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Practical Application of T-VEC in Melanoma Treatment

Panelists:Keith T. Flaherty, MD, Massachusetts General Hospital; Rene Gonzalez, MD, University of Colorado Melanoma Research Clinics; Jason J. Luke, MD, FACP, University of Chicago Medicine; Jeffrey S. Weber, MD, PhD, NYU Langone Medical Center
Published: Monday, Dec 28, 2015


Transcript:

Keith Flaherty, MD:
Thinking of the mechanism of T-VEC, if you had a patient who you and your surgical colleagues thought was borderline resectable (either within transits that are not so numerous or regional lymphadenopathy alone, where resection is feasible), could you imagine using this window of opportunity to inject that patient before taking them to surgery?

Jason Luke, MD, FACP: I absolutely think that’s an interesting approach. I think it’s something that probably should be more robustly investigated.

But I have to say that if we take from our colleagues in the breast cancer field of using neoadjuvant chemotherapy, correlating that with pathologic complete response with long-term survival, I think that approach is very interesting to think about. We see a fair number of patients where the question about resectability really is in the eye of the beholder.

And, certainly, if we can do anything to make it more likely that the resection really will get the patient disease free, I think any approach would be interesting in that regard.

Keith Flaherty, MD: Jeff was alluding to this so-called priming effect. Maybe you could expand a little bit for listeners for whom immune therapy is still a pretty new concept. What is it that local injection and the effect on tumor could do that’s different than what we believe the CTLA4 PD-1–blocking immune checkpoint antibodies could do?

Jason Luke, MD, FACP: It really has the potential to de novo generate the aspects of an immune response. We have to remember that we use immunotherapy. But, what was immunotherapy, why did our bodies develop it? Well, to fight infections. And that process was triggered around the generation of gamma interferon and the actual response to a local problem. And that’s really what you’re starting to do with T-VEC.

You’re injecting it into the tumor, blowing up the tumor, releasing these immune molecules. That’s going to, like, prime the pump, as we’ve said here before, and I think that has a potential to start a local reaction that perhaps, over time, we can find ways to generate and amplify with other agents, as well.

And I’ll just throw on that there is data as well with T-VEC with ipilimumab, which has actually looked quite impressive, relatively speaking, with what we knew about ipilimumab alone.

Again, more data is needed, but I think that that seconds this idea that combination approaches in the future could be an impressive way to go forward.

Jeffrey Weber, MD, PhD: We’re getting ahead of ourselves, but one of the nice things about ipilimumab is that almost anything that you add to ipilimumab appears to at least be additive or, in some cases you could argue, synergistic.

I like the idea of creating what I would think of as a danger signal. Polly Matzinger described this concept of the danger signal to alert the immune system to break tolerance. And I think that giving T-VEC perhaps creates a danger signal in the local regional disease, which could, I suppose, lead to this concept of immune priming and dissemination of T cells out of the lymph nodes into the circulation to have a systemic effect. But it’s not going to happen with T-VEC alone. Again, as I remember, the data suggested a 16% response rate in distant disease.

Keith Flaherty, MD: Durable response rate.

Jeffrey Weber, MD, PhD: Durable response rate with no systemic survival advantage with M1b or M1c disease. All the benefit was in the local regional stage IIIb/IIIc’s, the intransit metastases, and the M1a disease. And those are the patients that I would think should be injected.

For me, one of the issues is a practical one, and I’d be interested to hear everyone else’s opinion. It takes time to do a local injection, and I think there is probably some requirement at the institutions, since they’re using a virus, to clean the room before and then clean the room after, and this all takes some time.

Jason Luke, MD, FACP: This came up during the clinical trials. This actually is going to become a clinical grade therapeutic that goes in the general pharmacy. And so it’s actually passed muster for most GMP facilities. You don’t have to specially produce it. We went through all of that for the clinical trial and that slowed things down a fair amount, but now it’s been FDA-approved to just be housed with other medicines.

Rene Gonzalez, MD: It’s a good point though. We went through the same thing. Initially, there was concern. We had options like sending the patients to a hotel or actually admitting them into the hospital, an oncology unit. There was concern about pregnant women in the waiting room and cleaning up each room afterwards. There really isn’t any of that.

Jeffrey Weber, MD, PhD: Do you actually clean the rooms afterwards in your experience?

Rene Gonzalez, MD: No.

Jeffrey Weber, MD, PhD: So, it’s made it a lot easier.

Rene Gonzalez, MD: One logistical thing is the preparation of the injection. It has to be thawed. I don’t know how it’s going to come out, but at least the product we were using had to be thawed for about 45 minutes to prepare it, so that’s a lot of waiting—because they don’t actually start to prepare it until the patient shows up.

Keith Flaherty, MD: Storage in a –70º Centigrade freezer, in investigation and approval, is the starting point. One has to give a bit of time before that will equilibrate to room temperature, 4 mL of injectate.

Jeff, just before we leave this topic, this isn’t the first oncolytic virus to ever have been tried as a cancer therapeutic, although perhaps the most heavily thoroughly investigated. There are others that are being considered and even one that I’m aware of, the Coxsackie virus that’s in clinical development, also. What’s your sense in terms of what other innovation could come in this space?

Jeffrey Weber, MD, PhD: Well, I think that the idea of engineering GMCSF into the virus is a reasonable one, but it’s really kind of a first-generation approach.

I think that engineering co-stimulatory molecules—for example, given the ability to encode a single chain molecule that might block PD-1 within that molecule, so that it’s in the tumor microenvironment where you directly inject it—could you actually then block PD-1 using that engineered single-chain antibody? Could you block CTLA4 in the tumor microenvironment?

There are a lot of other molecules other than GMCSF that I could think of that logically would make sense. I’ve seen the Coxsackie virus data. As I remember, they don’t really engineer the Coxsackie virus. It’s very interesting.

Keith Flaherty, MD: That’s right.

Jeffrey Weber, MD, PhD: I have liked the data. I think I heard Robert Andtbacka, who’s a real leader in the field of local regional therapy, present the data. I think it has some promise. I think it should certainly be pursued.

I agree with Rene wholeheartedly that, at the end of the day, this will not be a standalone agent. We will see our immunologic and biologic drugs all in combinations, and the only question is how many can we logically get together without undue toxicity. That’s going to keep us in business for a long time because that’s complex.

Jason Luke, MD, FACP: One other area that I want to just touch on for injectables, as well, is the area of cyclic dinucleotides, which for the audience is probably a little bit far afield. But we’ve learned about how the body senses whether or not there’s cancer present, and we can now actually directly agonize some of those pathways, especially via one called STING.

And so that’s another molecule that’s coming in the injectable space very soon, which looks highly efficacious. We’re very interested in this topic of the injectables. I think there are many different ways we can do it. So I think there’s a lot more to come in this field.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Keith Flaherty, MD:
Thinking of the mechanism of T-VEC, if you had a patient who you and your surgical colleagues thought was borderline resectable (either within transits that are not so numerous or regional lymphadenopathy alone, where resection is feasible), could you imagine using this window of opportunity to inject that patient before taking them to surgery?

Jason Luke, MD, FACP: I absolutely think that’s an interesting approach. I think it’s something that probably should be more robustly investigated.

But I have to say that if we take from our colleagues in the breast cancer field of using neoadjuvant chemotherapy, correlating that with pathologic complete response with long-term survival, I think that approach is very interesting to think about. We see a fair number of patients where the question about resectability really is in the eye of the beholder.

And, certainly, if we can do anything to make it more likely that the resection really will get the patient disease free, I think any approach would be interesting in that regard.

Keith Flaherty, MD: Jeff was alluding to this so-called priming effect. Maybe you could expand a little bit for listeners for whom immune therapy is still a pretty new concept. What is it that local injection and the effect on tumor could do that’s different than what we believe the CTLA4 PD-1–blocking immune checkpoint antibodies could do?

Jason Luke, MD, FACP: It really has the potential to de novo generate the aspects of an immune response. We have to remember that we use immunotherapy. But, what was immunotherapy, why did our bodies develop it? Well, to fight infections. And that process was triggered around the generation of gamma interferon and the actual response to a local problem. And that’s really what you’re starting to do with T-VEC.

You’re injecting it into the tumor, blowing up the tumor, releasing these immune molecules. That’s going to, like, prime the pump, as we’ve said here before, and I think that has a potential to start a local reaction that perhaps, over time, we can find ways to generate and amplify with other agents, as well.

And I’ll just throw on that there is data as well with T-VEC with ipilimumab, which has actually looked quite impressive, relatively speaking, with what we knew about ipilimumab alone.

Again, more data is needed, but I think that that seconds this idea that combination approaches in the future could be an impressive way to go forward.

Jeffrey Weber, MD, PhD: We’re getting ahead of ourselves, but one of the nice things about ipilimumab is that almost anything that you add to ipilimumab appears to at least be additive or, in some cases you could argue, synergistic.

I like the idea of creating what I would think of as a danger signal. Polly Matzinger described this concept of the danger signal to alert the immune system to break tolerance. And I think that giving T-VEC perhaps creates a danger signal in the local regional disease, which could, I suppose, lead to this concept of immune priming and dissemination of T cells out of the lymph nodes into the circulation to have a systemic effect. But it’s not going to happen with T-VEC alone. Again, as I remember, the data suggested a 16% response rate in distant disease.

Keith Flaherty, MD: Durable response rate.

Jeffrey Weber, MD, PhD: Durable response rate with no systemic survival advantage with M1b or M1c disease. All the benefit was in the local regional stage IIIb/IIIc’s, the intransit metastases, and the M1a disease. And those are the patients that I would think should be injected.

For me, one of the issues is a practical one, and I’d be interested to hear everyone else’s opinion. It takes time to do a local injection, and I think there is probably some requirement at the institutions, since they’re using a virus, to clean the room before and then clean the room after, and this all takes some time.

Jason Luke, MD, FACP: This came up during the clinical trials. This actually is going to become a clinical grade therapeutic that goes in the general pharmacy. And so it’s actually passed muster for most GMP facilities. You don’t have to specially produce it. We went through all of that for the clinical trial and that slowed things down a fair amount, but now it’s been FDA-approved to just be housed with other medicines.

Rene Gonzalez, MD: It’s a good point though. We went through the same thing. Initially, there was concern. We had options like sending the patients to a hotel or actually admitting them into the hospital, an oncology unit. There was concern about pregnant women in the waiting room and cleaning up each room afterwards. There really isn’t any of that.

Jeffrey Weber, MD, PhD: Do you actually clean the rooms afterwards in your experience?

Rene Gonzalez, MD: No.

Jeffrey Weber, MD, PhD: So, it’s made it a lot easier.

Rene Gonzalez, MD: One logistical thing is the preparation of the injection. It has to be thawed. I don’t know how it’s going to come out, but at least the product we were using had to be thawed for about 45 minutes to prepare it, so that’s a lot of waiting—because they don’t actually start to prepare it until the patient shows up.

Keith Flaherty, MD: Storage in a –70º Centigrade freezer, in investigation and approval, is the starting point. One has to give a bit of time before that will equilibrate to room temperature, 4 mL of injectate.

Jeff, just before we leave this topic, this isn’t the first oncolytic virus to ever have been tried as a cancer therapeutic, although perhaps the most heavily thoroughly investigated. There are others that are being considered and even one that I’m aware of, the Coxsackie virus that’s in clinical development, also. What’s your sense in terms of what other innovation could come in this space?

Jeffrey Weber, MD, PhD: Well, I think that the idea of engineering GMCSF into the virus is a reasonable one, but it’s really kind of a first-generation approach.

I think that engineering co-stimulatory molecules—for example, given the ability to encode a single chain molecule that might block PD-1 within that molecule, so that it’s in the tumor microenvironment where you directly inject it—could you actually then block PD-1 using that engineered single-chain antibody? Could you block CTLA4 in the tumor microenvironment?

There are a lot of other molecules other than GMCSF that I could think of that logically would make sense. I’ve seen the Coxsackie virus data. As I remember, they don’t really engineer the Coxsackie virus. It’s very interesting.

Keith Flaherty, MD: That’s right.

Jeffrey Weber, MD, PhD: I have liked the data. I think I heard Robert Andtbacka, who’s a real leader in the field of local regional therapy, present the data. I think it has some promise. I think it should certainly be pursued.

I agree with Rene wholeheartedly that, at the end of the day, this will not be a standalone agent. We will see our immunologic and biologic drugs all in combinations, and the only question is how many can we logically get together without undue toxicity. That’s going to keep us in business for a long time because that’s complex.

Jason Luke, MD, FACP: One other area that I want to just touch on for injectables, as well, is the area of cyclic dinucleotides, which for the audience is probably a little bit far afield. But we’ve learned about how the body senses whether or not there’s cancer present, and we can now actually directly agonize some of those pathways, especially via one called STING.

And so that’s another molecule that’s coming in the injectable space very soon, which looks highly efficacious. We’re very interested in this topic of the injectables. I think there are many different ways we can do it. So I think there’s a lot more to come in this field.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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