Editor’s Note: Previous Phase II NEOTAX study results demonstrated that neoadjuvant therapy with toripalimab combined with axitinib effectively downstaged inferior vena cava tumor thrombi in some patients with renal cell carcinoma (RCC), significantly improving perioperative outcomes. However, resistance to therapy remains a challenge for some patients, necessitating further investigation. At the 2024 ESMO ASIA Congress, Dr. Liangyou Gu and Dr. Yaohui Wang from the Department of Urology at the Chinese PLA General Hospital shared insights into overcoming treatment resistance, providing valuable strategies for improving patient prognosis. Urology Frontier invited Dr. Yaohui Wang to offer an in-depth perspective.Urology Frontier: From your clinical experience and related research, what challenges exist in diagnosing and treating RCC with venous tumor thrombus?
Dr. Yaohui Wang: Venous tumor thrombus is a specific and complex manifestation during RCC progression, making the diagnosis and treatment of these patients more challenging compared to those without thrombus involvement.
First, the formation of tumor thrombus involves complex molecular mechanisms that are not yet fully understood, and there are currently no effective preventive strategies.
Second, accurate preoperative grading and evaluation of the tumor thrombus are crucial for ensuring the smooth execution of surgery. For example, assessing whether the thrombus is accompanied by blood clots or determining the extent of venous wall invasion significantly influences surgical strategy.
Third, surgical intervention for tumor thrombus carries extremely high perioperative risks. The complexity of the surgery increases when the thrombus extends into the heart’s atrium, drastically elevating the risk of complications during surgery and imposing high technical demands on the surgical team.
Fourth, there has been a lack of high-quality evidence supporting perioperative drug therapy in RCC with venous thrombus. Some patients may already have micrometastases at diagnosis, making surgery alone insufficient. Combining surgery with systemic neoadjuvant therapy is often necessary for curative treatment. However, responses to neoadjuvant therapy can vary among patients, and drug resistance remains a significant concern. This underlines the need for deeper exploration of the mechanisms driving resistance to neoadjuvant therapies.
Urology Frontier: Your recent study at the Chinese PLA General Hospital analyzed the efficacy of a targeted-immunotherapy combination as neoadjuvant therapy. What are the clinical implications for these patients?
Dr. Yaohui Wang: To address the challenges in treating RCC with venous tumor thrombus, our team has developed several strategies, including establishing a minimally invasive system for managing RCC with thrombus and launching the NEOTAX clinical trial.
In our study, among 25 treated patients, 44% experienced tumor thrombus downstaging, with no cases of Mayo grade progression. Even for patients whose thrombi were not downstaged, many still showed reductions in thrombus height. This change not only simplified the surgical process but also significantly reduced the surgical field, thereby lowering perioperative surgical risks. As a result, more patients with advanced RCC and venous tumor thrombus could safely undergo surgical intervention.
Additionally, during follow-up, we observed a 1-year progression-free survival (PFS) rate of 89.1% in this cohort, indicating that neoadjuvant targeted immunotherapy significantly improves the short-term prognosis for RCC patients with venous tumor thrombus.
Urology Frontier: At the ESMO ASIA Congress, you shared your team’s latest findings on targeted immunotherapy neoadjuvant treatments. Could you elaborate on these discoveries?
Dr. Yaohui Wang: As previously mentioned, our NEOTAX clinical trial validated the efficacy and benefits of neoadjuvant targeted immunotherapy for RCC patients with venous tumor thrombus. However, we also observed that not all patients achieved significant clinical benefits—some developed resistance to the therapy.
To investigate this, we conducted single-cell sequencing analysis on pre-treatment biopsy samples and post-treatment surgical specimens from 18 patients. In the group that did not respond to neoadjuvant therapy, we identified a substantial increase in SAA-positive tumor cells and LDHA-positive neutrophils, along with a marked decrease in CCL5-positive CD8+ T cells. This suggests that these distinct cell populations may contribute to and mediate resistance to combined targeted immunotherapy in RCC patients with venous tumor thrombus.
Further spatial transcriptomic analysis and functional clustering of these cell populations revealed significant interactions between SAA-positive tumor cells and LDHA-positive neutrophils, leading to metabolic reprogramming in non-responders. This metabolic shift ultimately caused the irreversible exhaustion of CCL5-positive CD8+ T cells, resulting in therapeutic resistance.
Additionally, in vivo animal experiments demonstrated that targeting SAA could enhance the effectiveness of combined targeted immunotherapy in RCC orthotopic models. These findings indicate that SAA may be a promising new target for overcoming resistance in RCC patients with venous tumor thrombus.
Urology Frontier: What are your key takeaways from this conference, and how might they influence your future clinical and research work?
Dr. Yaohui Wang: I’m honored to represent our team at the ESMO ASIA 2024 Congress and to participate in this interview with Urology Frontier. The conference featured numerous high-profile clinical trials, such as EV-302 and CheckMate 901, and presented subgroup data on HIF-2α inhibitor belzutifan in East Asian populations. This high-quality evidence supports the applicability of these leading therapies in East Asian patients.
I also noticed considerable progress in research on immune rechallenge for urological tumors. Reflecting on these studies provided valuable insights for my clinical practice, particularly in managing patients who develop resistance to immunotherapy. For example, in patients showing poor responses to PD-1 inhibitors in a short treatment cycle, the issue may stem from insufficient PD-1 blockade. In such cases, switching to a different PD-1 inhibitor for rechallenge might still be effective. However, for patients who develop resistance after long-term PD-1 therapy, continuing PD-1 treatment may offer only limited benefit. In these scenarios, switching to immunotherapies targeting other checkpoints like LAG-3 or TIGIT might be more effective.
These insights inspire me to further investigate the underlying mechanisms of immune rechallenge in urological tumors, which could have significant translational potential in future research.
About the Authors
Professor Liangyou Gu
- Deputy Chief Physician, Associate Professor, Master’s Supervisor
- Head of Comprehensive Urologic Oncology, Department of Urology, Chinese PLA General Hospital
- Secretary, Clinical Research Office, Chinese Urological Association
- Member, Basic and Translational Medicine Group, Beijing Medical Association Urology Branch
- Selected for the 2023 Beijing Science and Technology Rising Star Program
- Principal Investigator for two National Natural Science Foundation projects and two hospital-level projects
- Core member of National Key R&D Programs and Capital Health Development Research Projects
- First or corresponding author of 34 published papers in journals like STTT, Innovation, European Urology, Cancer Treatment Reviews, Journal of Urology, and Cancer
- Research findings have been presented at international conferences including ESMO, EAU, SIU, and UAA
- Editorial Board Member for BMC Urology and Frontiers in Oncology
- Reviewer for Cancer Letters and Surgery
- Recipient of the First Prize of the Chinese Medical Science and Technology Award, and First Prize in Medical Achievements and Second Prize in Scientific and Technological Progress at the PLA General Hospital
Dr. Yaohui Wang
- Postdoctoral Research Fellow, Department of Urology, Chinese PLA General Hospital
- First or co-first author of five SCI-indexed papers
- Contributor to a clinical trial on RCC transformation therapy
- Participant in a Sichuan Provincial Natural Science Foundation project
