Investigators

Summary

My laboratory studies tumor immunobiology and designs immunotherapies for the treatment of cancer based on results from translational modeling. My near-term research goal remains the development of novel phase I/II clinical trials for the treatment of patients with cancer, with a focus on melanoma and renal cell carcinoma (RCC). Such treatment modalities include dendritic cell (DC)-based vaccines, cytokine gene-modified DC injected directly into tumor lesions and combination treatment approaches integrating agents that modulate tumor cell immune recognition and/or alter the balance or Type-1 versus regulatory immunity in the tumor microenvironment (TME). We discovered that immune targeting of the tumor-associated vasculature occurs naturally during effective immunotherapy, and that vaccines targeting tumor blood vessel antigens (TBVA) can promote tumor regression, even in cases where cancer cells themselves cannot be directly recognized by protective/therapeutic CD8+ T cells. Notably, even though these vaccines target normal non-mutated peptide sequences in TBVA proteins, no untoward (auto)immune-related pathology was observed in translational mouse modeling. We determined that treatment with anti-angiogenic agents leads to tumor vascular normalization and to the improved chemokine-dependent recruitment of therapeutic T cells into the TME, resulting in local formation of tertiary lymphoid structures (TLS) in association with slowed tumor growth and extended survival in animal models. We recently completed a pilot phase II clinical trial (UPCI 12-048/NCT01876212) evaluating combined treatment of HLA-A2+ patients with autologous aDC1/TBVA peptide vaccines + dasatinib (employed as an immune adjuvant). Vaccines were well tolerated by patients and we observed objective clinical responses in 46% of evaluable patients with advanced-stage cutaneous or uveal melanoma, including 57% of patients with prior demonstration of primary resistance to anti-PD1-based immunotherapy. Novel DC/TBVA peptide vaccines are currently being investigated in pilot phase II studies supported by NIH R01 (NCT05127824) and P01 (NCT04093323) in the setting of checkpoint-refractory advanced melanoma and early-stage renal cell carcinoma. We are also currently investigating the use of IRF3 agonists (including STING agonists) delivered directly into the TME as components of in situ vaccines in the advanced disease setting with the intent to promote formation of TLS in situ for improved local cross-priming of novel therapeutic anti-tumor B cell and T cell repertoires.