TY - JOUR
T1 - An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity
AU - Xu, Yuanming
AU - Carrascosa, Lucia Campos
AU - Yeung, Yik Andy
AU - Chu, Matthew Ling Hon
AU - Yang, Wenjing
AU - Djuretic, Ivana
AU - Pappas, Danielle C.
AU - Zeytounian, John
AU - Ge, Zhouhong
AU - de Ruiter, Valeska
AU - Starbeck-Miller, Gabriel R.
AU - Patterson, James
AU - Rigas, Diamanda
AU - Chen, Shih Hsun
AU - Kraynov, Eugenia
AU - Boor, Patrick P.
AU - Noordam, Lisanne
AU - Doukas, Michael
AU - Tsao, Dave
AU - Ijzermans, Jan N.
AU - Guo, Jie
AU - Grünhagen, Dirk J.
AU - Erdmann, Joris
AU - Verheij, Joanne
AU - van Royen, Martin E.
AU - Doornebosch, Pascal G.
AU - Feldman, Renny
AU - Park, Terrence
AU - Mahmoudi, Salah
AU - Dorywalska, Magdalena
AU - Ni, Irene
AU - Chin, Sherman M.
AU - Mistry, Tina
AU - Mosyak, Lidia
AU - Lin, Laura
AU - Ching, Keith A.
AU - Lindquist, Kevin C.
AU - Ji, Changhua
AU - Londono, Luz Marina
AU - Kuang, Bing
AU - Rickert, Robert
AU - Kwekkeboom, Jaap
AU - Sprengers, Dave
AU - Huang, Tzu Hsuan
AU - Chaparro-Riggers, Javier
PY - 2021/10/1
Y1 - 2021/10/1
N2 - The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m, demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8+ TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8+ TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8+ T cells, as depletion of CD8+ cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from patients with cancer was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human primary cancers in vitro, whereas tumor-derived regulatory T cells were largely unaffected. Taken together, our findings showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD1+ TILs.See related Spotlight by Felices and Miller, p. 1110.
AB - The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m, demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8+ TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8+ TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8+ T cells, as depletion of CD8+ cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from patients with cancer was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human primary cancers in vitro, whereas tumor-derived regulatory T cells were largely unaffected. Taken together, our findings showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD1+ TILs.See related Spotlight by Felices and Miller, p. 1110.
UR - http://www.scopus.com/inward/record.url?scp=85118097437&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-21-0058
DO - 10.1158/2326-6066.CIR-21-0058
M3 - Article
C2 - 34376502
AN - SCOPUS:85118097437
VL - 9
SP - 1141
EP - 1157
JO - Cancer Immunology Research
JF - Cancer Immunology Research
SN - 2326-6066
IS - 10
ER -