“The concept behind this is adding a steering wheel. Can we direct the immune system and navigate it to specifically attack the kidney cancer tumors? The way we sought to do that is by a personalized cancer vaccine targeting neoantigens,” said David A. Braun, MD, PhD.
In addition to immune checkpoint inhibition, considering several other treatment domains, including engineered cytokines and immune agonists, antigen-directed therapies, and cellular therapies/bispecific T-cell engagers, may help advance immune therapy for patients with kidney cancer, according to David A. Braun, MD, PhD.
In a conversation with CancerNetwork®, Braun, assistant professor at Yale School of Medicine and principal investigator in the Center of Molecular and Cellular Oncology within the Yale Cancer Center, discussed considerations for immune therapy for the treatment of kidney cancer following a presentation of a phase 1 trial (NCT02950766) he gave at the 2025 Kidney Cancer Research Summit.1,2
Braun began by highlighting the background for and overview of the trial he presented. Acknowledging the “transformative” nature of immune therapies for kidney cancer treatment, he suggested that the use of a personalized cancer vaccine may help navigate immune therapies away from normal, healthy tissue and to malignant tissue. To illustrate this, he likened the use of the vaccine to a steering wheel and immune therapy to the vehicle––the vehicle benefits from the direction afforded by the steering wheel, but the steering wheel alone cannot navigate one to the destination.
Furthermore, he highlighted results from the trial he presented at the conference, highlighting its preclinical efficacy and safety in 9 patients treated with the vaccine-assisted immune therapy, with no cancer recurrence observed on study. He further explained that despite the low sample size which would inhibit the ability to make a definitive conclusion regarding the efficacy of the modality, further larger scale trials will attempt to elucidate its impact.
CancerNetwork: Can you start by giving an overview of the presentation?
Braun: We know that immune therapies have been transformative for kidney cancer, much like other tumor types. We’re just scratching the surface with current immune therapies. I use this concept of the immune system as a car, and you’re trying to drive it as quickly and accurately as possible towards the tumor to attack it, and many of the treatments that we have essentially lift the brakes on the immune system. They take your foot off the brake and allow the immune system to go faster, but don’t tell the immune system where to go.
The concept behind this is adding a steering wheel. Can we direct the immune system and navigate it to specifically attack the kidney cancer tumors? The way we sought to do that is by a personalized cancer vaccine targeting neoantigens.
What advantages might personalized vaccines offer over other therapeutic strategies in kidney cancer, and what data support the use of these vaccines?
Braun: Many of the treatments that we have, particularly the immune therapies, are phenomenal at essentially activating or reinvigorating the immune system, but they don’t tell the immune system where to go. They don’t say attack the tumor cells, and they don’t say spare or don’t attack the normal parts of the body. Because of that, while they have again been so transformative, we know that many patients don’t benefit because they lack on-tumor activity of the immune system, and there’s, unfortunately, many patients who have [adverse] effects [and] toxicities because the immune system is activated and attacks other parts of the body.
The question is, how can we flip the balance? How can we direct the immune system in a very specific way? I don’t think it’s [in place] of other treatments, but I think it’s a tool to use with other treatments, like the car analogy. It’s not that it’s sufficient to have a steering wheel by itself; you still need the car to go. Adding the steering wheel gives it directionality.
What does this research show regarding the role that this modality may play in this field?
Braun: This is the first proof of concept of this idea of a personalized cancer vaccine targeting neoantigens in kidney cancer, and we had some fundamental questions. Was it feasible? Kidney cancer doesn’t have a lot of mutations or neoantigens. It’s different from melanoma. Could we make this? The answer was yes. Was it safe? The answer was yes, [as well]. The [adverse] effects tended to be low grade, manageable, and transient. Is it doing what we thought it should do, which is activate and steer the immune system–are we getting immune responses? The answer to that was yes as well.
Next, were those responses transient or short-lived, or are they creating durable immunity, and are those immune cells now capable of recognizing and attacking the tumor? The answer to that was yes as well. Finally, is there at least some signal that it might have clinical activity that might help our patients, which is the ultimate goal? Now this was a small space, only 9 patients. It was a proof-of-concept, first-in-disease [study]. [It is] hard to draw many conclusions from 9 patients.
Encouragingly, those 9 patients had very high-risk disease, and none of those patients had their kidney cancer come back during the study. When we put this all together, this supports the idea that this should be investigated further. We’re not there yet, where this is still far from a standard treatment, but this is now being investigated on much larger-scale studies that will answer the question, “Is this having a positive impact for our patients?”
How would you describe the current state of adjuvant and neoadjuvant therapies in kidney cancer, and what ongoing research initiatives and clinical trials appear most promising in the field?
Braun: To give a bit of context, we had a prolonged period, [spanning] tens of thousands of patients and decades of work in the adjuvant setting that was unfortunately unsuccessful, that didn’t help patients live longer and significantly delay the recurrence of their cancer. The introduction of adjuvant pembrolizumab [Keytruda] has been a game-changer in that domain. [It was] the first to show benefit.
As I speak to my patients about it, it’s still far from a home run. Clearly, patients have benefited from it, but there’s also many patients who do not. It’s hopefully an inflection point. It’s the idea that we can bend the curve; we can decrease the chance of kidney cancer coming back, but it’s far from the end goal. We need to build on that, and there’s multiple ways to do that.
One is this idea of not just doing immunotherapy after surgery in the adjuvant setting, but before surgery as well, where there’s maybe more targets or antigens present, where there’s more functional immune cells. We have seen this take off in other diseases such as melanoma, where the idea of a substantial period of neoadjuvant therapy having quite substantial benefits, and that’s an area that needs to be investigated within kidney cancer.
The second is building on the success of pembrolizumab. What else can we add to it that might make it more efficacious? What might further augment immunity through something like a vaccine-based approach? In the phase 2 INTerpath-004 [NCT06307431] study that we’re helping to lead, which builds on checkpoint inhibition and adds that steering wheel of a vaccine. Also, other approaches like [phase 3 STRIKE trial (NCT06661720)], the Alliance trial led by Bradley A. McGregor, MD, ask, “Can you eliminate angiogenic clones with the addition of tivozanib [Fotivda] in a short-term but intensified period?” Those are the studies that are going to build up. The addition of belzutifan [Welireg] is something that represents new mechanisms of action, and [I am] excited to see all of those results of the coming years.
What do you hope your colleagues take away from that presentation, as well as this conversation?
Braun: I [hope they take away] a couple of things. One is a general conceptual framework for thinking about immune therapies. We think of one lever to pull on, which is those immune checkpoint inhibitors, but knowing there’s lots of others. They’re still pushing on the gas pedal with engineered cytokines and immune agonists. There’s antigen-directed therapies, including vaccines, but also cellular therapies [and] bispecific T-cell engagers.
Then finally, [there’s] this idea of clearing the traffic as well, that if everything can go right into those 3 other domains, but if there’s an adverse microbiome, immunosuppressive myeloid cells, [or] deregulatory cells that are suppressive, those could be insurmountable. [Thinking] about those other elements of immunity that you want to modulate as well. It’s addressing those 4 domains that’s going to push this field forward.
References
- Braun DA. Personalized vaccines in kidney cancer: a journey from concept to clinic. Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025. Boston, MA.
- Braun DA, Moranzoni G, Chea V, et al. A neoantigen vaccine generates antitumour immunity in renal cell carcinoma. Nature. 2025;638:474-482. doi:10.1038/s41586-024-08507-5
- A study of adjuvant intismeran autogene (V940) and pembrolizumab in renal cell carcinoma (V940-004). (INTerpath-004). ClinicalTrials.gov. Updated May 13, 2025. Accessed July 21, 2025. https://tinyurl.com/2fdpnyhz
- Testing the addition of the anti-cancer drug tivozanib to immunotherapy (pembrolizumab) after surgery to remove all known sites of kidney cancer (STRIKE). ClinicalTrials.gov. Updated June 26, 2025. Accessed July 21, 2025. https://tinyurl.com/ymx8zdhu