Local immunotherapy with the RNA-based immune stimulator CV8102 induces substantial anti-tumor responses and enhances checkpoint inhibitor activity

Abstract

Immunotherapy has revolutionized cancer treatment in recent years. Although currently approved checkpoint inhibitors (CPIs) yield remarkable anti-tumoral responses in several cancer types, a substantial proportion of patients do not benefit from such therapies. Local activation of innate immune signaling pathways is a promising approach to overcome the immunosuppressive tumor microenvironment, induce anti-tumor immunity, and improve the efficacy of CPI therapies. Here, we assessed the mode of action and efficacy of the RNA-based innate immune stimulator CV8102 for local immunotherapy in preclinical models. Intratumoral (i.t.) administration of CV8102 activated innate immune responses in the tumor microenvironment and draining lymph nodes, resulting in a dose-dependent anti-tumoral response. Combining i.t. CV8102 with systemic anti-programmed death protein 1 (PD-1) treatment further enhanced anti-tumoral responses, inducing tumor infiltration and activation of CD8+ T cells. The resulting memory response prevented tumor growth in rechallenged animals and impaired the growth of non-injected distal tumors. Therefore, i.t. CV8102 delivery is a promising approach for local cancer immunotherapy, especially in combination with CPIs. Clinical testing of CV8102 is ongoing (NCT03291002).

Immunogenicity of Non-Mutated Ovarian Cancer-Specific Antigens

“…The remarkable progress and efficacy demonstrated by mRNA-based vaccines against SARS-CoV-2 have underscored the transformative potential of this technology. Beyond their short manufacturing process and excellent safety record, mRNA vaccines present diverse design options to enhance antigen translation or interferon signaling [ 90 , 91 , 92 , 93 , 94 , 95 , 96 ]. Thus, several clinical trials of mRNA-based cancer vaccines are ongoing [ 97 ].…”

Immunogenicity of Non-mutated Ovarian Cancer-Specific Antigens

“…The remarkable progress and efficacy demonstrated by mRNA-based vaccines against SARS-CoV-2 have underscored the transformative potential of this technology. Beyond their short manufacturing process and excellent safety record, mRNA vaccines present diverse design options to enhance antigen translation or interferon signaling [87][88][89][90][91][92][93]. Thus, several clinical trials of mRNA-based cancer vaccines are ongoing [94].…”

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

“…It is unclear whether the dose of MK-4621 should be adjusted, or systemic delivery of RLRs agonists may have different outcomes. In addition, a preclinical study demonstrates that combining systemic anti-PD1 therapy and intratumoral administration of CV8102, a cationic peptide-complexed ssRNA agonist of TLR7/8 and RIG-I, can induce antitumoral immune response [ 281 ]. A phase I study of intratumoral CV8102 delivery alone or in combination with systemic anti-PD1 therapy in patients with advanced melanoma, squamous cell carcinoma of the skin, head and neck, or adenoid cystic carcinoma is supposed to be completed soon (Table 2 ).…”