- 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
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.
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
- 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.