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Drug: NKG2A antibody

Magazine: Cell & Nature

Highlights: Cancer immunotherapy has a new target – NKG2A, I / II clinical trial data “giving expectations”, but the future is still unclear

In recent years, cancer immunotherapy has achieved unprecedented success, but only a few patients have shown lasting efficacy. Improving clinical response and overcoming resistance mechanisms are currently facing challenges in this area, and blocking other inhibitory immune receptors may be a viable strategy.

 

The NKG2 family of proteins is a class of receptors in complex receptor-ligand signaling networks that combine inhibition and agitation and are attractive targets for the development of immunological checkpoint inhibitors.

The NKG2 protein is a C-type lectin that dimerizes with CD94 on the cell surface. NKG2A is an “inhibitory” member of the NKG2 family and is expressed in a subset of CD56hi NK cells, NKT cells, and CD8+ alpha beta T cells. The non-classical MHC class I molecule HLA-E is the major ligand for NKG2A-CD94.

Although expression levels are about 25-fold lower than for classical MHC class I molecules, HLA-E is expressed in most human tissues. HLA-E binds to signal peptides from the classical MHC class I molecules HLA-A, HLA-B, HLA-C and HLA-G to form stable, correct folds. Binding of NKG2A–CD94 to the peptide HLA-E results in phosphorylation of cytoplasmic immunoreceptor tyrosine-based inhibitory motifs in NKG2A, resulting in the transmission of inhibitory signals from activating receptors (eg NKG2D, TCR) Competitive signal. Briefly, the interaction of KG2A with HLA-E inhibits the activation of NK cells and T cells.

Similar to other receptor-ligands (such as PD-1/PD-L1), the NKG2A–HLA-E pair of immune checkpoints are also used by cancer cells to escape the immune system. Studies have shown that high concentrations of NKG2A–CD94-positive tumor infiltrating lymphocytes (TILs) are associated with worse survival in patients with ovarian or colorectal cancer. Co-culture experiments showed that cancer cells promoted the expression of CD94 and NKG2A on CD8+ T cells, and depleted (dysfunctional) TILs expressed higher levels of NKG2A than other T cells in the surrounding.

Furthermore, previous evidence revealed that HLA-E is overexpressed relative to normal tissues in a variety of different tumor types. Nadine van Montfoort of the University of Leiden in the Netherlands confirmed this in a Cell paper published last November.

 

Studies have found that tumor cells abnormally express HLA-E, thus leading to NKG2A-mediated cancer vaccine resistance. Head and neck squamous cell carcinoma (HNSCC) biopsy samples showed that NKG2A is mainly expressed on CD103+CD8+ tissue-resident intratumoral T cells, and this expression is associated with worse clinical outcomes. .

 

Studies have also shown that the anti-tumor activity of CD8+ T cells in response to cancer vaccination can be repaired by gene knockout or antibody inhibition of NKG2A or its ligand Qa-1 (murine-derived HLA-E). In a mouse tumor model, the anti-NKG2A antibody monalizumab binds to a cancer vaccine designed to stimulate an anti-tumor immune response, which reduces tumor growth and increases progression-free survival.

 

Michael J. Korrer, co-first author of the paper, believes that NKG2A may now be the third most successful immunotherapy checkpoint, which is very exciting.

 

However, two scientists at the H. Lee Moffitt Cancer Center and Institute in the United States said that despite these convincing evidence that blocking NKG2A induces effective anti-tumor immunity, the clinical efficacy of NKG2A immunological checkpoint inhibitors still not clear.

 

The NKG2A antibody monalizumab used by Montfoort et al. is a first-in-class humanized IgG4 antibody that prevents NKG2A-CD94 from binding to HLA-E.

 

Monalizumab’s first human phase I/II clinical trial (NCT01370902) was performed in patients with rheumatoid arthritis. Although the preliminary safety data was good, it did not reach the end point associated with rheumatoid arthritis and was therefore suspended for further development in this area. Later, the scientists conducted a phase I/II clinical trial (NCT02459301) of patients with gynecologic malignancies treated with monalizumab monotherapy. The results showed no radiographic responses. This result also led to the early termination of the HNSCC new assisted trial (NCT02331875).

 

Despite these setbacks, joint treatment based on monalizumab may still be worth looking forward to. On the same day as Montfoort et al., a team of French scientists confirmed in another Cell paper that data from Phase I/II clinical trials in patients with metastatic or recurrent HNSCC showed cetuximab in 40 patients with measurable responses. The EGFR antibody)+monalizumab achieved an overall response rate (ORR) of 27.5%, whereas in the earlier studies, the ORR of cetuximab alone was 13%.

Although these results suggest that blocking the other immune checkpoints in combination therapy is expected to increase the anti-tumor activity of NK cells and CD8+ T cells in cancer patients, the combined response response of cetuximab+monalizumab does not appear to be as durable as PD-1 therapy. In a trial update, only 3 of the 11 respondents were still in remission.

In addition, because the trial excluded cetuximab refractory patients, a larger trial was needed to determine whether monalizumab would increase the therapeutic benefit of cetuximab.

So, can NKG2A immunological checkpoint inhibitors synergize with PD-1/PD-L1 inhibitors? Studies have shown that microsatellite stable colorectal cancer patients usually do not respond to PD-1 axis inhibitors, whereas in the monalizumab+durvalumab (a PD-L1 antibody) trial, 3 of 39 patients responded. But the median response lasted only 3.7 months. At present, there are no clinical data reports on the treatment of other solid tumors with monalizumab+PD-1/PD-L1 inhibitors.

 

Scientists believe that based on current data, we should be cautious about NKG2A immune checkpoint inhibitors. This is because, previously, the antibody lirilumab targeting killer cell immunoglobulin-like receptors (KIRs) KIR2DL1, KIR2DL2 and KIR2DL3 showed promising results in a clinical trial (NCT017014739) in combination with PD-1 antibodies. Response rate, but unfortunately, this result was not verified in larger clinical trials. They hope that monalizumab will not have a similar fate.

In summary, available evidence suggests that NKG2A inhibitors can repair the function of NK cells and T cell effectors in preclinical cancer models. In addition, NKG2A inhibitors in combination with other antibodies showed an encouraging response in patients with partially metastatic colorectal cancer or head and neck cancer. However, there are currently no biomarkers predicting patient response to NKG2A inhibitors, and larger clinical trials are needed to verify whether NKG2A inhibitors are a new force in cancer immunotherapy.

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