Development of a small-molecule immunomodulator for the treatment of melanoma

SUMMARY Melanoma is the most lethal form of skin cancer with treatment costs exceeding $3 billion each year. Melanoma is successfully managed at early stages however, five-year survival rates for the advanced disease are as low as 20%. Immunotherapeutic checkpoint inhibitors (ICI) including agents that target PD1/PD-L1, have substantially improved melanoma survival rates. Unfortunately, only 35-60% of melanoma patients exhibit complete or partial responses to ICIs. Moreover, melanoma tumors that have mutations in the Braf protooncogene rapidly develop resistance to Braf/MEK inhibitors. Few treatment options remain for patients who fail to respond to ICIs or have developed resistance to Braf inhibitors. To prolong the lives of these individuals, optimized ICI regimens that are effective in ICI- and Braf-resistant melanoma are urgently needed. Claradele Pharmacetuicals is investigating whether pretreating melanoma with the novel, small molecule immunostimulatory endoplasmic reticulum (ER) stress inducer, 15dPMJ2, will sensitize the lesions to PD1 blockade. Our data demonstrate that 15dPMJ2 inhibited subcutaneous melanoma growth. In addition, 15dPMJ2 increased the tumor infiltration of active dendritic and memory T cells. Studies in this project will define doses of 15dPMJ2 that are safe to administer with anti-PD1 by determining the optimal biological dose (OBD). We will also test whether generating tumor inflammation with intratumorally administered 15dPMJ2 increases the rate at which melanoma responds to PD1 blockade. Our syngeneic murine models will be used to examine the effects of 15dPMJ2 on melanoma that contains or is devoid of human driver Braf mutations. Accomplishing our goals will provide proof-of-concept that optimizing the activity of ICIs with 15dPMJ2 will allow a significant proportion of melanoma patients to benefit from these life-saving therapeutics. The knowledge gained from this investigation will form the foundation of a Phase II STTR application that will examine agent formulation, optimize medicinal chemistry parameters, develop a CMC package, and define key toxicology and pharmacology properties of 15dPMJ2 to support an IND submission to the FDA.PROJECT NARRATIVE: Checkpoint immunotherapeutics have dramatically improved melanoma survival rates, but these drugs are only effective in 40-65% of melanoma patients. Hence, different therapeutic regimens are needed for patients who do not respond to checkpoint blockade. Our data indicates intratumor administration of 15dPMJ2, a novel small molecule immunostimulant, will sensitize non-responsive tumors to PD1 blockade without substantially increasing adverse effects.