BackgroundLAIR-1 is an immune inhibitory receptor expressed on several immune cell types including activated T cells, B cells, NK cells, macrophages, and dendritic cells. The ligands for LAIR-1 contain collagen-like domains which are commonly found in extracellular matrix collagens and complement component C1q. In numerous cancer types, including gastric, colon, ovarian, bladder, and others, upregulation of collagens has been shown to enhance tumor growth, metastases, and invasion while actively suppressing antitumor immunity. Although humans produce a natural, soluble decoy, LAIR-2, that competes with LAIR-1 for binding of collagen domains, excess LAIR ligands in the tumor often result in an immune suppressive environment.MethodsHere, we report on a novel immunotherapy approach which combined NC410, a LAIR-2-Fc fusion protein capable of blocking LAIR-1 signaling, and bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β ‘trap’) fused via a flexible linker to the C-terminus of each heavy chain of an IgG1 antibody blocking programmed death ligand 1 (anti–PD-L1).ResultsWe demonstrate that the combination of NC410 and bintrafusp alfa more effectively controls in vivo tumor growth of the collagen rich MC38 colon carcinoma compared to either monotherapy. We hypothesize that this potent anti-tumor immune response is propagated through the synergy of activated tumor infiltrating lymphocytes and a repolarization of macrophages towards a tumoricidal phenotype. MC38 tumors treated with the combination of NC410/Bintrafusp alfa contained higher numbers of infiltrating CD4+ and CD8+ T cells and higher numbers of CD38+ and MHCII+ M1 polarized macrophages.ConclusionsThis study highlights the synergy of reshaping the large suppressive myeloid cell populations often present in tumors with activation of adaptive T-cell immune responses dampened by checkpoint inhibition. The results also provide the rationale for the future evaluation of this combination therapy in the clinic.AcknowledgementsBintrafusp alfa was kindly provided by EMD Serono under a CRADA with the NCI.Trial RegistrationN/AEthics ApprovalMice were maintained under pathogen-free conditions in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care guidelines. All animal studies were approved by the NIH Intramural Animal Care and Use Committee under protocol LTIB-038.ConsentN/A
In vivo biodistribution study of TAT-L-Sco2 fusion protein, developed as protein therapeutic for mitochondrial disorders attributed to SCO2 mutations