An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity

• Published in: Cancer immunology research Vol. 9; no. 10; p. 1141
• Main Authors: Xu, Yuanming, Carrascosa, Lucia Campos, Yeung, Yik Andy, Chu, Matthew Ling-Hon, Yang, Wenjing, Djuretic, Ivana, Pappas, Danielle C, Zeytounian, John, Ge, Zhouhong, de Ruiter, Valeska, Starbeck-Miller, Gabriel R, Patterson, James, Rigas, Diamanda, Chen, Shih-Hsun, Kraynov, Eugenia, Boor, Patrick P, Noordam, Lisanne, Doukas, Michael, Tsao, Dave, Ijzermans, Jan N, Guo, Jie, Grünhagen, Dirk J, Erdmann, Joris, Verheij, Joanne, van Royen, Martin E, Doornebosch, Pascal G, Feldman, Renny, Park, Terrence, Mahmoudi, Salah, Dorywalska, Magdalena, Ni, Irene, Chin, Sherman M, Mistry, Tina, Mosyak, Lidia, Lin, Laura, Ching, Keith A, Lindquist, Kevin C, Ji, Changhua, Londono, Luz Marina, Kuang, Bing, Rickert, Robert, Kwekkeboom, Jaap, Sprengers, Dave, Huang, Tzu-Hsuan, Chaparro-Riggers, Javier
• Format: Journal Article
• Language: English
• Published: United States 01-10-2021
• Subjects: Animals; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Colonic Neoplasms - immunology; Colonic Neoplasms - therapy; Disease Models, Animal; Humans; Immunotherapy; Interleukin-15 - immunology; Interleukin-15 - therapeutic use; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor - immunology; Protein Engineering; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - therapeutic use
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-21-0058

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
, 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.
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