Intravesical VAX014 Synergizes with PD-L1 Blockade to Enhance Local and Systemic Control of Bladder Cancer

Abstract

Emerging clinical evidence indicates that the combination of local administration of immunotherapy with systemic immune checkpoint blockade targeting the PD-1/PD-L1 pathway improves response rates in select solid tumor indications; however, limited clinical experience with this approach exists in advanced bladder cancer patients. VAX014 is a novel bacterial minicell-based, integrin-targeted oncolytic agent undergoing clinical investigation for intravesical (IVE) treatment of non-muscle invasive bladder cancer. Here, we demonstrated that the antitumor activity of VAX014 following IVE administration was dependent upon CD4+ and CD8+ T cells in two syngeneic orthotopic bladder tumor models (MB49 and MBT-2). PD-L1 upregulation was found to be an acquired immune-resistance mechanism in the MB49 model, and the combination of VAX014 with systemic PD-L1 blockade resulted in a significant improvement in bladder tumor clearance rates and development of protective antitumor immunologic memory. Combination treatment also led to enhanced systemic antitumor immune responses capable of clearing distal intradermal tumors and controlling pulmonary metastasis. Distal tumors actively responding to combination therapy demonstrated a phenotypic shift from Treg to Th1 in intratumoral CD4+ T cells, which was accompanied by a higher percentage of activated CD8+ T cells and higher IFNγ. Finally, VAX014’s target integrins α3β1 and α5β1 were overexpressed in tumor biopsies from advanced stage bladder cancer patients, as well as in both the MB49 and MBT-2 orthotopic mouse models of bladder cancer. These collective findings provide rationale for clinical investigation of VAX014 and systemic PD-1/PD-L1 blockade in advanced stage bladder cancer.

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

“…VAX014 has been described extensively elsewhere but can be summarized as an rBMC designed to target tumor-associated integrins using a protein called invasin (Inv) to deliver an oncolytic protein toxin payload, perfringolysin O (PFO). [14][15][16] Here, we primarily used both single and bilateral tumor variations of the immune desert B16F10 murine melanoma model to explore the effectiveness of VAX014 as an oncolytic immunotherapy following intratumoral administration as monotherapy and in combination with systemically administered ICB. We demonstrate that shortly following injection into tumors, VAX014 facilitates rapid oncolysis while stimulating multiple immune pathways supporting adaptive antitumor immunity in the TME.…”

“…Previous studies demonstrate that the antitumor activity of VAX014 following topical intravesical treatment of orthotopic MB49 bladder tumors in mice is dependent on T lymphocytes. 16 Therefore, we investigated the role of CD8 + T cells, CD4 + T cells, or NK cells in the antitumor activity of VAX014 following intratumoral administration by depleting these immune cell subsets throughout treatment (figure 1E). The antitumor activity of VAX014 following intratumoral administration was entirely dependent on CD8 + T cells, dependent to a lesser degree on NK cells, and independent of CD4 + T cells.…”

Nanomaterials: A powerful tool for tumor immunotherapy

“…PD-L1 is overexpressed in many solid tumors and inhibits kinase signaling pathways by interacting with PD-1, ultimately suppressing the proliferation and activity of T cells ( 46 ). Also, the enzyme IDO is highly expressed in tumors, leading to the degradation of L-tryptophan to L-kynurenine.…”

VAX014, an Oncolytic Therapy, Reduces Adenomas and Modifies Colon Microenvironment in Mouse Model of CRC

“…In preclinical models of non-muscle-invasive bladder cancer, VAX014 improved survival and reduced tumor growth [ 14 , 18 ]. In these models, the antitumor activity of VAX014 resulted from both direct oncolysis and the ensuing induction of protective CD4 + and CD8 + antitumor immune responses [ 19 ]. These therapeutic actions suggest potential relevancy in other immune-associated cancers, where direct VAX014 interaction with tumors is feasible.…”