Melanoma is an aggressive form of skin cancer with low survival rates in later stages, particular once it has metastasized to distant regions. It is the fifth most commonly diagnosed cancer in the US with an estimated 90,000 new cases diagnosed annually. Melanoma is an ideal candidate for the development of novel immunotherapies that can stimulate the patientâs own immune system against the tumor through localized therapy as it is responsive to these types of therapies and accessible for injection directly into the tumor. Studies have shown that immune activating cytokines such as interleukin-15 (IL-15) can stimulate tumor regression of both the primary injected tumor and distant metastases. However, the range of immune activating cytokines available for clinical use is limited, as the high doses required to induce an anti -tumor response via systemic delivery can cause severe side effects. Efforts to deliver therapy locally to the tumor are hampered by the rapid diffusion rate of the small cytokines, requiring frequent (e.g., 2-3 times a week) intratumoral injections for effective treatment. To enable longer acting IL-15 drug activity, Valitor has developed a patented platform technology for generating soluble clusters of therapeutic proteins attached to single-chain biopolymers. In contrast to other methods of protein-polymer conjugation (e.g., PEGylation), our method of conjugation generates substantially larger conjugates with enhanced drug potency. Conjugate retention within a tumor can be further enhanced by adding copies of a second protein to bind extracellular melanoma-specific antigens such as anti-melanoma-associated chondroitin sulfate proteoglycan (MCSP). Therefore, we anticipate that a bifunctional conjugate made using IL-15 and anti-MCSP antibodies (i.e., mvAnti-MCSPxIL-15) will be retained within the tumor at least 5 times longer than an unmodified cytokine. Our objective during Phase I is to demonstrate proof-of-concept for our multivalent conjugates to provide a sustained effective intratumoral dose of an immunotherapy with minimal systemic exposure following a single local injection. We expect this mvAnti- MCSPxIL-15 therapy will follow a well-defined route to FDA market approval and commercialization, which we will continue during the next phase of this project.
Public Health Relevance Statement: Relevance Melanoma is the fifth most common type of cancer in the US, and it is a significant public health concern as an estimated 90,000 new cases are diagnosed annually and mortality rates increase greatly after metastasis. Valitor has developed a novel long-acting immunotherapy to treat melanoma by enabling a sustained and focused anti-tumor immune response following intratumoral injection.
Project Terms: Adverse effects; Affect; anti-tumor immune response; Antibodies; Antigens; Antitumor Response; Avidity; base; Binding; Binding Proteins; Biopolymers; cancer cell; cancer diagnosis; cancer therapy; cancer type; Carcinoma; Cells; Cessation of life; Chondroitin Sulfate Proteoglycan; Clinic; Clinical; clinical efficacy; commercialization; cytokine; cytotoxic; Development; Diagnosis; Diffusion; Distant; Distant Metastasis; Dose; effective therapy; Exposure to; extracellular; Half-Life; Human; humanized mouse; Immune; Immune Cell Activation; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Cytotoxicity; Immunotherapy; improved; In Vitro; in vivo imaging; Injections; Interleukin-15; Interleukin-2; Lead; Legal patent; Local Therapy; Malignant Neoplasms; Measures; MEL Gene; melanoma; Metabolic Clearance Rate; Methods; Modeling; mortality; mouse model; Mus; Neoplasm Metastasis; neoplastic cell; new technology; novel; Nude Mice; Output; Patients; Performance; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Polymers; preclinical development; Primary Neoplasm; Proteins; Public Health; Resistance; Risk; Route; Skin Cancer; Survival Rate; System; Technology; Therapeutic; therapeutic protein; therapy design; Time; tumor; Tumor Antigens; Vertebral colum
