종양 용해성 바이러스-암 치료에서의 새 시대

Oncolytic Viruses - A New Era for Cancer Therapy

Abstract

최근 수십 년 간 종양 용해성 바이러스(Oncolytic viruses; OV)는 암 치료제로서의 잠재성에 의해 광범위하게 연구되어왔다. 종양 용해성 바이러스는 두 가지의 독특한 장점을 가지고 있는데, 첫째로 암세포만을 특이적으로 감염시키고 사멸시킬 수 있다는 것이고, 두 번째로는 암이 진행되는 초기 단계에 숨어서 인식되지 않는 상태인 종양 관련 항원들을 인식하는 특정한 적응 면역을 활성화 시키는 것이다. 2015년에는 유전자 변형 종양 용해성 바이러스인 Talminogene laherparepvec (T-VEC)이 미국 식약청(FDA)의 승인을 받았으며, 현재는 다양한 종양 용해성 바이러스들이 단일로 사용되거나 기존의 암 치료 방법인 면역 치료법, 방사선 치료법, 화학 치료법과 함께 사용되어 임상 시험에서 활성이 연구되고 있다. 종양 용해성 바이러스 치료법의 효능은 항 종양 면역 활성과 항바이러스 반응의 균형이 어느 정도인가에 의해 조절되기 때문에, 획기적인 성과에도 불구하고 암 치료를 위한 종양 용해성 바이러스의 개발은 전달 방법, 바이러스를 인식하는 신체 내 항체 및 종양의 복잡성, 가변성, 반응성에 따른 항바이러스의 면역 유도와 같은 다양한 장애물을 극복하여야 하는 문제가 있다. 종양 내에 직접 종양 용해성 바이러스를 투여하는 방법은 눈에 띄는 부작용이 없이 고형 종양을 줄이는 것에 성공하였으나, 아쉽게도 뇌종양 같은 일부 종양에는 사용할 수 없고 전신 투여가 필요한 단점이 존재한다. 이러한 장애물들을 극복하기 위해서 종양 용해성 바이러스의 효능을 높이기 위한 형질 전환 유전자의 삽입 혹은 면역 조절 물질과 바이러스를 조합하는 등의 다양한 전략들이 개발되고 있다.

In recent decades, oncolytic viruses (OVs) have extensively been investigated as a potential cancer drug. Oncolytic viruses have primarily the unique advantage in the fact that they can only infect and destroy cancer cells. Secondary, oncolytic viruses induce the activation of specific adaptive immunity which targets tumor-associated antigens that were hidden during the initial cancer progression. In 2015, one genetically modified oncolytic virus, talimogene laherparepvec (T-VEC), was approved by the American Food and Drug Administration (FDA) for the treatment of melanoma. Currently, various oncolytic viruses are being investigated in clinical trials as monotherapy or in combination with preexistent cancer therapies like immunotherapy, radiotherapy or chemotherapy. The efficacy of oncolytic virotherapy relies on the balance between the induced anti-tumor immunity and the anti-viral response. Despite the revolutionary outcome, the development of oncolytic viruses for the treatment of cancer faces a number of obstacles such as delivery method, neutralizing antibodies and induction of antiviral immunity due to the complexity, variability and reactivity of tumors. Intratumoral administration has been successful reducing considerably solid tumors with no notable side effects unfortunately some tumors are not accessible (brain) and require a systemic administration of the oncolytic viruses. In order to overcome these hurdles, various strategies to enhance the efficacy of oncolytic viruses have been developed which include the insertion of transgenes or combination with immune-modulatory substances.

Fig. 1. Principle of oncolytic virotherapy. Oncolytic viruses are natural or programmed cancer-killing viruses. The infection of normal leads to the activation of antiviral pathway such as Type 1 interferons which will block the virus replication. In cancer cells, antiviral and cell proliferation pathways are altered and oncolytic viruses utilize these disruptions to specifically target and infect only cancer cells which lead to the lysis of infected cancer cells and the expansion of oncolytic viruses to other tumor cells.

Fig. 2. Mechanisms of oncolytic viruses. Oncolytic viruses enter the cell through the interaction with cell receptors that are usually overexpressed in cancer. Some viruses utilize more than one specific receptor but different viruses can also share one receptor. Other viruses enter the cell via endocytosis through fusion of membranes. Once in the cell, viruses take advantage of aberrant pathways to replicate. CD, Cluster of differentiation; CAR, Coxsackievirus-adenovirus receptor; ICAM-1, Intracellular adhesion molecule 1; LDLR, Low density lipoprotein receptor; HSV, Herpes simplex virus; HVEM, Herpesvirus entry mediator; SARs, Sialic acid receptors; SLAM, Signaling lymphocyte activation molecule; JAK, Janus kinase; STAT, Signal transducer and activator of transcription; Rb, Retinoblastoma; PKR, Protein kinase R; RIG-Ⅰ, Retinoic acid-inducible gene Ⅰ; TK, Thymidine kinase.

Fig. 3. The induction of immune response by oncolytic viruses. The cell lysis of cancer cells by oncolytic viruses is followed by the release of neo-oncolytic viruses, tumor-associated antigens (TAAs), danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). The new oncolytic viruses can infect other existing cancer cells and continue the cycle of cancer cells elimination. TAAs, DAMPs and PAMPs are processed by antigen presenting cells (APCs) and initiate adaptive immune response by CD8⁺T lymphocytes against cancer cells.

Table 1 Clinical trials of oncolytic virus