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The Beginnings of Immunotherapy for Renal Cell Carcinoma

(UroToday.com) At the ASCO 2020 virtual education program, Janice Dutcher, MD, discussed the beginnings of immunotherapy for renal cell carcinoma (RCC) as part of the evolution of RCC treatment session of talks. Cytokines are endogenous substances within the immune system and are responsible for cell signaling, as well as induction or inhibition of various cell regulatory proteins and processes. Several cytokines have clinical importance to RCC including interferon alpha, beta, and gamma, as well as interleukin-2 (IL-2). There are several key biological actions of interferons:
  • Suppression of apoptosis
  • Anti-angiogenic activity
  • Modulation of MHC I and MHC II expression
  • Down-regulation of certain oncogenes
  • Anti-proliferative effects
  • Simulation of macrophage, cytotoxic T-cells, and natural killer cell activity
Interferons in RCC have an objective response rate (the majority partial responses) of around 10-15%, with intermediate (5-15 million units/m2/day) to high dose (20-50 million units/m2/day) treatment producing most of the responses. Toxicity of high-dose for chronic use is often clinically prohibitive with median survival in many series of 10 months. 

Interleukin-2 activates and expands populations of cytotoxic T-cells and natural killer cells, and leads to secondary cytokine release by activated cells including interleukin-1 (IL-1), tumor necrosis factor, and gamma-interferon. Importantly, cytotoxic cells produce >90% of tumor kill in in vitro assays. In RCC, high-dose IL-2 has an objective response rate in multiple trials and registry data of 20-25% (with 10% of these being complete responses), and most complete responses are durable, lasting multiple years without subsequent treatment. As with interferons, IL-2 has a dose-response associated with objective response rate, durability of response, and overall survival: the current dose is 600,000-720,000 U/kg/dose every 8 hours up to 14 doses (week 1 and week 3), which may be repeated. Favorable and intermediate-risk groups have better tolerability and response to treatment. 

The PROCLAIM registry recently published long-term data of 810 mRCC patients receiving high-dose IL-2 from 2006-2017.1 Among these patients, 721 were treatment-naïve (89%) and 59% were intermediate risk. Overall, of the 249 patients with favorable risk, the median overall survival was 63.3 months and the 2-year overall survival rate was 77.6%. Of 480 patients with intermediate-risk, the median overall survival was 42.4 months, and the 2-year overall survival rate was 68.2%. Among 81 patients with poor-risk disease, the median overall survival was 14 months and the 2-year overall survival rate was 40.4%. Finally, among 356 patients that received IL-2 alone, the median overall survival was 64.5, 57.6, and 14 months for favorable, intermediate and poor-risk categories, respectively. 

PROCLAIM_registry_RCC_graph.png

The current status of IL-2 therapy after 20 years of clinical trials is that high-dose IL-2 has yielded the highest complete response rate with durable, treatment-free intervals. It requires careful patient selection, and there is a need for new combination clinical trials with the goal of increasing complete response rate, complete response duration, and treatment-free interval. 

Dr. Dutcher concluded with several take-home points from her presentation:

  • High-dose IL-2 is associated with an objective response rate of 20-25% and >10% of these being complete responses with long-term durability
  • L-2 has responses in all risk groups, but better overall survival in favorable and intermediate-risk patients
  • New directions should include different schedules to ameliorate cumulative toxicities during treatment course, combinations with newer immunotherapies, and re-evaluation of lower doses of IL-2 with monitoring of the immune cellular response

Presented by: Janice P. Dutcher, MD, Our Lady of Mercy Medical Center, The Bronx, NY

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, USA, Twitter: @zklaassen_md at the ASCO20 Virtual Education Program, #ASCO20, August 8-10, 2020


References:

  1. Fishman M, Dutcher JP, Clark JI, et al. Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIM registry. J Immunother Cancer 2019 Mar 27;7(1):84.