Summary
UCLA researchers in the Department of Medicine have developed a novel antitumor treatment that works alone or in combination with anit-PD-1 therapy to target interferon signaling-deficient tumors or tumors with alterations in the antigen presentation machinery, that are resistant to anti-PD-1 therapy.
Background
Programmed cell death protein 1 (PD-1) lies on the surface of cells and regulates immune response through suppression of T cell inflammatory activity. While PD-1 activity is crucial to prevent autoimmune disease, it may also prevent the immune system from attacking cancer cells. Two PD-1 inhibitors are clinically approved for the treatment of advanced metastatic melanoma. Response to single agent anti-PD-1 therapy is dependent on proper interferon signaling to induce antitumor effects, as well as antigen presentation to T cells. Anti-PD-1 resistance often occurs in interferon signaling-deficient tumors or tumors with alterations in the antigen presentation machinery. Although combination immunotherapy with the recruitment of new antigen-specific T cells into tumors has increased treatment response rates, there is a large unmet need for mechanistic strategies to overcome resistance to anti-PD1 therapy.
Innovation
UCLA researchers have demonstrated that anti-PD-1 resistance may be overcome with use of a TLR-9 agonist, SD-101. SD-101 may be used alone or in combination anti-PD-1 therapy, to produce type I interferons and stimulate T cell immune response. This treatment strategy strengths both innate and adaptive immune responses with minimal additional toxicity relative to anti-PD-1 therapeutics alone. Antitumor activity of SD-101 is effective in overcoming anti-PD-1 resistance at the injection site as well as distant tumors. In contrast to previous treatments, use of SD-101 alone or in tandem with anti-PD-1 therapy is effective in tumors with interferon signaling defects and tumors with perturbed antigen presentation machinery.
Applications
▶ Therapy of tumors in cases of anti-PD-1 resistance driven by alterations in the interferon signaling or antigen presentation pathways
Advantages
▶ SD-101 has antitumor activity alone or in combination with anti-PD-1 therapy in tumors resistant to anti-PD-1
▶ No current treatment available for interferon signaling-deficient tumors or tumors with alterations in the antigen presentation machinery that present with anti-PD-1 resistance
▶ Successful at overcoming anti-PD-1 resistance at the injection site and at uninjected contralateral tumors
▶ Induce immune activation at tumor site
▶ Increase clinical efficacy with minimal additional toxicity compared to anti-PD-1 treatment alone
State Of Development
Knockouts within the interferon pathway and in the antigen presentation pathway were introduced into a model of murine MC38 colon carcinoma. These sublines became resistant to anti-PD-1 treatment. Administration of TLR-9 agonist SD-101 in the JAK1/JAK2 or B2M KO sublines was able to overcome resistance to anti-PD-1, both at the injection site and uninjected distant-site tumors. Most recently, this combination therapy was successful in a clinical trial in patients with unresectable or metastatic malignant melanoma.