monalizumab (IPH2201)

Natural killer cells showed only a limited contribution to the killing of HNSCC cells pretreated with RT or RT + DDRi. However, a subset of patients with head and neck tumors-such as those represented by the HSC4 model-might still benefit from combining RT with ATMi rather than ATRi to enhance NK cell-mediated tumor killing.

P2, N=60, Recruiting, John Sfakianos | Trial completion date: Dec 2027 --> Dec 2032 | Trial primary completion date: Dec 2026 --> Dec 2027

P1/2, N=43, Completed, Assistance Publique Hopitaux De Paris | Not yet recruiting --> Completed

P2, N=0, Withdrawn, Assistance Publique - Hôpitaux de Paris | N=43 --> 0 | Not yet recruiting --> Withdrawn

P2, N=60, Recruiting, John Sfakianos | Trial completion date: Dec 2026 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2026

First, the effectiveness of blocking the NKG2A-HLA-E interaction in vitro and in pre-clinical models as well as the presence of infiltrating NKG2A+ CD8+ T cells in some solid tumors has led to the generation of clinical grade NKG2A-specific monoclonal antibodies, pioneered by monalizumab, currently tested in clinical trials. Second, controlling NKG2A expression by genetic engineering constitutes a promising approach to improve advanced adoptive NK cell-based immunotherapies. Challenges include identifying predictive biomarkers of responsiveness, selecting appropriate clinical settings and optimizing combinatorial regimens.

P2, N=52, Not yet recruiting, Montefiore Medical Center | Trial completion date: Feb 2028 --> Aug 2028 | Initiation date: Sep 2025 --> Mar 2026 | Trial primary completion date: Apr 2027 --> Oct 2027

P3, N=370, Active, not recruiting, AstraZeneca | Trial completion date: Sep 2025 --> Sep 2026

Interestingly, STAT1 phosphorylation (Y701) by adenosine (ADO) aligned with the HLA-E expression pattern by ADO, and fludarabine, a STAT1 inhibitor, effectively reduced phospho-STAT1 (Y701) levels, but not phospho-STAT1 (S727) levels. Moreover, Monalizumab, an NKG2A monoclonal antibody, significantly reduced tumor progression and lung metastasis with increased population of cytotoxic NK cells (CD25+NK1.1+ and CD69+NK1.1+) in the inguinal lymph nodes of RT-R-MDA-MB-231-injected mice. This study suggests that the A2AR-phospho-STAT1 (Y701)-HLA-E axis may serve as an alternative target for overcoming RT-resistance in TNBC.

P2, N=900, Recruiting, SWOG Cancer Research Network | Not yet recruiting --> Recruiting

P1, N=26, Completed, National Cancer Institute (NCI) | Trial completion date: Apr 2026 --> Sep 2025 | Active, not recruiting --> Completed

NKG2A blockade potentiated NK cell-mediated ADCC against malignant B cells treated with CD40L and IL-4 and improved anti-CD20 antibody therapy in a murine model of B cell lymphoma. These results reveal a novel mechanism of resistance to anti-CD20 therapy in B cell malignancies and demonstrate that the combination of anti-NKG2A with anti-CD20 could improve the treatment of patients with CLL or NHL.