021 upon commercial distribution.
A clinical study of G47Δ in patients with progressive olfactory neuroblastoma
Olfactory neuroblastoma is an uncommon malignant neuroectodermal tumor, which is thought tooriginate from the olfactory membrane of the sinonasal tract. Patients should receive aggressive treatment
with combined treatment such as surgery, radiation
therapy, and chemotherapy because there is no effective treatment once it recurs: An aggressive en bloc
resection, with combined radiation therapy was recommended. We have been conducting a phase I clinical trial of G47∆ in patients with progressive olfactory
neuroblastoma since August 2013. The key inclusion
criteria are histologically confirmed recurrent olfactory neuroblastoma despite previous or ongoing radiation therapy, age 18 or older, a measurable tumor lesion (≥1cm) on gadolinium-enhanced T1-MRI of thebrain, life expectancy of at least 3 months, a performance-status of 0-2 and adequate organ function. In
this protocol patients with advanced disease (eg,Kadish stage C) are covered. G47∆ will be repeatedly
inoculated to the residual tumor in nasal cavity every
4 weeks until tumor progression or excessive toxicity
occurred. The primary endpoint is safety, and the secondary endpoints include efficacy analysis.

A clinical study of G47Δ in patients with progressive malignant pleural mesothelioma
Malignant pleural mesothelioma is a rare asbestos-induced malignancy with an estimated incidenceof approximately 2,000 new cases diagnosed in Japan.
Worldwide, nearly 80% of mesothelioma deaths occur in ten countries, with Japan, the United Kingdom,
and the United States being in the top three. It is expected to continue to increase over the next several
decades. Median survival ranges from 9 to 18 months
and correlates with stages. Radiotherapy can be used
for different indications in mesothelioma: palliation,
as a preventive treatment, and as part of multimodality treatment. Combination doublet chemotherapy ofcisplatin, with either pemetrexed or raltitrexed, has
shown a more prolonged survival compared with cisplatin alone in randomized phase III trials. Carboplatin is an acceptable alternative to cisplatin and may bebetter tolerated in the elderly population. We conducted a phase I clinical trial of G47∆ for malignant
pleural mesothelioma from 2018 to 2021. The key inclusion criteria were histologically confirmed malignant pleural mesothelioma that was inoperable, recurrent or progressive, no prior thoracotomy orthoracoscopic surgery, except for biopsy, age 20 orolder, presence of one or more evaluable lesions oncontrast-enhanced CT scan, interval of 4 weeks ormore from prior chemotherapy if it was given, life expectancy of at least 3 months, a performance-status of
0-1 and sufficient major organ functions. In this protocol history of chemotherapy or radiotherapy was irrelative. A fixed dose of G47∆ was administered into
the pleural cavity every 4 weeks, maximum 6 times.
The primary endpoint was safety, and the secondary
endpoints included efficacy analysis. We completed
the enrollment and confirmed the safety of repeatedintrapleural administration with G47∆.
A phase 1/2 clinical trial of a recombinant herpes
simplex type 1 with human IL-12 expression,T-hIL12, in patients with malignant melanoma
Malignant melanoma is a tumor produced by themalignant transformation of melanocytes. Melanocytes are derived from the neural crest; consequently,melanomas, although they usually occur on the skin,can arise in other locations where neural crest cells
migrate, such as the gastrointestinal tract and brain.
The 5-year relative survival rate for patients withstage 0 melanoma is 97%, compared with about 10%
for those with stage IV disease. We started a phase 1/2
clinical trial of T-hIL12 in patients with malignantmelanoma since January 2020 jointly with Shinshu
University. T-hIL12 is a G47∆-based recombinant herpes simplex type I with IL-12 expression. This
IL-12-mediated antitumor immunity could be
T-cell-mediated. The main inclusion criteria in phase
1 are 1) histologically confirmed malignant melano-276
ma with stage 3 or 4, 2) patients who have at least one
metastatic skin lesion with 10 mm or larger (the longest diameter), or at least one metastatic lymph nodewith 15 mm or larger (the shortest axis), 3) patients
who were administered with anti-PD-1 antibody, or
targeted molecular drugs, 4) the size and distributionof all the metastatic lesions are recognized with clinical findings including imaging studies (CT, MRI), 5)
age >=20 years, 6) more than 30 days have passed
from the previous treatment, 7) Eastern Cooperative
Oncology Group (ECOG) performance Status (PS) of0-2, 8) patients without severe disorders (severe myelosuppression, liver dysfunction, chronic renal dysfunction), whereas in phase 2 they are eight items,
which are defined in the same way as in the phase 1
except for 3) of phase1. The 3rd inclusion criterion ofphase2 is 3) patients who have not been administeredwith anti-PD-1 antibody or targeted molecular drugs.
T-hIL12 will be administered into the tumor of skin orlymph node metastases in patients with advanced
stage of malignant melanoma. The assigned dose will
be repeatedly inoculated into the metastases 2 or 4times, with an interval of 14 (14 -28) days. The primary endpoint in phase 1 is safety, and in phase 2 a response rate (RECIST 1.1). The phase 2 part of this trial
is ongoing.

tive microscope, a 3-D neuro-navigation system, intraoperative motor evoked potential (MEP and SEP)
recording, intraoperative ultrasonography and an ultrasonic surgical aspirator.
Patients with newly diagnosed malignant glioma
have been treated with high dose or standard doseradiation therapy and concomitant chemotherapy.
Temozolomide was administered to glioma patientsduring radiation therapy followed by a maintenancetherapy every 28 days for as long as possible. The
overall survival of patients with glioblastoma was30.3 months (95% confidence interval, 24.5-36.1
months. The five-year overall survival rate was 26.5%.
Recurrent malignant glioma patients are treatedwith innovative non-standard therapies wheneverpossible. Recurrent glioma patients who have small
lesions, receive extended field stereotactic radiosurgery. To enhance the efficacy of stereotactic radiosurgery (SRS), the irradiation field is enlarged to include
as many tumor cells invasive to the surrounding tissue as possible. We demonstrated 93% local control
in patients who received 20 Gy to a 0.5-1.0 cm extended field SRS compared to 47% of patients who weretreated with 20 Gy to the gadolinium-enhancing margin only.

Routine activities

Treatment of primary central nervous system lymphoma

Patients with brain tumors are treated by fourneurosurgeons. A total of 112 operations were carriedout in 2023 including 107 gliomas and 3 olfactory neuroblastomas. More than 100 cases of oncolytic virus
therapy were performed. Standard craniotomies andimage guided stereotactic biopsies of deep seated lesions, as well as high-tech brain tumor resections areperformed. The high-tech equipment regularly usedin brain tumor resection surgeries includes an opera-Primary central nervous system lymphoma patients will first undergo biopsy for pathological diagnosis. In addition to the standard therapy regimen
using high-dose methotrexate followed by radiotherapy, an advanced treatment regimen utilizing rituximab, methotrexate, procarbazine, and vincristine(R-MPV) therapy followed by consolidation wholebrain radiation therapy has been used as a treatment
option.

Publications
1.		Yamada T, Tateishi R, Iwai M, Tanaka M, Ijichi H,Sano M, Koike K, Todo T: Overcoming resistanceof stroma-rich pancreatic cancer with focal adhesion kinase inhibitor combined with G47∆ and immune checkpoint inhibitors. Mol Ther Oncolytics
28: 31-43, 2023 [doi: 10.1016/j.omto.2022.12.001.
First published December 6, 2022].
2.		Fukuhara H, Sato YT, Hou J, Iwai M, Todo T: Fusion peptide is superior to co-expressing subunits
for arming oncolytic herpes virus with interleukin
12. Commun Med (Lond) 3 (1): 40, 2023 [doi: 10.
1038/s43856-023-00270-4. First published March25, 2023].
3.		Fukasawa K, Lyu J, Suzuki A, Horie T, Kubo T,Tomizawa A, Osumi R, Iwahashi S, Tokumura K,Murata M, Kobayashi M, Todo T, Hirao A, Hinoi
E: MEK5-ERK5 axis promotes self-renewal and tu-

morigenicity of glioma stem cells via the STAT3
pathway. Cancer Res Commun 3 (1): 148-159, 2023
[doi: 10.1158/2767-9764.CRC-22-0243. eCollection
2023 Jan].
4.		Nomura T, Endo S, Kuwano T, Fukasawa K,Takashima S, Todo T, Furuta K, Yamamoto T, Hinoi E, Koyama H, Honda R: ARL-17477 is a dual
inhibitor of NOS1 and the autophagic-lysosomal
system that prevents tumor growth in vitro and invivo. Sci Rep 13(1):10757, 2023 [doi: 10.1038/s41598-023-37797-4.].
5.		Inoue K, Ito H, Iwai M, Tanaka M, Mori Y, Todo T:
Neoadjuvant use of oncolytic herpes virus G47∆
prevents local recurrence after insufficient resection in tongue cancer models. Mol Ther Oncolytics
30:72-85, 2023 [doi: 10.1016/j.omto.2023.07.002.].