αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression.

Josephine G M Strijker,Esther Drent,Kimberley Ober,Andrea Bisso,Annelisa M Cornel,Jan J Molenaar,Jessica J F Van Der Hoek,Marleen M Van Loenen,Chris Coomans,Ronja Pscheid,Waleed M Kholosy,Bianca Koopmans,Sander R Van Hooff,Judith Wienke

doi:10.3390/jpm11090923

Abstract

Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients.

Highlights

In various adult cancers, innovations in immunotherapy, such as immune checkpoint inhibition, immunomodulatory antibodies, and engineered T cells expressing chimeric antigen receptors (CAR) have led to a big leap in survival rates [1]
We demonstrated that 50% of tested neuroblastoma organoids can effectively activate TEG002 and that killing of the organoids is independent of MHC-I expression
No specific antibodies are available for the direct measurement of CD277J expression; CD277 expression on the organoids indicates potential for conformational change and recognition by TEG002 in the presence of high levels of IPP

Summary

Introduction

Innovations in immunotherapy, such as immune checkpoint inhibition, immunomodulatory antibodies, and engineered T cells expressing chimeric antigen receptors (CAR) have led to a big leap in survival rates [1]. Immunotherapy is still in the early development stages, with one exception being the anti-GD2 antibody Dinutuximab for neuroblastoma patients [2]. Even though implementation of Dinutuximab into the neuroblastoma treatment protocol has significantly improved survival rates, the 5-year survival rate of ~50% for high-risk patients is still dismal and leaves room for improvement [3]. Neuroblastoma is a neuroendocrine solid tumor of early childhood. The prognosis for survival of patients depends on several risk factors including age, level of metastases at diagnosis and MYCN amplification of the tumor [5,6]. Since the chance of survival for high-risk patients has risen to ~50% after the addition of Dinutuximab to the treatment protocol, immunotherapy appears to be a promising approach for neuroblastoma

Methods

Results

Conclusion