Interleukin-2 (IL-2) is a key cytokine and immune-stimulating agent that is commonly used in the treatment of cancer patients to activate the immune system and offset the immuno-suppressive mechanisms exploited by the cancer cells. 

The IL-2 mediated pathway is critical for the expansion and differentiation of cancer-reactive T lymphocytes as well as natural killer (NK) cells that are available in the peripheral blood and accumulating within the tumour microenvironment. IL-2 analogues have been considered in the treatment of many solid tumours; however, the short half-life and treatment-related toxicities have limited their use. Nektar Therapeutics and Alkermes presented data for their modified IL-2 selective receptor agonists, NKTR-214 and ALKS 4230, respectively, at the 2019 Society for Immunotherapy of Cancer (SITC) conference in early November in Maryland, US, which could bring a revival for this drug class and is an encouraging step forward for the treatment of different types of solid tumours. 

The more prominent of the two drugs is NKTR-214 (bempegaldesleukin), which is an IL-2 agonist that preferentially binds to the beta chain of the IL-2 receptor (CD-122) found on the endogenous tumour-infiltrating lymphocytes (TILs) to induce expansion of immune cells, including PD-1+ T-cells. The latter makes NKTR-214 ideal for combining with PD-1 or PD-L1 inhibitors such as BMS’ Opdivo (nivolumab).

The data presented from a preliminary clinical study for the drug in combination with Opdivo in 38 patients with immunotherapy-naïve untreated melanoma showed a 53% objective response rate and a 34% complete response rate, resulting in a reduction of lesion volume in nearly half of the study population. The durable and deepening responses from treatment are encouraging moving forward in the ongoing Phase III trial in newly diagnosed advanced melanoma patients. NKTR-214 + Opdivo is also being investigated in other solid tumours such as advanced renal cell and metastatic urothelial carcinomas. 

ALKS 4230 is a fusion protein that binds to the alpha chain of the IL-2 receptor to induce clonal expansion of TILs. This drug selectively targets intermediate-affinity IL-2 receptors, avoiding the immunosuppression that can be caused by binding with the high-affinity IL-2 receptor. Data presented in poster format for the Phase I ARTISTRY-1 trial of ALKS 4230 in combination with Merck’s PD-1 inhibitor, Keytruda (pembrolizumab), showed promising safety in 36 patients with refractory advanced solid tumours. Interestingly, cohorts in the study focused on indications without PD-1/PD-L1 drug approvals, such as pancreatic cancer. PD-1/PD-L1 drugs are ineffective in certain “cold tumours” as monotherapy; thus, ALKS 4230 may have potential in these indications.

The new generation of IL-2 pathway agonist drugs, such as NKTR-214 and ALKS 4230, is aimed to improve the shortcomings of conventional IL-2 analogues. This has the potential for a resurgence of IL-2 agonists in the immuno-oncology field. Combination immunotherapy with IL-2 could be a substantial untapped opportunity, improving efficacy for tumour types that are traditionally unresponsive to PD-1 and PD-L1 inhibitors.

Related reports

GlobalData (2018) Immuno-oncology Development Trends and Opportunities, November 2018, GDHCHT015

GlobalData (2018) Challenges in I-O: Future Use, Trial Design and Combination Strategies, April 2018, GDHCHT003