Table 2.
Examples of innovative immunostimulatory IL-2 therapies undergoing clinical evaluation
IL-2 therapyClinical trial
TypeAgent (company)DescriptionDelivery routeIndicationCo-therapyPhaseStatusReferences
Immunocytokine ALKS 4230 (Alkermes) IL-2–CD25 fusion protein i.v. Solid tumors Pembrolizumab 1/2 Recruiting NCT02799095 (Vaishampayan et al., 2017) 
s.c. Solid tumors Pembrolizumab Recruiting NCT03861793 (Vaishampayan et al., 2017) 
Darleukin (Philogen) Anti-fibronectin diabody–IL-2 fusion protein i.v. (?) NSCLC Radiotherapy; surgery Not yet recruiting NCT03705403 (Johannsen et al., 2010; Eigentler et al., 2011; Danielli et al., 2015) 
EMD273063/hu14.18-IL2 (Merck) Anti–GD2–IL-2 fusion protein i.v. Melanoma Surgery Active, not recruiting NCT00590824 
i.t. Melanoma Radiotherapy; nivolumab; ipilimumab 1/2 Not yet recruiting NCT03958383 
i.v. Neuroblastoma EEAHD NK cells Recruiting NCT03209869 
RG7461/RO6874281 (Roche) Anti–FAP–IL-2 mutein (F42A, Y45A, and L72G) fusion protein i.v. NSCLC; SCCHN; ESCC; cervical cancer Atezolizumab; gemcitabine; vinorelbine Recruiting NCT03386721 (Klein et al., 2017) 
i.v. Pancreatic cancer Atezolizumab 1/2 Recruiting NCT03193190 (Klein et al., 2017) 
i.v. TNBC Atezolizumab 1/2 Recruiting NCT03424005 (Klein et al., 2017) 
i.v. Melanoma Pembrolizumab 1b Recruiting NCT03875079 (Klein et al., 2017) 
i.v. Breast cancer; HNC; other solid tumors Trastuzumab; cetuximab Recruiting NCT02627274 (Klein et al., 2017) 
i.v. RCC Atezolizumab; bevacizumab Active, not recruiting NCT03063762 (Klein et al., 2017) 
RG7813/cergutuzumab amunaleukin (Roche) Anti–CEA–IL-2 mutein (F42A, Y45A, and L72G) fusion protein i.v. Solid tumors Atezolizumab Active, not recruiting NCT02350673 (Klein et al., 2017; Lo et al., 2017) 
PEGylated IL-2 NKTR-214 (Nektar Therapeutics) PEG–IL-2 with IL-2Rβ bias > IL-2Rα bias i.v. Melanoma Nivolumab Recruiting NCT03635983 (Charych et al., 2016) 
i.v. RCC Sunitinib; nivolumab; cabozantinib Recruiting NCT03729245 (Charych et al., 2016) 
i.v. Bladder cancer Nivolumab Recruiting NCT03785925 (Charych et al., 2016) 
i.v. Sarcoma Nivolumab Recruiting NCT03282344 (Charych et al., 2016) 
i.v. Melanoma; RCC; NSCLC; urothelial cancer; TNBC Nivolumab; ipilimumab 1/2 Recruiting NCT02983045 (Charych et al., 2016) 
i.v. Skin cancers (melanoma, MCC); TNBC; ovarian cancer; RCC; CRC; urothelial cancer; sarcoma NKTR-262; Nivolumab 1/2 Recruiting NCT03435640 (Charych et al., 2016) 
   i.v. NHL TAK-659 Recruiting NCT03772288 (Charych et al., 2016) 
i.v. NSCLC; bladder cancer; melanoma Pembrolizumab; atezolizumab Recruiting NCT03138889 (Charych et al., 2016) 
i.v. Prostate cancer Nivolumab Recruiting NCT03835533 (Charych et al., 2016) 
i.v. Solid tumors Nivolumab Recruiting NCT03745807 (Charych et al., 2016) 
IL-2 therapyClinical trial
TypeAgent (company)DescriptionDelivery routeIndicationCo-therapyPhaseStatusReferences
Immunocytokine ALKS 4230 (Alkermes) IL-2–CD25 fusion protein i.v. Solid tumors Pembrolizumab 1/2 Recruiting NCT02799095 (Vaishampayan et al., 2017) 
s.c. Solid tumors Pembrolizumab Recruiting NCT03861793 (Vaishampayan et al., 2017) 
Darleukin (Philogen) Anti-fibronectin diabody–IL-2 fusion protein i.v. (?) NSCLC Radiotherapy; surgery Not yet recruiting NCT03705403 (Johannsen et al., 2010; Eigentler et al., 2011; Danielli et al., 2015) 
EMD273063/hu14.18-IL2 (Merck) Anti–GD2–IL-2 fusion protein i.v. Melanoma Surgery Active, not recruiting NCT00590824 
i.t. Melanoma Radiotherapy; nivolumab; ipilimumab 1/2 Not yet recruiting NCT03958383 
i.v. Neuroblastoma EEAHD NK cells Recruiting NCT03209869 
RG7461/RO6874281 (Roche) Anti–FAP–IL-2 mutein (F42A, Y45A, and L72G) fusion protein i.v. NSCLC; SCCHN; ESCC; cervical cancer Atezolizumab; gemcitabine; vinorelbine Recruiting NCT03386721 (Klein et al., 2017) 
i.v. Pancreatic cancer Atezolizumab 1/2 Recruiting NCT03193190 (Klein et al., 2017) 
i.v. TNBC Atezolizumab 1/2 Recruiting NCT03424005 (Klein et al., 2017) 
i.v. Melanoma Pembrolizumab 1b Recruiting NCT03875079 (Klein et al., 2017) 
i.v. Breast cancer; HNC; other solid tumors Trastuzumab; cetuximab Recruiting NCT02627274 (Klein et al., 2017) 
i.v. RCC Atezolizumab; bevacizumab Active, not recruiting NCT03063762 (Klein et al., 2017) 
RG7813/cergutuzumab amunaleukin (Roche) Anti–CEA–IL-2 mutein (F42A, Y45A, and L72G) fusion protein i.v. Solid tumors Atezolizumab Active, not recruiting NCT02350673 (Klein et al., 2017; Lo et al., 2017) 
PEGylated IL-2 NKTR-214 (Nektar Therapeutics) PEG–IL-2 with IL-2Rβ bias > IL-2Rα bias i.v. Melanoma Nivolumab Recruiting NCT03635983 (Charych et al., 2016) 
i.v. RCC Sunitinib; nivolumab; cabozantinib Recruiting NCT03729245 (Charych et al., 2016) 
i.v. Bladder cancer Nivolumab Recruiting NCT03785925 (Charych et al., 2016) 
i.v. Sarcoma Nivolumab Recruiting NCT03282344 (Charych et al., 2016) 
i.v. Melanoma; RCC; NSCLC; urothelial cancer; TNBC Nivolumab; ipilimumab 1/2 Recruiting NCT02983045 (Charych et al., 2016) 
i.v. Skin cancers (melanoma, MCC); TNBC; ovarian cancer; RCC; CRC; urothelial cancer; sarcoma NKTR-262; Nivolumab 1/2 Recruiting NCT03435640 (Charych et al., 2016) 
   i.v. NHL TAK-659 Recruiting NCT03772288 (Charych et al., 2016) 
i.v. NSCLC; bladder cancer; melanoma Pembrolizumab; atezolizumab Recruiting NCT03138889 (Charych et al., 2016) 
i.v. Prostate cancer Nivolumab Recruiting NCT03835533 (Charych et al., 2016) 
i.v. Solid tumors Nivolumab Recruiting NCT03745807 (Charych et al., 2016) 

CEA, carcinoembryonic antigen; CRC, colorectal cancer; EEAHD, ex vivo expanded and activated haploidentical donor; ESCC, esophageal squamous cell carcinoma; FAP, fibroblast activation protein-alpha; GD2, ganglioside D2; HNC, head and neck cancer; i.t., intratumoral; MCC, Merkel cell carcinoma; NHL, Non-Hodgkin lymphoma; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; TNBC, triple negative breast cancer.

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