访谈原文

　　Oncology Digest: We will start off by thanking you for that informative update of the oncolytic viruses， it’s a clinical fascinating study of treating cancers and tumors. So maybe you could give us a quick summary about which viruses are available， which ones are in clinical trial， pre-trial and what the results are of using the virus.

　　《肿瘤瞭望》：目前可用于临床或临床前研究的溶瘤病毒有哪些？效果如何？

　　Prof. Andtbacka: It’s been a very good conference and had a lot of information about different ways of treating melanoma and I think what has become clear for us is that there is not really a “one size fits all”; I think it really depends on the type of the tumor the patients have， it also depends on the genetic profile and the genetic mutations of those tumors. One of the newer modalities that patients have， which is not very new， this has been around for 200 years using viruses to treat cancer. We know that in the 1800’s and 1900’s they actually used viruses to treat certain patients with cancers. This is not a new therapy. What has happened though over the past 15 to 20 years we really have asked the question ‘How can we use viruses to treat cancer?’ and this has led to whole concept of  oncolytic immunotherapy. What this is， is using viruses that we often directly inject into tumors and when the viruses get into the tumor cells it replicates and causes tumor cell liaises， exposure of tumor specific proteins to the immune system; then activation of the immune system locally to fight the tumor but also the activation of the immune system to fight tumor cells at distant sides. There are several mechanisms that we can do this; viruses are really the main therapy that is currently being developed for this and the melanoma really lends itself to these oncolytic immunotherapis because we have lesions that we can easily inject since melanomas can develop both in transit metastases these are cutaneous subdural lesions or lymph node lesions.

　　Looking then at the viruses that are the furthest along in development at this point in time， there really are 2 viruses， one of them has just completed a phase 2 study is the Coxsackie virus A21and that virus is a natural occurring virus it has not been modified， but it has been shown to be a very living virus when exposed to cancer cells. In that study， patients with stage 3C equivalent or stage 4 melanoma with at least one lesion that could be injected; either dermal， subcutaneously or via lymph node underwent injection with the Coxsackie virus and what we found was that it was very tolerable by patients. There were no grade 3 or 4 toxicities from that study， also found that there were responses not only in injected tumors but also in bi-standardizations that were not injected both in regional bi-standardizations legions and in legions that were distant sites such as in the lung and other visceral sites (very encouraging data). I think that in moving forward， we will also be looking at combination therapies and certain mono-therapies.

　　The other virus that we spoke about is talimogenela herparepvec (TVEC)?and this is a herpes simplex type 1 virus. Now herpes as many of the readers are probably familiar with that herpes type 1 causes mouth sores but this virus does not cause us mouth sores by itself as it has been genetically modified， so it really only replicates in tumor cells. The virus has to be directly injected into the tumors where the mechanism of replication action seems to be the same in tumor cells; leads to your exposure then of a melanoma specific protein which activates the immune system locally to fight the melanoma but also creates a memory in the immune system to fight the melanoma at distant sides. The optimum study which is the phase 3 rounds of my study which again is stage 3B， 3C and stage 4 disease that had at least one injectable either dermal， subcutaneous or via lymph nodes lesion. Patients were random and selected in a 2:1 fashion with a GM CSF and the primary end point of this was actually was an appropriate primary end point. It looked at what’s called Durable Response Rate. So within these newer response therapies not only do we want to see patients having a response we want that response to be long-lasting， to be durable. So the way this was defined as part of the study patients had to respond during the first 12 months of the initiating the treatment. There was a modified WHO criteria used for this and that response had to last for at least 6 month for the patient to be considered to have a durable response. This study showed that there was a significantly greater durable response rate in the TVEC in comparison to the competitor which was GM CSF. The objective response rate was greater for TVEC compared to GM CSF. Also we found that the durability of the response was there in the patients that responded. Over 65% of patients had a response that lasted 12 months or longer. We found that there was minimal toxicity to patients， very few grade 3 and grade 4 toxicities; the most common grade 3 and 4 toxicity was cellulitis occurring in 2.1% of patients. So I think that overall this treatment is very well tolerated by patients. The next question in the melanoma community is ‘How do we then position these treatments?’ I think that we want to see response in both injecting the lesion and not injecting the lesions and TVEC did show us responses in all these areas so I think moving forward there will be a treatment modality that has the potential to be used as mono-therapy but also looking at this in combination therapy due to very low side effect profile from these; they can very well be combined with other immunotherapies but also potentially help other targeted therapies as well.

　　Oncology Digest: It seems like the newer modalities have to do with mostly controlling the tumor and not letting it get to where it’s causing disease states. But if we can keep it there you can probably live with it and die with it but not die from it.

　　《肿瘤瞭望》：看来现在的一类新趋势是控制肿瘤（而非消灭肿瘤），使患者长期带瘤生存。

　　Prof. Andtbacka: I think that some of the paradigms have shifted， in that previously when we had only chemotherapy available we really wanted to completely eliminate the tumor. I think we still have that as our goal; ultimately we would like our patients to have a complete response to our treatments. But we do know that many patients do not have a complete response. So I agree with you from the perspective that we can have patients having a stable disease and having no progression of their disease and having a durable no evidential progression. I think we are winning the game， especially if we can do this with minimal toxicity to the patient.

　　Oncology Digest: Well it sounds like a step in that direction.

　　Prof. Andtbacka: I think it is a step in that direction. Also， with this there are many patients that have this disease and they have not yet developed a distant metastatic disease and really for me as a surgeon I ultimately would like those patients never to develop distant metastatic disease. I think that is where modalities such as the oncolytic immunotherapy  can potentially be beneficial， we can use these treatments to try to control their disease when it’s still local regional and have not developed distant metastatic disease. To that effect where actually now about to initiate anew regiment study; patients with resectable stage 3B， 3C and stage 4 N1a melanoma; patients will be randomized to either receive surgery upfront which currently would be the standard of care versus TVEC followed by surgery. The primary end point for this is recurrence free survival and trying to prevent these patients for high regiment setting for developing recurrence of the disease trying to activate the immune system upfront to develop resistance against their disease.

　　Oncology Digest: Here in China they are doing a study on the ORNEX 010.

　　《肿瘤瞭望》：您如何评价中国目前开展的ORNEX 010研究？

　　Prof. Andtbacka: Yes actually it’s an interesting concept so right now Dr. Guo Jun in the Beijing Cancer Hospital is also doing an oncolytic immunotherapy and it is called ORNEX 010. Which is also a herpes simplex virus but what is interesting about this virus is that it is a little bit more modeled according to that type of herpes simplex type 1 virus that is seen in Asia versus the talimogenela herparepvec that we see in western countries， this is an attempt to really use a virus that is more local in nature and where the patients with the disease are located. So it’s a phase one study and they have enrolled patients on to this; it’s been very well tolerated and they also have seen responses in both injected and non injected lesions. I think that this is something that really lends itself to the patients that we see in China; they are different many times compared to what we see in implications in the western countries. Patients in China tend to have more acrallentiginous melanoma; these are also the patients that then develop the intrinsic disease. When we know that patients develop these intrinsic lesions often they do not have any distant disease. So again， these local regional therapies with oncolytic immunotherapy; is one modality that can be used to control and really treat these. I think that from that perspective using oncolytic immunotherapy in China is really an ideal place to try to evaluate and try to find the true role of these in the treatment of melanoma.

　　Oncology Digest: Is the development of the virus more cost effective than developing a BRAF inhibitor? Are these going to be more available to get to countries that perhaps don’t have the money for BRAF and other treatment supplies?

　　《肿瘤瞭望》：您觉得与BRAF抑制剂和其他药物相比，溶瘤病毒疗法会更具成本效益优势吗？

　　Prof. Andtbacka: I think that that is a really good question and it bring to the concept of drug development and cost of drug development and how do we make these available. We know that especially in the United States the currently available drugs for metastatic melanoma whether they are anti-CTLA-4 treatments or BRAF inhibitors or now the anti-PD1 inhibitor. They are extremely expensive and long term; we are happy to see the responses but they are very expensive so from that perspective we would like to see developmental treatments that are less expensive. Whether these oncolytic immunotherapies will have that we don’t know that is really going to be up to companies developing these and also to the regulator agencies that look at the approval for these to try to determine multiple factors including approval processes as well as the cost for these to the public once they become available.

　　Oncology Digest: Let’s talk about the sentinel lymph node biopsy. When are you planning on using that for melanomas?

　　《肿瘤瞭望》：有关前哨淋巴结活检，您在临床实践中是如何实施的？

　　Prof. Andtbacka: So I think sentinel biopsy has been a game changer in the treatment with stage 1 and stage 2 melanoma， these are patients that do not clinically have any evidence of metastatic disease. So we do know that patients who present primary melanoma and no evidence of metastatic disease there is a graded percentage of patients that will have microscopic metastatic disease. To frame this in the perspective of the western countries the majority of patients presenting have fairly thin melanomas while in China and most Asian countries is a little bit different. Here the melanomas seem to be thicker on initial presentation; we know that as the thickness of the melanoma increases， the risk of lymph node involvement also increases. Our current guidelines， in the United States， is that for patients who have 1mm melanomas or thicker we would recommend a sentinelbiopsy to evaluate the sentinel lymph nodes.

　　In my own practice， the way I look at this is any treatment renders our patients we have to look at the risks， benefits and alternatives to this. So if we look at the risk of doing a sentinel biopsy those morbidities and risks are fairly low to patients， they tend to be 5% or less and tend to be transient. What I have done in my own practice， the risk of finding metastases in the lymph node has to be at least 5% for us to discuss and offer this to the patient. We then have to look at the perimeters that makes this a 5% risk， so we do know that thicker melanomas that are 0.75 mm or greater tend to have 5% or greater risk of having lymph node involvement. This is where I have chosen that my cut off is 0.75 mm that I would discuss this with my patients and recommend it. There are patients that have melanomas that are less than 0.75 mm but they have other features such as ulceration and increase in mitotic count which is also known to increase the risk of lymph node involvement. I would also discuss the procedure with them and recommend it. It is important to recognize that our role as physicians is really to educate the patient and it’s ultimately up to the patient to decide how they wish to proceed with this; balancing the risks， benefits and alternatives for this.