Heart Health Articles

Novel Approaches To Metastatic Renal Cell Carcinoma: Autologous Thymocytes Genetically Retargeted Against Carbonic Anhydrase IX

May 28, 2017

UroToday - In this letter to the editor, Lamers and colleagues out of the Netherlands describe their initial experience with genetically retargeted autologous lymphocytes directed against carbonic anhydrase IX (CA9). The authors genetically engineered a retrovirus with the single chain antibody-type receptor based on the murine monoclonal antibody G250 which targets CA9. This retrovirus is then used to infect autologous T cells harvested from patients with metastatic renal cell carcinoma (RCC). These cells should then traffic back to tumor which expresses CA9, and trigger antigen specific effector functions such as cytokine production. In turn these cascades of events should trigger tumor cell death.

The authors report in the middle of their ongoing phase I study with this treatment strategy on three patients, all of whom have biopsy proven metastatic RCC that expresses CA9, and have failed systemic interferon therapy. In addition to the autologous lymphocytes, all patients received concurrent subcutaneous interleukin 2 therapy. The authors noted that all patients had a significant elevation in their liver enzymes after infusion of the autologous lymphocytes, which limited the amount that could be infused. Liver biopsy demonstrated a discrete cholangitis, with T-cell infiltration around bile ducts, which are also positive for CA9 expression. In addition, patients demonstrated low level antibodies to the single chain antibody-type receptor for G250.

The authors have subsequently now modified their protocol to include a pre-infusion of G250 antibody prior to the introduction of the genetically engineered autologous lymphocytes. These antibodies can then preferentially saturate CA9 sites in the liver and prevent the cholangitis noted. This experience highlights the fact that there truly are few, if any, tumor specific antigens, and thus targeted therapy against specific molecular species may have significant untoward consequences.

By Christopher G. Wood, M.D.

J Clin Oncol. 24(13): e20-e22, 2006
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