Combination of TEW-7197 and Adoptively Transferred NK Cells Leads to Improved Antitumor Responses in Vivo

Transforming growth factor beta (TGF-β) supports tumor cell proliferation, metastasis, and invasion in later stages of cancer while suppresses the proliferation and survival of lymphocytes including Natural Killer (NK) cells. The current therapeutic approaches of targeting TGF-β include inhibiting its transcription through anti-sense oligonucleotides, blocking TGF-β receptor binding through the use of antibodies, or suppressing the TGF-beta signaling pathways using small molecules, such as TEW-7197. Here, we report the anti-tumorigenic role of TEW-7197, an orally administered TGF-b receptor kinase ALK5 inhibitor, by synergizing with adoptively transferred NK cells in the human xenograft A375 melanoma model. Addition of TEW-7197, at its therapeutic doses, in cultures of A375 melanoma cells did affect neither the growth nor the apoptotic killing of tumor cells in vitro, however, it caused reduction of tumor cell growth in vivo. This was possibly due to the upregulation of TGF-b mRNA upon tumor implantation in the xenograft tissues, which became a target of TEW-7197. Adoptive transfer of ex-vivo expanded human NK cells into these mice also inhibited tumor growth but co-administration of TEW-7197 resulted in significantly higher degree of tumor regression, by both inhibiting TGFb signaling as well as increasing the NK cell’s availability within tumor tissues. These data highlight that the anti-tumor response exhibited by TEW-7197 and NK cells are distinct, and can be synergized by the combination of the two. Therefore, our data provide the scientific rationale for the combination therapies of TGF-b small molecule kinase inhibitors with adoptively transferred NK cells in advanced cancer patients.