Novel CD40 Antibody Treatment for BCG-Unresponsive Bladder Cancer - Bernard Bochner

June 27, 2024

Sam Chang and Bernard Bochner discuss a novel antibody treatment targeting the CD40 receptor for non-muscle invasive bladder cancer resistant to BCG therapy. Dr. Bochner presents findings from a phase one study showing promising results with minimal toxicity. The treatment activates dendritic cells, leading to CD8+ T cell recruitment and tumor elimination. Preliminary data indicates a 50% complete response rate at six months. Correlative studies reveal a connection between CD40 expression and treatment response, suggesting potential for personalized therapy. The discussion explores future directions, including combining the CD40 antibody with IL-15 to enhance efficacy in non-responders. They also consider intratumoral injections and applications for more advanced bladder cancer. The conversation highlights the importance of multidisciplinary collaboration in translational medicine and the potential for this approach to revolutionize bladder cancer treatment.


Bernard H. Bochner, MD, FACS, Urologic Surgeon, Sir Murray Brennan Endowed Chair, Memorial Sloan Kettering Cancer Center, New York, NY

Sam S. Chang, MD, MBA, Urologist, Patricia and Rodes Hart Professor of Urologic Surgery, Vanderbilt University Medical Center, Chief Surgical Officer, Vanderbilt-Ingram Cancer Center Nashville, TN

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Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University. And I am here today with actually one of the true leaders in urologic oncology. I've known Dr. Bernie Bochner now for more than two decades. Dr. Bochner is the Sir Murray Brennan Endowed Chair at the Memorial Sloan Kettering Cancer Center. He's an attending there and also a Professor of Urology at the Cornell Weill Medical School. I've known Dr. Bochner and all his contributions to the field of urologic oncology, but really focused on urothelial carcinoma, and I was fortunate enough to actually moderate a session where he presented some very exciting work looking at a novel agent for patients with non-muscle invasive bladder cancer that had resistance or were not responding totally to BCG.

And that actually, that poster and abstract was the best poster abstract of that session. And so we've asked Dr. Bochner actually to go over some of his presentation and we'll be able to then actually pick his brain a little bit about kind of the next steps in the future. So Bernie, thanks so much for spending some time with us and look forward to hearing your presentation.

Bernard Bochner: So Sam, thank you first of all, always an honor and a pleasure to spend some time with you and grateful for the opportunity to discuss some of this exciting information. So this is really very exciting for us to have the opportunity to present this early data on a phase one moving into phase two study looking at a novel antibody. I say novel, it's novel to bladder cancer but it's been around for quite a while, but it's focusing on its activity against the CD40 receptor. And you can see a list of wonderful collaborators both within the Memorial Sloan Kettering and the Rockefeller Institute as well, primarily led by Jeffrey Ravetch and his laboratory, who is a real card-carrying immunologist and has developed and focused on this CD40 antibody. The CD40 receptor has been recognized to be a very important receptor in the activation of antigen-presenting cells, specifically dendritic cells, although macrophages and B cells also contain the CD40 receptor.

Once it's activated, it leads to a whole series of events that sort of cascade into an activation of the immune system, both maturation of B cells but for this discussion it really focuses on the recruitment and activation of CD8+ T cells, so killer cells as well. The antibody got a lot of attention early on by big pharma, and the antibody had gone into a variety of phases of testing, and it all failed to basically show any clinical activity but produced a lot of toxicity when given systemically. And so Dr. Ravetch spent a couple of decades working on figuring out mechanistically why this antibody wasn't working in humans, and found that the CD40 receptor, like many of the TNF receptor members, requires trimerization to be activated and the antibody was not allowing for this trimerization to occur.

So Jeff and his group worked on changing the scaffolding of this antibody, specifically the FC portion of the receptor, to interact with this R2B receptor. And by doing this, it essentially formed a scaffolding that allowed now for the antibody to properly, or I should say the receptor, to properly trimerize. And once it was activated in this trimeric configuration, then you saw all this cascading effect of dendritic cell maturation, the formation of co-stimulatory molecules so that it could more effectively antigen present to CD8+ T cells. And this then led to T-cell activation and tumor elimination. Because it was toxic when given systemically, Jeff had developed a peritumoral injection program for patients, for instance with cutaneous metastases from breast cancer and other tumor types, and found a remarkable response locally in the lesions that were injected, but then contralaterally on the other arm or within the liver for instance, he was also seeing antitumor activity suggesting that true antitumor specific activity was being locally developed but then trafficking of these immune cells to these other locations to affect their cancer response.

So after Jeff and I had met and I got a chance to understand his work, we began to start an intravesical program, the first in human intravesical use for this particular antibody. And so that was the phase one study that was developed using this specific antibody. And you can see the design here. It was designed so that based on animal data showing remarkable activity in BCG unresponsive cancers within a mouse model, that a three-weekly instillation of this antibody could generate the antitumor effect that we were looking at. And this was with basically about a one-hour instillation of the antibody within these tumor-bearing mice. So the protocol was developed as you see. As we followed these patients, at the 12-week mark if there was no progression of their disease and this was all basically meeting the standard criteria for BCG unresponsive disease, then they were re-treated at the end of the second treatment.

If they still demonstrated a good response then they could go on for a third treatment. Now, like all phase one studies, the primary endpoint of this was safety and tolerability, but we were also looking at some of the preliminary clinical activity of the treatment as well. So here's the study population that we presented. It was the first 21 of the proposed 25 patients in this phase one study, and they looked like the typical BCG unresponsive group of patients. A rather high-risk group overall, but almost 50% of these patients had at least a T1 tumor at some point. And at the time of enrollment, you can see that about a little over 70% of these patients had a CIS component as well. From a tolerability standpoint, we saw zero grade three, four or five toxicities. In general, we saw a few minor episodes of hematuria, minimal frequency. I mean this was exceedingly well tolerated, and we escalated it to the top dose based upon the dosing that we sort of extrapolated from the animal models.

The preliminary anti-cancer activity is shown here. So at three months we found that we did identify the majority of patients who either had a response or stable disease and were eligible for re-treatment. At six months about 50% of these patients did in fact demonstrate a complete response and at any point that sort of held up as well. So with no grade three or four toxicities at the maximum doses and this signal that we were seeing in some clinical responses it sort of spurred us on to move to the next level. We also did a variety of correlative experiments to really, again, see from a science standpoint if we were hitting the target for doing what we need to and it was quite interesting. So on pre and post biopsies what we're finding is that the level of CD40 expression within patients prior to the exposure of the anti-CD40 molecule, did correlate with complete responses.

And so again, this identifies a kind of interesting opportunity here in that if CD40 is not being expressed by dendritic cells that may identify a group of patients who are less likely to respond to this treatment and potentially may benefit from treatment that could induce CD40 expression. And so the other interesting thing was that if this in fact was all leading to an antitumor effect, then what we would expect to see are dendritic cells bringing in these FC receptor-bearing sort of scaffolding cells, if you will, to identify these activated dendritic cell complexes, which should then be interacting with CD8+ cells. And in fact, what we were finding in the complete responders, was in fact that there was this development, if you would, of these immune hubs.

And here's some pictures from the codex, which is a 25 multiplexed imaged view of some of the tissue in responders and non-responders that are focused on specific immune cells. And so if we walk through this, we can see that not only in the responders are we seeing nice clustering of CD40+ cells, those are the dendritic cells, but they are also now interacting with these CD8+ cells as well. And you can see in the merged image here on the top right panel that in fact we're seeing exactly what we would expect and hope to see, which is this immune interaction now of activated dendritic cells that are now what we hope are effectively activating tumor-specific CD8+ cells.

And you see the exact opposite of that in the non-responders. You don't see dense CD40+ cells, and because of that there's a lack of these immune hubs being developed. So we're not seeing what we would expect or hope to see, but again, this is maybe explaining the mechanism of some resistance. And so this is kind of the basis of what we've developed so far, and it's also serving as the science and the clinical correlates for the next steps, which we can talk about as well. So this is kind of the basis of the information from this initial phase one study.

Sam Chang: Bernie, what an absolutely combination of exciting presentation but one that begs a lot of questions. I mean, the first is, okay, we've got phase one data, what's next? Where are you going to go next with this?

Bernard Bochner: So I think that most immunologists would recognize that because of the complexity of the immune system and all the inputs that are going in and required to develop an effective response, it's unlikely that a single agent is going to end up sort of answering all the questions here. And I think we're seeing that with other immune-based treatments in the bladder, where now the single agent shows a little bit of activity but it's really kind of a combination approach to try and drive those response numbers up. So for CD40, as we saw in the non-responders, it may be that CD40 expression is just not happening in some dendritic cells. They're classified as immature dendritic cells. And even though there may be tumor antigen in the area, and there may even be CD8+ effector cells in the area, they're not being activated, and this would be sort of the cold immune phenotype of some tumors.

Well, as it turns out, for many decades it's been recognized that IL-15, interleukin 15, is a very potent inducer of CD40 expression. And so the animal data subsequent to this study has now shown this incredible synergy and the ability to effectively treat non-responding, BCG unresponsive disease in the mouse model. And it's based upon that data now, this combined approach of an IL-15 and anti-CD40 approach, that that's exactly what's being designed now in the next phase one, two, study. IL-15 is being given now systemically for a variety of tumor types. And we're working with a company that actually was developed in some of the other IL-15 molecules that are currently in play even in bladder cancer. And so kind of the next generation of IL-15 super agonists, if you will, and that's the molecule that we'll be using as part of the intravesical CD40 project.

Sam Chang: So I guess that leads into a question, initially you showed some of the prediction of response of CD40- pretreatment and those much less likely to respond and those that were in some ways present starting to be activated, etc. Do you have any idea, and I know it's early, in general, how many patients have these cold versus these hot tumors? Obviously we're looking at already a group of people who haven't responded to BCG already, so any 50/50, 30/40, or maybe it just correlates to those who responded versus those who didn't, so somewhere in that time, in that range?

Bernard Bochner: This is the spot-on question, and so what we're currently doing, Sam, is we're looking back through the archives at Memorial on BCG-treated patients and to look before and after BCG treatment and see how CD40 expression actually correlates. BCG, although we've learned a lot about the mechanism of it, I mean to me it's just a perfect example of the massive activation that occurs when we put a mycobacterium into the system. There's just a cascade of things that are happening. And so we are absolutely looking at that to try and get a sense as to just whether this correlates with that response rate that we would expect. Right? The CD40+ patients are the ones that are responding, even to BCG alone, and we're looking at that data. So yeah, it's a spot-on question.

Sam Chang: Yeah, I think that's really true and we have a better understanding of BCG. But boy, I still think we are going to learn a lot more as time goes of what really happens, because the multiple facets of interaction, just as you described, I think really will help us better understand but really it probably predicts on who's going to respond in some way versus those who don't. So follow-up question, you talked about the initial kind of pre-nascent approach where we saw injections for cutaneous lesions, peritumoral injections, and then actually having a systemic response to liver lesions for breast cancer patients you mentioned. So say you get a super amped up version and you get some kind of synergistic or at least additive effect of an IL-15 super agonist and your CD40, what about injecting to make sure that you're getting a response? That's my first question, have you guys thought about that in terms of-

Bernard Bochner: Yes.

Sam Chang: ... efficacy versus-

Bernard Bochner: Yes.

Sam Chang: Clearly intravesical treatment, that's easier, etc., but what about the injection as the next step?

Bernard Bochner: So again, perfect insight, Sam, because we initially had our discussions about how best to start the first phase one, and even though Jeff's original data really was an injection model, the reality is the logistics of how we treat bladder cancer is all based on intravesical administration, washing in, flushing in different fluids. And so we asked the first question, which was when we started the animal experiments, could just putting in a temporary intravesical exposure work, and it did. And so because of that it sort of spurred us on.

Sam Chang: Got it, it makes sense.

Bernard Bochner: The entire time I kept thinking, boy, would the intratumoral injection work better? And so we are currently expanding one of the arms of the protocol where we actually are doing a series of intravesical peritumoral injections of the CD40 antibody, and we're doing this in non-muscle invasive patients, but because we're looking for a biologic response we're actually using a cohort of muscle invasive patients who are going to cystectomy as well because we're looking for those biologic correlates.

Sam Chang: I love that because that was my next follow-up is like, if you think about what you've mentioned in terms of the possible systemic acceleration and stimulation and you injected there, gosh, you could think, boy, we already have some intravesical exposure causing this why couldn't we recruit and be effective for invasive disease? Why couldn't we make, by just injecting the tumor, make other therapies more effective for nodal disease, for even metastatic disease, just as the cutaneous lesions affected liver lesions? I am just thinking about that. And so I love the fact that you're already not only looking at a non-muscle invasive but clearly a great evaluation is neoadjuvant prior to bladder removal. You can do all the measurements. I think that's fantastic.

Bernard Bochner: I mean, you may have recognized that in the series of investigators in the study are some of our medical oncologists as well. Right? I mean, as many of us know, and Sam, I know you know better than most, is that now non-muscle invasive disease has really become a team sport as far as the group that's treating this stage of disease. I mean, we have relied heavily on the medical oncologists to get us access to many of the drugs that they use to treat advanced disease. And so the checkpoint inhibitors are coming into play largely because of the work that was done. So we work very closely with Jonathan Rosenberg and Gopa Iyer and many of the other incredible medical oncologists that we have on our team, and they are keeping a very keen eye on exactly what you mentioned is that could we develop trafficking tumor-specific CD8 activity by exposing these tumor cells to this type of a localized immune treatment?

And so we are looking at that. We're going to be looking at lymph nodes and looking at TCR activation within the lymph nodes as well as systemically what's happening to the lymphocyte population. And so again, this is not a urologist trying to do immunology. We're working a real high-level immunology laboratory. I thought I knew immunology, I remember, I think I was awake during medical school, but boy, when I listened to them talk about immunology it's just another field. And so again, it's part of that team sport. This is how translational medicine is done, and it's just exciting to be a little part of that team.

Sam Chang: Well, Bernie, thank you so much for obviously all your past involvements, but your continued interest and curiosity and willingness to work with the multidisciplinary team because you're exactly right, the expertise that so many other individuals in other fields have that you can garner and then say, well, what about bladder cancer? What about this? And then your understanding, it makes things work and it just stimulates, well, just like you said, well, what about more advanced disease? Well, what about combining it perhaps with radiation? I mean, all these things you start thinking about. And I think Memorial obviously... I don't think, I know... Memorial Sloan Kettering has been so fortunate to have you make the move out from the left coast to New York City. So I want to say thanks for all your contributions. Thanks for spending some time with us and we look forward to the next iterations, the next publications, and your next contributions. So thanks again, Bernie. I appreciate it very much.

Bernard Bochner: A great pleasure, Sam. Thank you so much for the opportunity.