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. 2023 Apr:90:104539.
doi: 10.1016/j.ebiom.2023.104539. Epub 2023 Mar 31.

A systematic review of interleukin-2-based immunotherapies in clinical trials for cancer and autoimmune diseases

Miro E Raeber  1 , Dilara Sahin  2 , Ufuk Karakus  2 , Onur Boyman  3
Affiliations

A systematic review of interleukin-2-based immunotherapies in clinical trials for cancer and autoimmune diseases

Miro E Raeber et al. EBioMedicine. 2023 Apr.

Abstract

Background: The cytokine interleukin-2 (IL-2) can stimulate both effector immune cells and regulatory T (Treg) cells. The ability of selectively engaging either of these effects has spurred interest in using IL-2 for immunotherapy of cancer and autoimmune diseases. Thus, numerous IL-2-based biologic agents with improved bias or delivery towards effector immune cells or Treg cells have been developed. This study systematically reviews clinical results of improved IL-2-based compounds.

Methods: We searched the ClinicalTrials.gov database for registered trials using improved IL-2-based agents and different databases for available results of these studies.

Findings: From 576 registered clinical trials we extracted 36 studies on different improved IL-2-based compounds. Adding another nine agents reported in recent literature reviews and based on our knowledge totalled in 45 compounds. A secondary search for registered clinical trials of each of these 45 compounds resulted in 141 clinical trials included in this review, with 41 trials reporting results.

Interpretation: So far, none of the improved IL-2-based compounds has gained regulatory approval for the treatment of cancer or autoimmune diseases. NKTR-214 is the only compound completing phase 3 studies. The PIVOT IO-001 trial testing the combination of NKTR-214 plus Pembrolizumab compared to Pembrolizumab monotherapy in metastatic melanoma missed its primary endpoints. Also the PIVOT-09 study, combining NKTR-214 with Nivolumab compared to Sunitinib or Cabozantinib in advanced renal cell carcinoma, missed its primary endpoint. Trials in autoimmune diseases are currently in early stages, thus not allowing definite conclusions on efficacy.

Funding: This work was supported by public funding agencies.

Keywords: Autoimmune disease; Cancer; IL-2; Immunotherapy; Interleukin 2; Systematic review.

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Conflict of interest statement

Declaration of interests MR, UK, and OB hold patents on improved IL-2-based compounds and OB is a shareholder of Anaveon AG. MR discloses paid consulting activities for Urogen. DS states no competing interests related to this work.

Figures

Fig. 1
Fig. 1
Biology of interleukin-2 (IL-2). Low-dose IL-2 and improved IL-2 formulations with CD25 bias preferentially stimulate the trimeric IL-2 receptor consisting of CD25, CD122, and CD132, thus expanding regulatory T (Treg) cells. Treg cell expansion restores immune balance in patients with autoimmune diseases, including systemic lupus erythematosus and inflammatory bowel disease (left panel). On the other hand, high doses of IL-2 or CD122-biased IL-2 formulations preferentially stimulate the dimeric IL-2 receptor consisting of CD122 and CD132 and expressed on effector-type lymphocytes, such as resting antigen-experienced (memory) T and natural killer cells. Stimulation of these effector immune cells improves anti-tumour responses in cancer patients (right panel). Another approach focuses on delivery of IL-2 to either the tumour microenvironment or anti-tumour effector immune cells by using targeted IL-2 formulations (right panel).
Fig. 2
Fig. 2
Registered clinical trials testing improved IL-2-based compounds. Top panel displays trials in cancer and bottom panel trials in autoimmune diseases.
Fig. 3
Fig. 3
PRISMA flow chartof literature research.
See this image and copyright information in PMC

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