Novel Targets for Immunotherapy

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Immune checkpoint blockade (ICB) therapies with monoclonal antibodies directed against the programmed cell death 1 receptor (PD-1) or its ligand PD-L1 have shown remarkable clinical benefit across various cancer types; however, only a subset of patients demonstrate durable clinical responses. The presence of a collagen-dense extracellular matrix and high numbers of suppressive immune cell populations in the tumor microenvironment are among multiple factors that could contribute to the lack of responses to ICB. In addition, high levels of the cytokine TGF-beta in the tumor microenvironment can stimulate the production of collagens by fibroblasts and induce enzymes that mediate collagen crosslinking. Collagens in the tumor can function as a physical barrier preventing the infiltration of immune cells while also suppressing anti-tumor immunity via binding to inhibitory receptors on the surface of immune cells. One such receptor is the leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1, CD305), which delivers an inhibitory signal following binding to collagen-like domains resulting in the inhibition of T cells, natural killer (NK) cells, macrophages, and dendritic cells. We recently interrogated a novel immunotherapy combination in murine tumor models, consisting of co-inhibition of TGF-beta, PD-L1, and LAIR-1 signaling. To inhibit TGF-beta and PD-L1 we used the bifunctional fusion protein bintrafusp alfa, which is composed of two extracellular domains of the TGF-BRII fused to an anti-PD-L1 antibody. This agent is currently being evaluated in multiple clinical studies. To block LAIR-1 signaling, we utilized NC410, a fusion protein consisting of 2 LAIR-2 decoy molecules that bind to collagen-like motifs thus preventing LAIR-1 signaling. NC410 is also currently being evaluated in the clinic. We were able to show that this combination immunotherapy effectively controls the growth of the collagen-rich murine MC38 colon and EMT6 breast carcinomas, resulting in tumor cures and long-term tumor-specific protection. We also demonstrated that this potent anti-tumor immune response was accompanied by the remodeling o f collagens in the tumor microenvironment, enhanced infiltration of activated T cells, and remodeling of the macrophage cell population. This study provided rationale for testing of this combination immunotherapy in the clinic, potentially in tumor types that do not respond to ICB and are characterized by high levels of collagen and/or TGF-beta. Small cell lung cancer (SCLC) is an aggressive tumor type that accounts for approximately 15% of all lung cancers. ICB therapy has been recently added as frontline therapy in the treatment of SCLC; however, ICB has only achieved minor improvements in the overall survival of SCLC patients. We have recently investigated an alternative approach for the treatment of SCLC utilizing an NK-based therapy based on the use N-803, a clinical-stage super-agonist complex of a mutant human IL-15 combined with the sushi domain of the human IL-15Ra and fused to an IgG1 Fc domain. Our preclinical data in vitro and in vivo showed that N-803-activated NK cells effectively lyse SCLC tumor cells across all variant molecular subtypes, including those previously refractory to traditional NK cell lysis. These results provided rationale for the potential use of N-803 as an alternative immune-based intervention for the treatment of SCLC.