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ИССЛЕДОВАНИЕ КРОВО-ЛИМФОТОКА В БИОЛОГИЧЕСКИ АКТИВНЫХ ТОЧКАХ СЕРДЕЧНОГО МЕРИДИАНА
Pushkar_IM_RUDN_2018_isp-1.pdf
ИЗМЕРЕНИЕ ГЕМО-ЛИМФОЦИРКУЛЯЦИИ МОЛОЧНОЙ ЖЕЛЕЗЫ В НОРМЕ
ONCOLYTIC VIRUS THERAPY
Y. Chapurin T. Volkova
Peoples' Friendship University of Moscow
4apyrin@gmail.com
satoshi.hid@ya.ru
Abstract
Oncolytic viruses (OV) are viruses that can selectively infect, replicate and kill cancer cells while not affecting normal tissue[3]. Although the mechanisms of action are not fully elucidated oncolytic viruses are thought to mediate antitumour activity through two distinct modes of action: selective replication within cancer cells resulting in a direct lysis of tumour cells and an induction of systemic antitumour immunity. Although oncolytic viruses can enter cancer cells as well as normal cells, cancer cells are defective at killing the virus. One reason is that the protection mechanisms against viral infections are impaired in most of the cancer cells [4].
Local replication of oncolytic virus induces specific antitumor immunity in the course of its oncolytic activities that act on remote lesions. A combination with immune checkpoint inhibitors or chemotherapy may enhance the efficacy of oncolytic virus therapy. Arming oncolytic viruses with immunostimulatory gene(s) or cancer therapeutic genes may also be beneficial.
Keywords: oncolytic viruses (OV), oncology, cancer treatment, antitumour immunity.
History of Clinical use
The concept of using virus as antitumour agents emerged over a century ago. In 1904 a tumour regression has been observed for a woman diagnosed with uterine cancer and after being given the rabies vaccine. Between 1950 and 1980, many patients were treated with a wide range of wild type or attenuated viruses (West Nile fever, adenoviruses, hepatitis, measles) with no success. Controlling and maintaining the replication of the oncolytic virus in cancer cells was the main challenge. Attempts to develop cancer cell-specific viruses gave birth to a variety of native and genetically engineered viruses used as oncolytic agents.
The idea of using naturally occurring viruses for the treatment of cancer was almost abandoned after vigorous attempts during the 1960s and 1970s because of the lack of means to control viral pathogenicity at the time. However, the idea was revived along with the emerging development of genetically engineered viruses, and newly
developed naturally occurring viruses are typically those that are not pathogenic in humans.
Modern clinical researches
With the development of modern techniques of genetic engineering and increasing knowledge regarding the functions and structures of viral genes, designing and manipulating the viral genome to create a non-pathogenic virus has become the standard method for oncolytic virus development. Typically, DNA viruses are used for this strategy.
T-Vec research. The safety of T-Vec was tested in a phase I study in patients with various metastatic tumors, including breast, head/neck and gastrointestinal cancers, and malignant melanoma. Overall, intralesional administration of the virus was well tolerated by patients [6]. Although no complete or partial responses were observed, stable disease was observed in several patients, and most tumor biopsies showed tumor necrosis. T-Vec was further tested in phase II studies in patients with metastatic melanoma [12]. A single arm phase II study resulted in an overall response rate of 26%, with responses in both injected and uninjected lesions, including visceral lesions. A randomized phase III trial was performed in patients with unresected stage IIIB–IV melanoma [1]. A total of 436 patients were randomly assigned in a 2:1 ratio to intralesional T-Vec or subcutaneous GM-CSF treatment arms. T-Vec was administered at a concentration of 10^8 plaque forming units (pfu)/mL injected into 1 or more skin or subcutaneous tumors on Days 1 and 15 of each 28-day cycle for up to 12 months, while GM-CSF was administered at a dose of 125 lg/m²/day subcutaneously for 14 consecutive days followed by 14 days of rest, in 28-day treatment cycles for up to 12 months. At the primary analysis, 290 deaths had occurred (T-Vec, n = 189; GM-CSF, n = 101). The durable response rate (objective response lasting continuously ≥6 months) was significantly higher in the T-Vec arm (16.3%) compared with the GM-CSF arm (2.1%). The overall response rate was also higher in the T-Vec arm (26.4 vs 5.7%). This phase III trial was the first to prove that local intralesional injections with an oncolytic virus can not only suppress the growth of injected tumors but also prolong the OS, supposedly via induction of systemic antitumor immunity. Based on this observation, several clinical trials of T-Vec in combination with systemic administration with immune check point inhibitors are ongoing.
G47Δ research. G47Δ is currently the only third generation HSV-1 to be tested
in humans [13]. Following the phase I–IIa study in patients with recurrent glioblastoma that was conducted in Japan and successfully completed in 2014, a phase II study started in 2015 in patients with residual or recurrent glioblastoma. G47Δ is injected stereotactically into the brain tumor twice within 2 weeks and then every 4 weeks, for
a maximum six times. In February 2016, G47Δ was designated as a “Sakigake” breakthrough therapy drug by the Ministry of Health, Labour and Welfare of Japan (MHLW). “Sakigake” is a Japanese word meaning “ahead of the world.” This new system by the Japanese government provides the designated drug candidate, namely G47Δ, with an early assessment and priority reviews by the Pharmaceuticals and Medical Devices Agency of Japan (PMDA), and therefore should allow its fast-tracked drug approval by MHLW.
JX-594 research. JX-594 (pexastimogene devacirepvec, Pexa-Vec) is a genertically engineered vaccinia virus. The advantages of using vaccinia virus include intravenous stability for delivery, strong cytotoxicity and extensive safety experience as a live vaccine [8]. In a phase I study, intralesional injection of primary or metastatic liver tumors with JX-594 was generally well tolerated in the context of JX-594 replication, GM-CSF expression and systemic dissemination. Direct hyperbilirubinemia was the doselimiting toxicity [10]. High dose JX-594 was used for a doseescalation phase I trial to test the feasibility of intravenous delivery [2]. A randomized phase II dose-finding trial was performed in patients with hepatocellular carcinoma [5]. When a low or high dose of JX-594 was infused, OS was significantly longer in the high dose arm compared with the low dose arm (n = 14 vs 16, median OS 14.1 vs 6.7 months, respectively). A phase III trial in patients with advanced stage hepatocellular carcinoma began enrolling patients in late 2015 (PHOCUS, NCT02562755). In this trial, JX-594 is administered intralesionally three times bi-weekly at days 1, 15 and 29, followed by sorafenib at day 43, whereas, in the control arm, sorafenib begins on Day 1 at 400 mg twice daily.
Conclusion
It would not be too early to say that oncolytic virus therapy is now established as an approach to treat cancer. Because an induction of specific antitumor immunity in the course of oncolytic activities is the common feature that plays an important role in presenting antitumor effects, the efficacy of oncolytic virus therapy is expected to improve further when combined with immunotherapy. By arming oncolytic viruses with functional transgenes, a whole panel of oncolytic viruses with a variety of antitumor functions would be available in the future, from which a combination of appropriate viruses can be chosen according to the type and stage of cancer. A new era of cancer treatment seems at dawn, where cancer patients can freely choose oncolytic virus therapy as a treatment option.
Future directions
Significant progress has been made in the development of oncolytic viruses as a cancer therapy in the last few years. Improved tumor cell targeting and methods for enhancing the antitumor immune response have been particularly useful for increasing
the therapeutic potency of oncolytic viruses. A better understanding of the functional roles of various viral genes has aided the modification of oncolytic viruses to alter tumor selectivity, pathogenicity, and immunogenicity, and to optimize the clinical potential of these vectors. Further investigation will need to focus on optimal selection of viruses, tumor types and stages of disease, viral dose and schedules, routes of delivery, and identifying potential combinations that may enhance or add to the pharmacological mechanisms of action for these unique vectors. Oncolytic viruses represent a highly targeted approach to established cancer that brings a multimechanistic approach and an acceptable safety profile to patients with a variety of cancers. The next few years will likely be exciting with the completion of several large randomized clinical trials and additional refinements in vector design and combination therapy.
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