Preclinical evaluation of an affinity-enhanced MAGE-A4-specific T-cell receptor for adoptive T-cell therapy.

Abstract:

:A substantial obstacle to the success of adoptive T cell-based cancer immunotherapy is the sub-optimal affinity of T-cell receptors (TCRs) for most tumor antigens. Genetically engineered TCRs that have enhanced affinity for specific tumor peptide-MHC complexes may overcome this barrier. However, this enhancement risks increasing weak TCR cross-reactivity to other antigens expressed by normal tissues, potentially leading to clinical toxicities. To reduce the risk of such adverse clinical outcomes, we have developed an extensive preclinical testing strategy, involving potency testing using 2D and 3D human cell cultures and primary tumor material, and safety testing using human primary cell and cell-line cross-reactivity screening and molecular analysis to predict peptides recognized by the affinity-enhanced TCR. Here, we describe this strategy using a developmental T-cell therapy, ADP-A2M4, which recognizes the HLA-A2-restricted MAGE-A4 peptide GVYDGREHTV. ADP-A2M4 demonstrated potent anti-tumor activity in the absence of major off-target cross-reactivity against a range of human primary cells and cell lines. Identification and characterization of peptides recognized by the affinity-enhanced TCR also revealed no cross-reactivity. These studies demonstrated that this TCR is highly potent and without major safety concerns, and as a result, this TCR is now being investigated in two clinical trials (NCT03132922, NCT04044768).

journal_name

Oncoimmunology

journal_title

Oncoimmunology

authors

Sanderson JP,Crowley DJ,Wiedermann GE,Quinn LL,Crossland KL,Tunbridge HM,Cornforth TV,Barnes CS,Ahmed T,Howe K,Saini M,Abbott RJ,Anderson VE,Tavano B,Maroto M,Gerry AB

doi

10.1080/2162402X.2019.1682381

subject

Has Abstract

pub_date

2019-11-24 00:00:00

pages

1682381

issue

1

eissn

2162-4011

issn

2162-402X

pii

1682381

journal_volume

9

pub_type

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