Antitumor activity of STAT3 protein deactivating agents that enhance tumor sensitivity to PD-1 inhibitors

Kymera Has announced the results of a trial of kTX-201, a protein inhibitor targeting STAT3 proteins. The results showed that KTX-201 can change the characteristics of tumor microenvironment in a mouse solid tumor model, making tumors more sensitive to PD-1 inhibitors, thus enhancing the effect of PD-1 inhibitors.

STAT3 is a transcription factor that can be activated by different cytokine and growth factor receptors and may also be activated by mutations in oncogenic fusion proteins and STAT3 itself. It has many functions in promoting tumor growth and metastasis. Over-activated STAT3 has long been considered as an "unmarketable" target, and targeted protein degradation provides a new strategy to address the "unmarketable" nature of this target.

                                             STAT3 has multiple roles in tumor survival and growth.

Previously, Kymera found that the stat3-targeting protein inhibitor KTX-201, as a single agent, caused ALK-positive anaplastic large cell lymphoma (ALCL) and NK/T cell lymphoma carrying STAT3 mutants in both in vitro and in vivo. And ALK negative ALCL cell lines increased growth stagnation and cell death.

Analysis of gene expression profiles in tumors treated with KTX-201 found significant increases in the expression of pro-inflammatory genes, as well as biomarkers of T cell activation and M1 macrophage activation, compared with controls. Notably, the gene expression profile associated with the interferon γ response implies that degradation of STAT3 leads to an inflammatory T-cell phenotype associated with immune checkpoint therapy responses.

                                                                                                           Ktx-201 modifies tumor microenvironment

Furthermore, when kTX-201 was combined with anti-PD-1 antibody, it resulted in a 60% complete response in a solid tumor mouse model and allowed the animals to acquire immune memory, as well as inhibited the growth of reimplanted tumors.

                                                                                                               Ktx-201, combined with anti-PD-1 antibody, showed better anticancer activity.

Ktx-333, a potential "first-in-class" STAT3 protein inhibitor currently under development based on KTX-201, is expected to receive IND approval by the end of 2021 for phase 1 clinical trials in patients with hematological cancers and solid tumors, Kymera said.