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

Yuanming Xu, Lucia Campos Carrascosa, Yik Andy Yeung, Matthew Ling-Hon Chu, Wenjing Yang, Ivana Djuretic, Danielle C Pappas, John Zeytounian, Zhouhong Ge, Valeska de Ruiter, Gabriel R Starbeck-Miller, James Patterson, Diamanda Rigas, Shih-Hsun Chen, Eugenia Kraynov, Patrick P Boor, Lisanne Noordam, Michael Doukas, Dave Tsao, Jan N IjzermansJie Guo, Dirk J Grünhagen, Joris Erdmann, Joanne Verheij, Martin E van Royen, Pascal G Doornebosch, Renny Feldman, Terrence Park, Salah Mahmoudi, Magdalena Dorywalska, Irene Ni, Sherman M Chin, Tina Mistry, Lidia Mosyak, Laura Lin, Keith A Ching, Kevin C Lindquist, Changhua Ji, Luz Marina Londono, Bing Kuang, Robert Rickert, Jaap Kwekkeboom, Dave Sprengers*, Tzu-Hsuan Huang*, Javier Chaparro-Riggers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

35 Citations (Scopus)

Abstract

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 þ 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 þ TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1–IL15m treatment induced the expansion of an exhausted CD8 þ TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1–IL15m was dependent on CD8 þ T cells, as depletion of CD8 þ 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 þ and CD4 þ 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 þ TILs. See related Spotlight by Felices and Miller, p. 1110.

Original languageEnglish
Pages (from-to)1141-1157
Number of pages17
JournalCancer Immunology Research
Volume9
Issue number10
DOIs
Publication statusPublished - 1 Oct 2021

Bibliographical note

Funding Information:
The authors thank German Vergara and Teresa Radcliffe for supporting the animal studies. They thank Barbra Sasu, Samantha Bucktrout, and Will Somers for support of this project. The design, study conduct, and financial support for this research were provided by Pfizer Inc. Pfizer Inc. participated in the interpretation of data, review, and approval of the publication. Financial support for this research was provided by Pfizer Inc.

Funding Information:
L. Campos Carrascosa reports grants from Pfizer Inc. during the conduct of the study. Y.A. Yeung reports a patent for US20190263877 pending to Pfizer Inc. M.L.-H. Chu reports a patent for IL15 variants and uses thereof (11059876) issued. V. de Ruiter reports grants from Pfizer Inc. during the conduct of the study. E. Kraynov reports other support from Pfizer Inc. during the conduct of the study. P.P. Boor reports grants from Pfizer Inc. during the conduct of the study. R. Feldman reports a patent for US20190263877 pending to Pfizer Inc. L. Mosyak reports a patent for US62/636,371 pending (USAPP Not Published IL15 variants and uses thereof) and a patent for US62/636,362 pending (USAPP Not Published IL15 variant and uses thereof). L. Lin reports a patent for IL15 variants and uses thereof pending. K.A. Ching reports other support from Pfizer Inc. during the conduct of the study, as well as other support from Pfizer Inc. outside the submitted work. J. Kwekkeboom reports grants from Pfizer Inc. during the conduct of the study. J. Chaparro-Riggers reports a patent for US62/636,371 pending and a patent for US62/636,362 pending. No disclosures were reported by the other authors.

Publisher Copyright:
© 2021 American Association for Cancer Research.

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