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Vaccines for Renal Cell Carcinoma

Panelists:Carlos H. Barrios, MD, PUCRS School of Medicine; Daniel HEng, MD, MPH, FRCPC, Tom Baker Cancer Center; Paul Nathan, MBBS, PhD, FRCP, Mount Vernon Cancer Centre; Susanne Osanto, MD, PhD, Leiden University Medical Center; Nizar M. Tannir, MD, FACP, University of Texas MD Anderson Center
Published: Wednesday, Feb 24, 2016


Transcript:

Daniel Heng, MD, MPH, FRCPC:
So we’ve talked about TKIs and PD-1 inhibitors. Let’s talk about vaccines. There are a few in study. Nizar, do you want to talk about the ADOPT trial?

Nizar M. Tannir, MD, FACP: Sure. There are two phase III trials with vaccines that have been recently conducted; one was presented at ECC this last September by Brian Rini. Both phase III trials, although they’re using different vaccines, had similar design, with sunitinib as a comparator versus the experimental arm of sunitinib, plus the vaccine. The difference in the vaccine between the two trials is that the IMA901 trial used an off-the-shelf tumor associated peptide vaccine. They give it to all patients. So, the primary endpoint for both was overall survival (OS). The IMA trial was negative. It did not show a survival advantage for this tumor-associated peptide vaccine in combination with sunitinib.

The ADAPT trial is using a patient unique vaccine taken from patients own kidney where, at the time of nephrectomy the specimen is harvested, and the vaccine is generated. It’s a dendritic cell-based vaccine that’s RNA—so it’s an RNA vaccine in combination with sunitinib. The trial finished accrual this past summer. It’s somewhere around 450 patients. We’ll see what the results will be. I think they are not anticipated before 2017. Again, the primary endpoint is OS. I hope it will be positive because it will be another option for our patients to use a patient unique vaccine, but we’ll wait and see if the results will be positive.

Paul Nathan, MBBS, PhD, FRCP: Obviously, all vaccines are not the same. You really do need to look at the specifics of each vaccine rather than making decisions about all vaccines. But we’ve now got two negative large phase III studies in renal cancer with vaccines. It’s not just the most recent one. There’s the TroVax vaccine from years ago as well.

Daniel Heng, MD, MPH, FRCPC: That’s right.

Paul Nathan, MBBS, PhD, FRCP: And in other cancers there are a number of large negative phase III studies. And the bottom line looks as if when you’re dealing with diseases that have the potential to be controlled by the immune system, if you suboptimally try to activate the immune system, you may be inducing allergy or nonresponsiveness in those tumor lymphocytes and patients do worse. And, actually, I’m wary now about considering trials of vaccines on their own without some really robust data that make me feel comfortable offering to patients. Because there aren’t many settings where we’re randomizing patients, where we’ve got some historical data implying that if we’re not careful, patients may do worse than with standard of care. So I think the role of vaccines increasingly is probably going to be with combinations and taking some of the more highly active immunotherapeutics and seeing whether we can increase the bar of those with vaccination. I think that’s obviously where the field is going to be going.

Carlos H. Barrios, MD: Another important concept in that line is the fact that vaccines are directed through a specific antigen. And in an evolving disease, heterogeneous disease, we cannot guarantee that that antigen will remain as an active part of progression of the disease. So it may work to a certain clone or at a certain time in treatment evolution and not necessarily at the end. So the combination certainly is a good concept when you apply it, and, and I agree with you, that the data, in general with vaccines, has been not very impressive so far.

Daniel Heng, MD, MPH, FRCPC: Carlos, do you want to talk more about the combination trials? So now checkpoint inhibitors are also being combined and even with TKIs. Can you comment on those?

Carlos H. Barrios, MD: Certainly. Nizar was presenting the data of the combination of the anti-VEGF and the mTOR inhibitor as the first time over the last 15 years that we have been able to target both pathways in that regard. So this has been a concept that has been clearly established in oncology in general. We manage complex and heterogeneous disease by targeting different pathways at the same time, and routinely or in most cases we found better results. So this concept actually leads to the fact that if we have single agent activity with immunotherapy, single agent activity with other targeted agents, the idea is to combine them. The problem has been the fact that all these agents have not necessarily been able to combine with each other because of toxicity. As we mentioned before, [there is] the trial that comparing sunitinib as a first agent after first-line therapy with combination nivolumab and ipilimumab. That [immunotherapy combination] has been proven effective in other tumor types, melanoma. It’s obviously a very important step forward.

Whether we can combine this combination with other targeted agents, obviously, is something we still don’t know but there remains a lot of interest in that kind of situation. So far, the combinations of immunotherapy as single agents with targeted agents has been very preliminary with some results. We don’t know what the best dose is. We don’t know the toxicity and some of the initial trials have been very complicated to analyze. I think it remains a subject of active investigation and we should pursue this kind of line of research further, although I would encourage everybody that is doing this to collect biological material in order to rationally develop this area.
                                                                                                                                                                                                                                                                                                                Transcript Edited for Clarity
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Transcript:

Daniel Heng, MD, MPH, FRCPC:
So we’ve talked about TKIs and PD-1 inhibitors. Let’s talk about vaccines. There are a few in study. Nizar, do you want to talk about the ADOPT trial?

Nizar M. Tannir, MD, FACP: Sure. There are two phase III trials with vaccines that have been recently conducted; one was presented at ECC this last September by Brian Rini. Both phase III trials, although they’re using different vaccines, had similar design, with sunitinib as a comparator versus the experimental arm of sunitinib, plus the vaccine. The difference in the vaccine between the two trials is that the IMA901 trial used an off-the-shelf tumor associated peptide vaccine. They give it to all patients. So, the primary endpoint for both was overall survival (OS). The IMA trial was negative. It did not show a survival advantage for this tumor-associated peptide vaccine in combination with sunitinib.

The ADAPT trial is using a patient unique vaccine taken from patients own kidney where, at the time of nephrectomy the specimen is harvested, and the vaccine is generated. It’s a dendritic cell-based vaccine that’s RNA—so it’s an RNA vaccine in combination with sunitinib. The trial finished accrual this past summer. It’s somewhere around 450 patients. We’ll see what the results will be. I think they are not anticipated before 2017. Again, the primary endpoint is OS. I hope it will be positive because it will be another option for our patients to use a patient unique vaccine, but we’ll wait and see if the results will be positive.

Paul Nathan, MBBS, PhD, FRCP: Obviously, all vaccines are not the same. You really do need to look at the specifics of each vaccine rather than making decisions about all vaccines. But we’ve now got two negative large phase III studies in renal cancer with vaccines. It’s not just the most recent one. There’s the TroVax vaccine from years ago as well.

Daniel Heng, MD, MPH, FRCPC: That’s right.

Paul Nathan, MBBS, PhD, FRCP: And in other cancers there are a number of large negative phase III studies. And the bottom line looks as if when you’re dealing with diseases that have the potential to be controlled by the immune system, if you suboptimally try to activate the immune system, you may be inducing allergy or nonresponsiveness in those tumor lymphocytes and patients do worse. And, actually, I’m wary now about considering trials of vaccines on their own without some really robust data that make me feel comfortable offering to patients. Because there aren’t many settings where we’re randomizing patients, where we’ve got some historical data implying that if we’re not careful, patients may do worse than with standard of care. So I think the role of vaccines increasingly is probably going to be with combinations and taking some of the more highly active immunotherapeutics and seeing whether we can increase the bar of those with vaccination. I think that’s obviously where the field is going to be going.

Carlos H. Barrios, MD: Another important concept in that line is the fact that vaccines are directed through a specific antigen. And in an evolving disease, heterogeneous disease, we cannot guarantee that that antigen will remain as an active part of progression of the disease. So it may work to a certain clone or at a certain time in treatment evolution and not necessarily at the end. So the combination certainly is a good concept when you apply it, and, and I agree with you, that the data, in general with vaccines, has been not very impressive so far.

Daniel Heng, MD, MPH, FRCPC: Carlos, do you want to talk more about the combination trials? So now checkpoint inhibitors are also being combined and even with TKIs. Can you comment on those?

Carlos H. Barrios, MD: Certainly. Nizar was presenting the data of the combination of the anti-VEGF and the mTOR inhibitor as the first time over the last 15 years that we have been able to target both pathways in that regard. So this has been a concept that has been clearly established in oncology in general. We manage complex and heterogeneous disease by targeting different pathways at the same time, and routinely or in most cases we found better results. So this concept actually leads to the fact that if we have single agent activity with immunotherapy, single agent activity with other targeted agents, the idea is to combine them. The problem has been the fact that all these agents have not necessarily been able to combine with each other because of toxicity. As we mentioned before, [there is] the trial that comparing sunitinib as a first agent after first-line therapy with combination nivolumab and ipilimumab. That [immunotherapy combination] has been proven effective in other tumor types, melanoma. It’s obviously a very important step forward.

Whether we can combine this combination with other targeted agents, obviously, is something we still don’t know but there remains a lot of interest in that kind of situation. So far, the combinations of immunotherapy as single agents with targeted agents has been very preliminary with some results. We don’t know what the best dose is. We don’t know the toxicity and some of the initial trials have been very complicated to analyze. I think it remains a subject of active investigation and we should pursue this kind of line of research further, although I would encourage everybody that is doing this to collect biological material in order to rationally develop this area.
                                                                                                                                                                                                                                                                                                                Transcript Edited for Clarity
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