ASCO 2024: Harnessing the Immune System in Renal Cell Carcinoma: Current and Novel Immunotherapy Approaches

(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, IL between May 31^st and June 4^th, 2024 was host to diagnostic and therapeutic strategies in renal cell carcinoma (RCC) state-of-the-art session. Dr. David Braun discussed current and emerging immunotherapy approaches to harness the immune system for the treatment of advanced RCC.

Dr. Braun noted that there are multiple ways to modulate the immune system to ‘attack’ RCC:

• “Release the brakes”: Immune checkpoint inhibitors
• “Press the gas pedal”: Cytokine therapies
• “Add a steering wheel”: Vaccines and cell therapies
• “Clear the traffic”: Non-T cell targets (e.g., microbiome)

Starting off with “releasing the brakes”, Dr. Braun noted that immuno-oncology (IO)-based combinatory therapies (IO+IO or IO + tyrosine kinase inhibitors [TKIs}) have emerged as the 1^st line systemic therapy option for the treatment of patients with advanced clear cell RCC.

How do we choose between IO + IO versus IO + TKI combinations? While CheckMate-214 (ipilimumab + nivolumab) was limited to patients with IMDC intermediate-poor risk disease,¹ it appears that IO + TKI may be the best approach in patients with aggressive disease due to the high objective response rates (ORR) and low progressive disease rates observed with IO + TKI combinations.^2-4 
On the other hand, while ORRs may be lower in patients receiving IO + IO (ipilimumab + nivolumab), those patients who do achieve responses appear to have long-term durable ones, with updated data presented at ASCO 2024 from the CheckMate-214 trial demonstrating that half of the responding patients maintained a response >7 years later.
These considerations have helped inform Dr. Braun’s personal front-line clear cell RCC treatment paradigm:
Patients with oligometastatic disease may be candidates for local therapies (e.g., SBRT, resection, ablation). If ‘polymetastatic’ and demonstrating evidence of sarcomatoid features, then IO ‘intensification’ with IO + IO is likely the treatment of choice given the known efficacy of IO agents in the sarcomatoid setting. If polymetastatic and not exhibiting sarcomatoid features, then the requirement (or lack thereof) for a rapid response dictates the choice of IO + IO versus IO + TKI.

There are currently numerous additional immune checkpoint inhibitors under investigation, as illustrated below:
Next, moving on to “pressing the gas pedal”, cytokine therapy has the potential to generate durable responses in RCC. While responses were rare in the cytokine era, they were durable when they did occur. What are the lessons we can learn from these durable responses, and how can we harness them to improve upon current responses in the IO era?
‘Next generation’ engineered cytokine therapies are currently under investigation to enhance systemic therapy responses. One such agent is CD8-targeted ILD2 fusion molecule that aims to selectively reactivate intratumoral CD8+ T cells in patient-derived tumor fragments.  Treatment with CD8-IL2 broadly arms intratumoral CD8+ T cells with enhanced effector capacity, enabling reinvigoration of the dysfunctional T cell pool to elicit potent immune activity. The revival of dysfunctional T cells to mediate effector activity by CD8-IL2 depends on simultaneous antigen recognition and is quantitatively and qualitatively superior to that achieved by PD-1 blockade. Additionally, CD8-IL2 is able to functionally reinvigorate T cells in tumors resistant to anti-PD-1, underscoring its potential as a novel treatment strategy for cancer patients.⁵

Another potential candidate is “decoy-resistant” IL-18. While the cytokine IL-18 has immunostimulatory effects, it is negatively regulated by a secreted high-affinity binding protein, IL-18BP, that functions as an immune checkpoint that limits IL-18’s therapeutic efficacy. “Decoy-resistant” IL-18 can avoid trapping by IL-18BP while maintaining immune signaling potential.

Dr. Braun next moved on to “adding a steering wheel” by discussing strategies for antigen-directed therapies.
Antigen-directed therapies can target either cell-surface antigens or HLA- restricted antigens and might require personalization or, alternatively, be available as ‘off-the-shelf’ therapies for multiple patients.⁶ Options include:

1. Autologous CAR T cell therapies targeting an RCC-specific cell-surface antigen, such as CAIX or CD70. Novel CAR constructs have the potential to improve specificity (through logic gates), increase persistence, add safety features (such as suicide switches), and/or engender secretion of additional immunomodulatory molecules. CD70-targeting allogenic CAR-T cells include CTX130 (COBALTC-RC) and ALLO-316 (TRAVERSE), both of which have demonstrated promising early efficacy outcomes. 

1. Strategies targeting HLA-restricted antigens require a personalized approach to therapy, including expansion and infusion of TILs, engineered TCR therapy against one specific HLA-restricted antigen, or neoantigen vaccination therapies.

Finally, techniques to “clear the traffic” have included utilizing live bacterial products (e.g., Clostridium butyricum) to enhance the efficacy of ipilimumab + nivolumab in the metastatic clear cell RCC setting.
Dr. Braun concluded as follows:

• Immunotherapy is the backbone of treatment for advanced RCC
  • IO + TKI regimens have high response rates
  • IO + IO regimens are associated with durable responses
• There are multiple ways to modulate the immune system to attack RCC
  • "Release the brakes" - immune checkpoint inhibitors
  • "Press the gas pedal" - cytokine therapies
  • "Add a steering wheel" - vaccines and cell therapies
  • "Clear the traffic" - non-T cell targets (e.g. microbiome)

Presented by: David A. Braun, MD, PhD, Assistant Professor of Medicine (Medical Oncology), Department of Medicine, Yale University, New Haven, CT

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, May 31^st – June 4^th, 2024 

1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378(14):1277-1290.
2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841.
3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1116-1127.
4. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300.
5. Kaptein P, Slingerland N, Metoikidou C, et al. CD8-targeted IL2 unleashes tumor-specific immunity in human cancer tissue by reviving the dysfunctional T cell pool. Cancer Discov. 2024.
6. Braun DA, Bakouny Z, Hirsch L, et al. Beyond Conventional Immune Checkpoint Inhibition: Renal Cell Carcinoma at the Forefront of Solid Tumor Immunology. Nat Rev Clin Oncol. 2021;18(4): 199-214.