Innovative Research for Advanced Kidney Cancer - David Braun

Alicia Morgans and David Braun discuss his innovative research in metastatic kidney cancer which focuses on understanding and improving immunotherapies in kidney cancer.  His work utilizes immunogenomic approaches to generate mechanisms of response and resistance to existing immunotherapies.  He is working to develop novel immune-based treatments.  David’s key talking points are driven from the thought-provoking question of what is driving the response and resistance to these existing adjuvant therapies in advanced disease, to understand how can we better fit the right drug with the right patient, and also thinking about approaches to overcome resistance.  He focuses on the recurrence in patients who have had their cancerous kidney removed where about half will recur with advanced kidney cancer.  Today immune checkpoint inhibitors are approved and used in metastatic kidney cancer and yet many patients do not benefit from the therapy. The new approach in a phase 1 clinical trial, is aimed at improving the success of immunotherapy for these patients by combining a checkpoint-blocking antibody with a personalized vaccine designed to recognize cancer-specific proteins, called neoantigens, that are present on the individual’s cancer cells but not on normal cells.  

Biographies:

David Braun, MD, Ph.D., the John R. Svenson Fellow in Oncology at the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute,  Fellow Brigham and Women's Hospital, and Massachusetts General Hospital, Boston, MA. 

Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Read the Full Video Transcript

Alicia Morgans: Hi, I'm thrilled to have here with me today Dr. David Braun, who is a Medical Oncology Fellow at the Dana-Farber. Thank you so much for being here with us today.

David Braun: Of course. My pleasure.

Alicia Morgans: Wonderful. I wanted to talk to you a little bit about your innovative research in kidney cancer, and how the approaches that you're taking in sort of a vaccine kind of venue fit into the current clinical landscape and how they're going to really take us to the next level.

David Braun: Yeah absolutely. First of all, thank you for the opportunity. This is really nice to sort of have this discussion. It's been so exciting to see the development of kidney cancer therapeutics, particularly in the advanced disease state.

Alicia Morgans: Yes.

David Braun: And really checkpoint blockade now has become part of the mainstream, the standard of care in various sorts of combinations. While that it is tremendously exciting and there's many, many patients who are receiving benefit, we know that still, unfortunately, the majority of patients won't have a long-term durable benefit from these drugs. While there's a lot of room for excitement, myself included, there's still a long way to go in terms of things that need to be developed.

So, kind of the work that I've been doing under the strong mentorship of both Toni Choueiri and Catherine Wu is really try to understand what's driving the response and resistance to these existing therapies to understand how can we better fit the right drug with the right patient, and also thinking how to overcome resistance. Then think of novel therapies within that sort of immune therapy world to really focus the immune response onto the tumor itself and try to increase efficacy and safety of these approaches.

Alicia Morgans: Give us an example of one of these approaches. What are you thinking about for localized disease for example?

David Braun: Yeah absolutely. For localized disease, right now if the tumor is cut out, there's really not an incredibly effective therapy that's going to help patients to live longer.

Alicia Morgans: In this adjuvant setting.

David Braun: In this adjuvant setting, yeah. Of course, there's ongoing trials of checkpoint blockades that are exploring this question, but right now we really don't know if some of that is going to improve the overall survival of those patients. That's really where we're taking an initial step is to look at okay how can we not only use existing immune based therapies but actually build off of those to really focus the immune system onto the tumor. Again, try to increase the efficacy of these drugs, but also in the adjuvant setting particularly the safety of these drugs. I sort of think of the existing immune checkpoint drugs as really cutting the brakes. We hope that when we cut the brakes and let the immune system loose it's really going to attack the cancer. We know that happens, but it can attack many other things as well. So what we're examining is really the addition of vaccine based approaches, personalized vaccines with the goal of not just cutting the brakes, but really steering the immune system into the tumor specifically.

Alicia Morgans: How are you developing these vaccines and making them so personalized?

David Braun: That's a great question. I think the short answer is it sort of takes a village. It's a huge collaborative effort. This really builds off the pioneering work of Cathy Wu in this space of personalized cancer vaccines. Now working with the clinical team here, primarily Dr. Choueiri, and then huge collaborative team including the Broad Institute, who are world leaders in genomics. What we do is for each individual patient we perform custom sequencing on their tumor and on normal parts of the body as well, and we try to predict what are the specific changes or mutations in that patient's tumor that not just are present but are likely to generate an immune response, which are ones that are going to be recognized by the immune system and the immune system is going to be likely to attack.

Once we have that list, we actually custom make a peptide-based vaccine for each individual patient. Then we give that vaccine together with a checkpoint blockade agent. Again, the idea is we both cut the brakes, but then steer the immune system as well. Rather than just letting the immune system loose we're trying to really focus it onto things that are unique and specific to the tumor itself.

Alicia Morgans: How long does that take, that sequencing and then development of the vaccine that's targeting those abnormalities?

David Braun: Right now, the turnaround time is about 12 weeks. It really comes from how personalized this approach is. There's the sequencing aspect where every tumor has to be sequenced, but then there's actually a board of experts, genomics experts, immunology experts, peptide experts, who say okay out of all these mutations which are the ones that we think are most likely to be recognized by the immune system and give the immune system the best chance to sort of attack this tumor specifically. Once that's done the peptide itself, the vaccine, is a custom product and that takes about eight weeks or so to make. The end to end time from a patient has surgery to when they receive their first dose is onto or around 12 weeks. This is a first in disease type study, so we expect that as we improve and as things become more standardized that that timeframe will decrease.

Alicia Morgans: But even so that timeframe is not bad. We're thinking about in adjuvant studies these patients technically I'm sure have follow-up imaging suggesting no evidence of disease, really healing from the surgical procedures that they just had, so it's not uncommon to start therapy somewhere around the 12 week mark. That's really commendable.

David Braun: That's absolutely right. That's one of the reasons we sort of thought about this particular disease setting for this type of trial is because this is something that fits well I think into a standard of care type approach. As we start to shrink down that turnaround time, going from 12 weeks to much, much shorter, then we can think of how this might fit into trials in more advanced disease stages.

Alicia Morgans: Okay. Have you put patients on the trial at this point?

David Braun: We have our first patient now, yes.

Alicia Morgans: Wonderful. Without giving anything away because certainly, this is a clinical trial, I assume you're assessing tolerability. If we're thinking about these combinatorial strategies, one of the things I would be very much on the lookout for would be overactive immune responses or immune-related adverse event.

David Braun: Absolutely.

Alicia Morgans: So is that something that you're capturing on the trial?

David Braun: Absolutely. That's really our primary objective at this point is to really determine the safety and feasibility of this sort of approach. Now we have strong reason to believe that it will be safe and that comes from a couple of lines of evidence. One is from Dr. Wu's earlier work in other disease settings of just using a personalized vaccine by itself. Those have been incredibly well tolerated. No one on those trials had any Grade 3 or 4 toxicities related to the vaccine itself. So those have all been incredibly well tolerated by themselves.

The addition in this trial, in addition to improving the vaccine itself, is we're adding a checkpoint blockade ipilimumab, which of course can have toxicity of its own. The different approach we're taking here, and I think this is probably the first time it's being used in this way, is rather than administering the higher doses systemically, we're actually administering ipi at a low dose right at the site of the vaccine.

Alicia Morgans: Interesting.

David Braun: The idea is be delivering right at the site of the vaccine it's going to have its effect at the local draining lymph node, and that's where this sort of priming, the T cell priming takes place. But by giving it at that local site we can give it at a much, much lower dose. Rather than giving it even the one mg per kg metastatic dose, we're giving it at an eighth of that, or even less.

Alicia Morgans: Wonderful. If there are patients who are watching, or clinicians who have patients with high risk disease, or a T3 T4 kidney cancer, what do they need to do if they want to consider, be considered to be involved in this trial?

David Braun: Absolutely. I would say to contact us early. It's something where we like to speak with the patient even before the surgery. Part of that is as we're doing this vaccine trial we are studying safety and efficacy, how the immune system is responding, but also learning about the tumor itself to constantly improve these approaches. For this particular trial, it's really important to actually talk to patients and go through the consent process actually prior to surgery.

Alicia Morgans: Prior to surgery.

David Braun: We are so tremendously grateful to the patients and the families themselves because it is a lot. There's a lot to go through in terms of receiving the treatments themselves, coming to Dana-Farber, and so that's a huge ask on their part, but the patient we've enrolled so far has been fantastic.

Alicia Morgans: Yeah. Well, and I'm sure many more will want to come and learn about this approach. I really appreciate you sharing this truly innovative approach to personalization of therapy, designing a personalized vaccine just for one individual. It does not get more personalized than that. I hope that in a year or so we can talk about how this is both safe and being moved forward into studies of early efficacy. So thank you so much for your work and for your time today.

David Braun: My pleasure. Thank you so much for having me.
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