Intralesional administration of VAX014 facilitates in situ immunization and potentiates immune checkpoint blockade in immunologically cold tumors

Abstract

BackgroundImmunologically cold tumors with an ‘immune desert’ phenotype lack tumor-infiltrating lymphocytes (TILs) and are typically impervious to systemic immune checkpoint blockade (ICB). Intratumoral treatment of tumors with immunomodulatory agents can promote local tumor inflammation leading to improved T cell responses in injected tumors. Addition of systemic ICB increases response frequency and immune-mediated clearance of injected and distal non-injected lesions, and this promising approach is being widely investigated clinically. In this work, we evaluate and characterize the local and systemic antitumor immunotherapeutic activity of VAX014, a novel non-viral targeted oncolytic agent based on recombinant bacterial minicells, following intratumoral administration and in combination with systemic ICB.MethodsThe immunotherapeutic activity of VAX014 following weekly intratumoral administration was investigated in multiple preclinical tumor models with B16F10 murine melanoma serving as the primary model for evaluation of immune desert tumors. Mice bearing a single intradermal tumor were used to evaluate tumor response and overall survival (OS), assess changes in immune cell populations, and explore global changes to immunotranscriptomes of injected tumors. Mice bearing bilateral intradermal tumors were then used to evaluate non-injected tumors for changes in TIL populations and phenotypes, compare immunotranscriptomes across treatment groups, and assess distal non-injected tumor response in the context of monotherapy or in combination with ICB.ResultsVAX014 demonstrated strong immune-mediated tumor clearance of injected tumors coinciding with significantly elevated CD8+TILs and upregulation of multiple immune pathways essential for antitumor immune responses. Modest activity against distal non-injected immune desert tumors was observed despite elevated levels of systemic antitumor lymphocytes. Combination with systemic CTLA-4 blockade improved survival and elevated TILs but did not improve clearance rates of non-injected tumors. Immunotranscriptomes of non-injected tumors from this treatment combination group exhibited upregulation of multiple immune pathways but also identified upregulation of PD-1. Further addition of systemic PD-1 blockade led to rapid clearance of non-injected tumors, enhanced OS, and provided durable protective immunological memory.ConclusionsIntratumoral administration of VAX014 stimulates local immune activation and robust systemic antitumor lymphocytic responses. Combination with systemic ICB deepens systemic antitumor responses to mediate clearance of injected and distal non-injected tumors.

Ultrathin Cu9S5 Nanosheets with Sulfur Vacancy for Multimodal Tumor Therapy

“…Malignant tumors, one of the most formidable threats to human life and health, have been extensively explored. − With the rapid advancements in medical and nanoscience technologies, burgeoning therapeutic methods, including photothermal therapy (PTT), − photodynamic therapy (PDT), − chemodynamic therapy (CDT), − sonodynamic therapy (SDT), and immunization therapy, − have emerged and received significant attention due to their fewer side effects, high antitumor efficacy, and noninvasive nature. However, relying solely on a single therapy modality is usually unable to eliminate the entire tumor and prevent tumor metastasis, which shows unsatisfied tumor treatment efficacy in both experimental studies and clinical practice. , For instance, PPT is a promising tumor light therapy for its noninvasiveness, low toxicity, and high spatial selectivity, etc. − Nevertheless, the limited tissue penetration depth of laser hampers the complete eradication of deep-seated tumors, posing an inherent challenge for PTT. − In addition, reactive oxygen species (ROS), such as singlet oxygen ( 1 O 2 ), hydroxyl radicals (•OH), and superoxide radicals (O 2 •– ), can induce cell apoptosis through oxidative stress in vivo. − However, the therapeutic efficiency of ROS-mediated tumor therapy strategies (PDT, CDT, SDT, etc.)…”