JACQUES GHYSDAEL (ORSAY)
HUMANIZED, FC RECEPTOR NON-BINDING ANTI-CD3 ANTIBODIES AS NEW THERAPEUTIC
TOOLS IN T CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL)
C. Tran Quang1, B. Zanibobi1, A Avila Avila1, R. Ganesan2, Scheer J2, V. Asnafi3 and J. Ghysdael1
1. Institut Curie, PSL Research University, CNRS UMR 3348; Université Paris-Sud, Université Paris-Saclay, Orsay,
France.
2. Boehringer-Ingelheim Pharamaceuticals, Inc, Ridgefield, CT, USA
3 Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de
Recherche Médicale (INSERM) U1151, Paris, France
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that accounts for about 20%
ALL cases. Intensive chemotherapy regimens result in >85% cure rates in children and <50% in adults,
calling for search of novel therapeutic strategies. While immune-based therapies have tremendously
improved the treatment of B-ALL and other B- cell malignancies, they are not available yet in T-ALL.
We previously reported that activation of the TCR developmental checkpoint by the anti-CD3
monoclonal antibody (mAb) OKT3 induces cell death and potent anti-leukemic effects in xenografts (T-ALL
PDX) generated from diagnostic TCR+ T-ALL cases (Trinquand, dos Santos, Tran Quang et al Cancer
Discov 2016). Being of murine origin, OKT3 is highly immunogenic and induces a life-threathening
cytokine release syndrome associated with its ability to recruit FcR-bearing cells that limits its clinical
use. We now report that humanized anti-CD3 antibodies carrying two point mutations in their Fc region
that decrease their affinity for FcR by 2-3 orders of magnitude, namely Teplizumab and Foralumab, are
endowed with anti-leukemic effects similar to OKT3 and prolong host survival. We also found that
these antibodies cooperate with chemotherapy to enhance anti-leukemic effects and host survival. As
these antibodies show only minor, manageable side effects in humans, they offer a new therapeutic
option for the treatment of T-ALL (Tran Quang et al Blood 2020)
Mechanistically, our data indicate that recruitment/activation of FcR-dependent ADCP-type
mechanisms are not critical to the anti-leukemic activity of anti-CD3 mAbs in T-ALL PDX. Rather,
Teplizumab and OKT3 induce in vivo a common core transcriptomic signature in T-ALL PDXs that
partially overlaps that induced during thymocyte negative selection. Interestingly, unique molecular
features are also strongly de-regulated that are amenable to therapeutic intervention to further
enhance vulnerability of T-ALL to TCR-directed therapy.