Phase 1 trial of CD40 agonist, Flt3L, and chemotherapy in breast cancer

Summary: 

Triple negative breast cancer (TNBC) is associated with more aggressive disease compared to other subtypes of breast cancer, with a median survival of less than 18 months for a patient diagnosed with metastatic disease. Despite the success of immune checkpoint inhibitors in many cancer types, breast cancers and specifically metastatic breast cancers have shown limited responses. Increasing data suggests that priming T-cells with antigen presenting cells (APCs), cells that present foreign material to immune cells, are defective in breast cancer. There are four critical steps for optimal antigen presentation, the first being the release of antigens in the tumor microenvironment (TME). This followed by the increase of APCs in the TME to uptake tumor antigens (step 2) and then the activation of APCs through co-stimulatory pathways such as the CD40/CD40L pathway to prime T-cells against tumor antigens (step 3). APCs and T-cells then interact to form what are called tertiary lymphoid structures (step 4). This phase I study will assess the safety of two experimental drugs, CDX-1140 and CDX-301, in combination with chemotherapy in patients with stage III-IV TNBC. CDX-1140 targets CD40, activating APCs through the CD40/CD40L pathway to prime T-cells and promotes the formation of tertiary lymphoid structures (steps 3 and 4 above). CDX-301 promotes the proliferation of APCs called dendritic cells in the TME (step 2 above). Lastly, chemotherapy is thought to increase antigen presentation when combined with CD40 agonists in preclinical models. The goal of this 3-drug regimen is to optimize all 4 steps of antigen presentation, increasing long-term adaptive immunity and improving TNBC disease control.

Trial Registration: ClinicalTrials.gov Identifier: NCT05029999