The focus of this research theme is to develop more effective ways to stimulate innate and adaptive immune responses to human tumors and to evaluate the efficacy of therapeutic strategies based on such approaches in better animal models of human cancer, and to identify candidate immune biomarkers and state-of-the-art immunomonitoring assays to detect therapeutically effective immune modulation.
- Cell surface chondroitin sulfate proteoglycan 4 (CSPG4) is an attractive target for antibody-based cancer immunotherapy because of its role in tumor cell biology, its high expression on malignant cells including cancer-initiating cells, and its restricted distribution in normal tissues. The clinical use of CSPG4 has been hampered by the lack of a CSPG4-specific chimeric, humanized, or fully human monoclonal antibody. To overcome this limitation, we generated a CSPG4-specific fully human single-chain antibody termed scFv-FcC21 and characterized its specificity and antitumor activity. (Wang et. al., Cancer Res. 2011 Dec 15;71(24):7410-22).
- ECOG 1696 was a Phase II multi-center trial testing vaccination with melanoma peptides, gp100, MART-1 and tyrosinase delivered alone, with GM-CSF, IFN-α2b or both cytokines to HLA-A2(+) patients with metastatic melanoma. The frequency of CD8(+) tetramer (+) (tet(+)) T cells in the circulation was increased for the melanoma peptides (p < 0.03-0.0001) but not for influenza (FLU) peptides (p < 0.9). Only gp100- and MART-1-specific T cells differentiated to CD45RA(+) CCR7(-) effector/memory T cells. In contrast to the IFN-γ ELISPOT frequency, previously correlated with overall survival (Kirkwood et al., Clin Cancer Res 2009;15:1443-51), neither the frequency nor differentiation stage of CD8(+) tet(+) T cells correlated with clinical responses. Delivery of GM-CSF and/or IFN-α2b had no effects on the frequency or differentiation of CD8(+) tet(+) , CD8+ or CD4+ T cells. Phenotypic analyses of CD8(+) tet(+) T cells did not correlate with clinical responses to the vaccine, indicating that functional assessments of peptide-specific T cells are preferable for monitoring of anti-tumor vaccines. (Schaefer et. al., Int J Cancer. 2011 Oct 24. [Epub ahead of print]).
- Squamous cell carcinoma of the head and neck (SCCHN) cells can escape recognition by tumor antigen (TA)-specific cytotoxic T lymphocytes (CTL) by downregulation of antigen processing machinery (APM) components, such as the transporter associated with antigen processing (TAP)-1/2 heterodimer. Recent study results show that (TAP)-1/2 downregulation is regulated primarily by an IFN-γ-pSTAT1-mediated signaling pathway, independent of oncogenic STAT3 overexpression in SCCHN cells (Leibowitz et.al., Cancer Immunol Immunother. 2011 Apr;60(4):525-35).
- The safety and immunogenicity of a novel vaccination was evaluated in a clinical trial with α-type 1 polarized dendritic cells loaded with synthetic peptides for glioma-associated antigen epitopes and administration of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant gliomas. For at least 12 months, nine patients achieved progression-free status, and one patient with recurrent GBM had a sustained complete response (Okada et.al., J Clin Oncol. 2011, 29:330-6).