Malignant melanoma is one of the most aggressive types of skin cancer, causing a largemajority of skin-cancer related deaths worldwide. Recently, there have been staggeringbreakthroughs with the advent of drugs that act on checkpoint inhibitors. These are paradigm-shifting immunotherapeutic agents not only for melanoma, but for cancers in general, becausethey harness the body's innate ability to target and destroy malignant cells. The original FDAapproval for anti-CTLA-4 and anti-PD-1 therapies for melanoma contributed to better patientoutcomes. The recent FDA approval for their combination for metastatic melanoma showed thatattacking cancers through dual pathways led to better efficacy than with any single agent alone.Although promising, the incidence of high-grade immune-related adverse events (irAEs) due tothe combination therapy is over 50%. Therefore, there is a pressing clinical need to developtherapeutic agents that may enhance the therapeutic effect of anti-PD1 therapy withoutsignificantly increasing toxicity in cancer patients. Resiquimod is TLR 7/8 agonist that ischemically related to imiquimod (Aldara). Resiquimod is more potent than imiquimod in inducingcytokine release owing to its ability to target two, not one, TLRs and its increased bioavailability.Our goal is to harness this small molecule to destroy malignant melanocytes, but to keep itseffects localized to the site of injection to prevent systemic side effects. In addition, we plan toboost resiquimod with chemical enhancers that will increase the local anti-tumor immuneresponse. Our preliminary data demonstrate that topical resiquimod has surprisingly potenttherapeutic efficacy against established melanoma in multiple genetically engineered mouse(GEM) and syngeneic melanoma mouse models. Topical resiquimod treatment not onlyinhibited melanoma growth, but also suppressed lymph node metastasis while exhibiting theabscopal effect, whereby tumors distant from the site of treatment were also affected. We planto develop an injectable form of resiquimod, which we believe will be even more effectiveagainst melanomas. Our goal is to minimize the dose of resiquimod needed to induce a localanti-melanoma immune response. We will formulate the safest and most effective form ofinjectable resiquimod first and test our best resulting product with anti-PD1 therapy. We areconfident based on our preliminary data that combination injectable resiquimod/anti-PD1treatment will be groundbreaking for melanoma as well as for many other malignancies such aslung and bladder cancers. We have the scientific and personnel capability to achieve these aimsquickly and meticulously. Our innovative product will lay a solid foundation for IND-enablingstudies that will ultimately bring a novel and effective therapy to clinicians and patients in theirfight against melanoma.
PROJECT NARRATIONResiquimod is a powerful immune response modifier that stimulates the body's own immunesystem to attack cancer cells through activation of toll-like receptors 7/8. In our proposedproject; we will create an injectable form of resiquimod that is safe; effective; and capable ofdirect delivery into the tumor of interest ? in our case; malignant melanoma. We expect theresiquimod formulation generated from our animal studies to be used as the first and preferredinjectable agent in combination with anti-PD1 therapy to treat hard-to-cure malignant melanomaand other metastatic cancers in humans.