motolimod (VTX 2337)

Classification of AML cases into primitive (n=12) and mature (n=10) revealed that primitive cells were more sensitive to 22 compounds including azacitidine and navitoclax. In contrast, mature cells were preferentially sensitive to 17 compounds including the MLC1 inhibitor A-1210477, the TLR8 agonist motolimod, the ROS inducer auranofin and 4 IAPs inhibitors...Mature cells increased the phosphorylation of stress response proteins like ASK1, P38A, JNK1 at and ATF7 at regulatory sites, but were more resistant to the P38 and JNK inhibitors ralimetinib and tanzisertib, respectively.ConclusionThe higher activity of the stress response pathway in mature cells could be the reason for their higher sensitivity to compounds that either induce (Auranofin) or modulate (IAPs inhibitors) the stress response. Overall, our integrative analysis is a rich source of molecular information to rationalize specific drug sensitivities of poor risk AML cases with mature and primitive phenotypes. This knowledge could be used for the implementation of precision medicine in AML by selecting therapeutic approaches based on specific immunophenotypic and proteomic signatures.

In terms of mechanism, cellular experiments in AML cell lines proved that TLR8 and LKB1/AMPK are the key distinct mechanisms for MTL triggered caspase-3-dependent cell death and the expression of a large number of inflammatory factors. In conclusion, our findings identified the immunoactivator MTL as a single agent exerting significant anti-AML activity in vitro and in vivo, with strong potential for clinical translation.

P1, N=1, Terminated, Presage Biosciences | N=12 --> 1 | Recruiting --> Terminated; Partner Termination

The core-shell small-molecule nanomedicine DTX@VTX NP (DTX: Docetaxel and VTX: VTX-2337 or Motolimod) was used to reverse immunosuppressed TME through the depletion of myeloid-derived suppressor cells (MDSCs) and the polarization of macrophages from an M2-like phenotype to M1-like phenotype. Combining BMS-1 NPs with DTX@VTX NPs, synergistic chemo-immunotherapy of 4T1 tumors was performed, and the results indicate that the inhibition rates of primary and rechallenge tumors achieved 90.5% and 94.3%, respectively. These results indicate that DTX@VTX NPs can synergize PD-L1 nanoinhibitor BMS-1 NPs to reshape the immunosuppressive tumor microenvironment for enhancing the anti-tumor effect of chemo-immunotherapy for breast.

P1, N=12, Recruiting, Presage Biosciences | Trial completion date: Aug 2021 --> Mar 2022 | Trial primary completion date: Aug 2021 --> Dec 2021

P1, N=12, Recruiting, Presage Biosciences | Not yet recruiting --> Recruiting

Depletion of CD4+ T cells, CD8+ T cells and NK cells were all able to abolish the anti-tumor effect of VTX-2337+ cetuximab. Altogether, VTX-2337 remains promising as an adjuvant for cetuximab-based therapy however patients with high TLR8 expression may be more likely to derive benefit from this drug combination compared to patients with low TLR8 expression.

P1, N=12, Not yet recruiting, Presage Biosciences