Net-Kleng Zell Lung Cancer: New Preclinical Data

Results suggest that mesothelin-targeted TriKE can work alongside current standard of care and provide benefit even in the hypoxic environment of a solid tumor.

GT Biopharma, Inc., a clinical stage immuno-oncology company focused on developing innovative therapeutics based on the Company’s proprietary tri-specific natural killer (NK) cell engager, TriKE® protein biologic technology platform, presented preclinical data demonstrating its novel TriKE driving NK cell immunotherapy against non-small cell lung cancer (NSCLC) in the hypoxic solid tumor microenvironment at ESMO’s Targeted Anticancer Therapies Congress (TAT).

Gregory Berk, M.D., the Company’s President of R&D and Chief Medical Officer noted, “This pre-clinical evidence suggests, despite the difference in circulating immune cells of Stage IVB NSCLC patients, a mesothelin-targeted TriKE can work alongside current standard of care and provide benefit even in the hypoxic environment of a solid tumor, meriting further investigation of this novel, targeted TriKE.”

Driving NK cell immunotherapy against NSCLC, in the context of hypoxia, using Tri-specific Killer Engager (TriKE®)

Background – Currently, Tri-specific killer engagers (TriKE®) are being tested in the clinic to treat leukemia and lymphoma. These TriKE’s cross-link CD16/FcγRIII and the tumor antigen on NK cells which drives cytotoxicity while IL15 provides survival and proliferation signals to NK cells. Mesothelin (MSLN), is currently a tumor antigen being targeted in various cancers including NSCLC. The current study conducted by Dr. Jeff Miller’s laboratory, University of Minnesota, evaluated whether a MSLN-targeted TriKE could drive cytotoxicity towards NSCLC cells at all stages of disease in the presence of hypoxia, a challenge in the NSCLC tumor microenvironment.

Study design and analysis – Using peripheral blood mononuclear cells (PBMC) collected from NSCLC patients, (1) before patients started standard treatment, (2) after initial treatment and (3) at disease progression where applicable. The study challenged patient PBMC with a NSCLC cell line (NCI-H460) for 5 hours in the presence of monensin and brefeldin A, measuring degranulation (CD107a) and cytokine production (IFNγ) by flow cytometry (live, single CD56+/CD3- cells). Compared to NK cells alone (NT); NK cells alone with drug (‘TriKE’); or NK cells with tumor alone.

Resultater

NSLC have altered NK cells – Differential abundance analysis of immune subsets in early stage or late stage patient groups were performed using Astrolabe Diagnostics software. The TriKE was able to induce significant (p<0.0001) activity against H460 cells for both groups. The analysis revealed a greater abundance of CD56+/CD16+ NK cells and fewer CD33+/CD14- myeloid cells in early stage patients compared to late stage patients before treatment onset. The lack of CD16, which drives cytotoxicity, and the abundance of myeloid cells, that can suppress NK cell function, suggested late stage NSCLC patients may respond differently to biologics targeting NK cell cytotoxicity.

Mesothelin-targeted TriKE drives NK cell function regardless of disease stage and at all stages of treatment: While hypoxia impairs NK cell cytotoxicity, the study’s MSLN-targeted TriKE enhanced NK cell cytotoxicity of lung cancer cells (H460) after exposure to hypoxia for 7 days, during exposure to hypoxia and in the assay itself. The data demonstrated that TriKE induced degranulation and cytokine production in patient NK cells when in the presence of tumor cells (H460) at all stages of treatment (before treatment, after initial treatment and at progression).

Conclusion – This pre-clinical evidence suggests, despite the difference in circulating immune cells of Stage IVB NSCLC patients, mesothelin-targeted TriKE can work alongside current standard of care and provide benefit even in the hypoxic environment of a solid tumor.