Novel Targets for Immunotherapy

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Our laboratory has previously identified the embryonic transcription factor transcription as a tumor antigen and a driver of cancer plasticity and tumor resistance to various therapeutics. Brachyury is expressed in various types of cancer, including lung cancer, triple negative breast cancer, small cell lung carcinomas, germ cell tumors, and the rare tumor type chordoma, while being almost undetectable in the majority of adult normal tissues. A phase I clinical study of a modified vaccinia Ankara (MVA) priming followed by a fowlpox virus boosting, each encoding for brachyury and three costimulatory molecules has been completed in patients with advanced solid tumors. The vaccine was well-tolerated and induced immune responses to brachyury and the cascade antigens carcinoembryonic antigen (CEA) and mucin-1 (MUC1) in the majority of patients, with some evidence of clinical benefit. A phase I clinical trial of a multi-targeted recombinant adenovirus 5-based vaccine targeting brachyury, CEA and MUC1 was also completed, demonstrating the generation of CD4+ and/or CD8+ T-cell responses against all three antigens in the majority of patients, without any evidence of antigenic competition or toxicity. Similarly, an adenovirus vaccine platform using adenovirus 5 vectors targeting prostate-specific antigen (PSA), brachyury, and MUC1 was evaluated in patients with metastatic castration prostate cancer (mCRPC). The vaccine was tolerable and safe, elicited multifunctional T-cell responses to all three antigens, and showed evidence of clinical activity. The study of brachyury as a tumor antigen and its role as a driver of cancer plasticity led us to investigate and demonstrate a link between the acquisition of mesenchymal features by carcinoma cells and mechanisms of resistance to lysis by immune effector cells. Following these observations, we investigated approaches to improve tumor susceptibility to immune attack via modulation of tumor phenotype. We previously showed that one of the drivers of tumor EMT is the chemokine IL-8 which also promotes the recruitment of immunosuppressive cells to the tumor site, particularly the migration of granulocytic myeloid suppressor cells (G-MDSCs). One of the tumor types with a high degree of infiltration with G-MDSCs is head and neck carcinoma (HNSCC), also characterized by high expression of IL-8. In collaboration with Dr. C. Allen (NIDCD), the benefit of blocking IL-8 signaling in HNSCC models via inhibition of the IL-8 receptors, CXCR1 and CXCR2, was shown in combination with NK-cell mediated immunotherapy. In addition to IL-8, transforming growth factor beta (TGF-beta) is a master regulator of tumor plasticity. We recently showed that the combined use of a CXCR1/2 inhibitor with a bifunctional agent that simultaneously blocks PD-L1 and 'traps' soluble TGF-beta at the site of the tumor, termed bintrafusp alfa, results in more effective anti-tumor control, compared to each monotherapy. We showed that simultaneous inhibition of CXCR1/2, TGF-beta, and PD-L1 signaling synergizes to reduce mesenchymal tumor features in murine models of breast and lung cancer, and to markedly enhance the expression of tumor epithelial markers while reducing infiltration with suppressive G-MDSCs, enhancing tumor infiltration and activation of T-cells, and leading to improved anti-tumor activity. The addition of vaccine to the combination of bintrafusp alfa and CXCR1/2 inhibition was subsequently shown to induce greater tumor infiltration with T cells highly positive for markers of proliferation and cytotoxicity, and to restructure the tumor microenvironment with reduced Tregs and CD11b+Ly6G+ myeloid cells. Altogether, these results provide the rationale for the use of strategies that simultaneously block IL-8 signaling, neutralize TGF-beta in the tumor microenvironment, inhibit PD-L1, and activate tumor-specific immunity via the use of cancer vaccines.