Serial stimulation of invariant natural killer T cells with covalently stabilized bispecific t-cell engagers generates antitumor immunity while avoiding anergy

Shalu Sharma Kharkwal, Christopher T. Johndrow, Natacha Veerapen, Himanshu Kharkwal, Noemi A. Saavedra-Avila, Leandro J. Carreño, Samantha Rothberg, Jinghang Zhang, Scott J. Garforth, Peter J. Jervis, Lianjun Zhang, Alena Donda, Amareeta K. Besra, Liam R. Cox, Steven C. Almo, Alan Howell, Elizabeth E. Evans, Maurice Zauderer, Gurdyal S. Besra, Steven A. Porcelli

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

CD1d-restricted invariant natural killer T cells (iNKT cells) mediate strong antitumor immunity when stimulated by glycolipid agonists. However, attempts to develop effective iNKT cell agonists for clinical applications have been thwarted by potential problems with dose-limiting toxicity and by activation-induced iNKT cell anergy, which limits the efficacy of repeated administration. To overcome these issues, we developed a unique bispecific T-cell engager (BiTE) based on covalent conjugates of soluble CD1d with photoreactive analogues of the glycolipid α-galactosylceramide. Here we characterize the in vivo activities of iNKT cell-specific BiTEs and assess their efficacy for cancer immunotherapy in mouse models using transplantable colorectal cancer or melanoma tumor lines engineered to express human Her2 as a tumor-associated antigen. Systemic administration of conjugated BiTEs stimulated multiple iNKT cell effector functions including cytokine release, secondary activation of NK cells, and induction of dendritic cell maturation and also initiated epitope spreading for tumor-specific CD8+ cytolytic T-cell responses. The antitumor effects of iNKT-cell activation with conjugated BiTEs were further enhanced by simultaneous checkpoint blockade with antibodies to CTLA-4, providing a potential approach for combination immunotherapy. Multiple injections of covalently stabilized iNKT cell-specific BiTEs activated iNKT cells without causing iNKT cell anergy or exhaustion, thus enabling repeated administration for effective and nontoxic cancer immunotherapy regimens.

Original languageEnglish (US)
Pages (from-to)1788-1801
Number of pages14
JournalCancer research
Volume81
Issue number7
DOIs
StatePublished - Apr 2021
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Serial stimulation of invariant natural killer T cells with covalently stabilized bispecific t-cell engagers generates antitumor immunity while avoiding anergy'. Together they form a unique fingerprint.

Cite this