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Developing a Rational Tumor Vaccine Therapy for Renal Cell Carcinoma: Immune Yin and Yang

Authors' Affiliations: ¹ Medical Oncology Immunotherapy Group, ² Section of Hematology/Oncology, ³ Norris Cotton Cancer Center, ⁴ Cell Therapy Center, ⁵ Department of Pathology, ⁶ Section of Urology, ⁷ Department of Surgery, ⁸ Department of Diagnostic Radiology, ⁹ Department of Microbiology and Immunology, ¹⁰ Section of Biostatistics and Epidemiology, Department of Family and Community Medicine, and ¹¹ Immunotherapy Program, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; ¹² Dartmouth Medical School, Hanover, New Hampshire; and ¹³ Earle A. Chiles Cancer Research Center, Portland, Oregon

Requests for reprints: Marc S. Ernstoff, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756. Phone: 603-650-5534; Fax: 603-650-7791; E-mail: Marc.S.Ernstoff{at}Hitchcock.org.

In patients with progressive malignancy, the natural balance between proinflammatory (Yang) and inhibitory (regulatory or Yin) immune pathways is disrupted and favors cancer-specific immune suppression. Therapy with interleukin 2 (IL-2) can mobilize immune effector cells that recognize and destroy cancer. High-dose IL-2 is the only therapy that has consistently induced complete durable remissions in patients with metastatic renal cell carcinoma (RCC) but only in a few of them. The lack of benefit in most metastatic RCC patients is likely due to the ineffective manipulation of other immune circuits critical in regulating tumor cytotoxic pathways. The limited clinical activity of IL-2, RCC vaccines, and other immune therapies to date leads us to postulate that effective clinical treatment strategies will need to simultaneously enhance proinflammatory pathways and disrupt regulatory pathways. We present preliminary studies in RCC patients to highlight the complexity of the regulatory pathways and our approach to shifting the balance of proinflammatory and regulatory immune pathways using dendritic cell–tumor lysate vaccine followed by cytokine therapy.