A tri-specific killer engager against mesothelin targets NK cells towards lung cancer

Abstract

New treatments are required to enhance current therapies for lung cancer. Mesothelin is a surface protein overexpressed in non-small cell lung cancer (NSCLC) that shows promise as an immunotherapeutic target in phase I clinical trials. However, the immunosuppressive environment in NSCLC may limit efficacy of these therapies. We applied time-of-flight mass cytometry to examine the state of circulating mononuclear cells in fourteen patients undergoing treatment for unresectable lung cancer. Six patients had earlier stage NSCLC (I-IVA) and eight had highly advanced NSCLC (IVB). The advanced NSCLC patients relapsed with greater frequency than the earlier stage patients. Before treatment, patients with very advanced NSCLC had a greater proportion of CD14- myeloid cells than patients with earlier NSCLC. These patients also had fewer circulating natural killer (NK) cells bearing an Fc receptor, CD16, which is crucial to antibody-dependent cellular cytotoxicity. We designed a high affinity tri-specific killer engager (TriKE®) to enhance NK cytotoxicity against mesothelin+ targets in this environment. The TriKE consisted of CD16 and mesothelin binding elements linked together by IL-15. TriKE enhanced proliferation of lung cancer patient NK cells in vitro. Lung cancer lines are refractory to NK cell killing, but the TriKE enhanced cytotoxicity and cytokine production by patient NK cells when challenged with tumor. Importantly, TriKE triggered NK cell responses from patients at all stages of disease and treatment, suggesting TriKE can enhance current therapies. These pre-clinical studies suggest mesothelin-targeted TriKE has the potential to overcome the immunosuppressive environment of NSCLC to treat disease.

Tri-specific killer engager: unleashing multi-synergic power against cancer

“…The last domain of TriKE is antigen-specific which takes a role in specifically target the cancer cells to complete their bridge function which connects enhanced NK cells to the targeted cancer cells. Previously, various types of specificity were designed, such as anti-CD33 AML [ 7 , 25 ], anti-EpCAM against carcinomas [ 13 ], anti-CD19 against B-CLL [ 15 ] anti-TEM8 and anti-mesothelin against NSCLC [ 10 , 27 ], anti-CLEC12A against AML [ 9 ], and anti-HER2 against ovarian cancer [ 26 ]. However, there are some interesting target antigens those have been used as potential target immunotherapy in other platforms, like monoclonal antibody (mAb), CAR-T cell, and other immune cell-engager: T cell engager and macrophage engager which can be applied to TriKEs construction [ 47 ].…”

“…Until now, there have been a lot of TriKE constructs that are progressing on in vitro studies ( Table 1 ) [ 9 – 11 , 13 – 16 , 20 , 25 – 27 ], but there is only one reached clinical studies. GTB-3550 TriKE which is a primal construct with CD16 scFv and targets on CD33 + AML and myelodysplastic syndromes (MDS) is the first TriKE in phase I clinical trials (NCT03214666) [ 7 , 12 ].…”

“…As it is looked ahead to the future of TriKEs, these innovative immunotherapies hold great promise in the realm of cancer treatment. However, like any evolving medical technology, there are challenges and disadvantages that researchers are actively working to address [ 11 , 27 ]. In this section, we will explore some of the key considerations and strategies for overcoming these drawbacks, with a focus on optimizing the function of TriKEs while attenuating the risks of off-target effects.…”

“…Another problem that NK cell-based immunotherapy has to face is CD16 downregulate in some cancer patients especially in solid tumors [ 20 , 26 ] and TMEs [ 88 ]. It’s still unclear about their exact mechanism, the existed results suggested the downregulation of CD16 on activated NK cell [ 20 , 27 ]. Another avenue for future exploration in TriKE-based therapies is the combination with A disintegrin and metalloprotease 17 (ADAM17) inhibition [ 77 , 89 , 90 ].…”

Harnessing natural killer cell effector function against cancer

“…For instance, a CD16/IL-15R/HER2 targeting TRiKE induced NK-cell proliferation and demonstrated promising efficacy against ovarian cancer cells in vitro and in vivo [ 100 ]. A CD16/IL15R/mesothelin TriKE enhanced the proliferation, cytotoxicity, and cytokine production of patient-derived NK cells against lung cancer cell lines [ 101 ]. In addition, this NKCE significantly improved control of tumour growth in a metastatic xenograft model [ 101 ].…”