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Evidence for Oligoclonal T-Cell Response in a Metastasis of Renal Cell Carcinoma Responding to Vaccination with Autologous Tumor Cells and Transfer of in Vitro-sensitized Vaccine-draining Lymph Node Lymphocytes¹

Departments of Pathology [E. W., S. Y., M. T., T. L. W.], Medicine [T. F. L., J. M. K.], Pediatrics [M. T.], School of Medicine, and Pittsburgh Cancer Institute [E. W., T. F. L., S. Y., J. M. K., M. T., T. L. W.], University of Pittsburgh, Pittsburgh, Pennsylvania 15213

Peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) of a patient with von Hippel-Lindau disease and renal cell carcinoma were studied for the T-cell receptor ß chain variable region (TCR-Vß) repertoire. The patient was vaccinated with irradiated autologous tumor cells from a renal tumor mass, a vaccine-draining lymph node was removed, and lymphocytes were cultured in the presence of autologous tumor cells and low-dose interleukin 2 (IL2). These lymphocytes were adoptively transferred to the patient together with systemic IL2 (30,000 IU/kg every 8 h). Analysis of TCR-Vß expression was performed by polymerase chain reaction in PBL before, during, and after therapy, in vaccine-draining lymph node lymphocytes, and in TIL obtained from moderately infiltrated, nonresponding renal tumor mass and from a more intensely infiltrated lung metastasis, which was responding to treatment. Significant differences in the expression of TCR-Vß13.1 by T-cells recovered from these various sites were observed. Also, TIL recovered from the responding lung metastasis and cultured in the presence of IL2 gave rise to autologous tumor-reactive CD4⁺ T-cells, whereas the nonresponsive renal tumor yielded a mixture of T- and natural killer cells. In PBL obtained prior to treatment and during IL2 therapy, expression of Vß13.1 was 0.7 and 1.8%, respectively, of the total Vß gene repertoire. Fresh vaccine-draining lymph node lymphocytes contained 5.9% of Vß13.1-expressing T-cells. After IL2 therapy, Vß13.1 gene expression increased to 5.4% in PBL. In the nonresponding tumor mass, the frequency of Vß13.1 gene expression among TIL was 12%, whereas in the responding, highly infiltrated nodule, it was 28%, with a striking loss of expression of other Vß gene families. Sequencing of the amplified product of Vß13.1 complementary DNA from the responding pulmonary metastasis showed restrictions in the complementarity-determining region 3. Thus, in vivo expansion of Vß13.1-expressing CD4⁺ T-cells, possibly in response to a tumor-associated antigen, occurred in the responding tumor mass following this form of therapy and correlated with tumor course.

¹ This work was supported in part by the Pathology Education Research Foundation. E. W. was supported in part by the Deutsche Forschungsgemeinschaft (We1335/1-1). T. F. L. was supported in part by Clinical Oncology Cancer Development Award 90-214 of the American Cancer Society.

Received 4/19/93. Accepted 9/ 2/93.

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