In Vivo Effect and Parallel in Vitro Lymphocyte-mediated Tumor Cytolysis after Phase I Xenogeneic Immune RNA Treatment of Patients with Widespread Melanoma or Metastatic Renal Cell Carcinoma

Seven patients with metastatic renal cell carcinoma or widespread melanoma were included in a Phase I clinical trial of xenogeneic immune RNA (I-RNA). I-RNA, extracted from the lymphoid tissues of guinea pigs immunized with the patient's primary tumor, was incubated in vitro with autologous lymphocytes harvested by leukapheresis. Each patient received five separate i.v. injections (every other day) of 3 to 5 × 109 autologous lymphocytes immediately after in vitro incubation with I-RNA. Peripheral blood lymphocytes (PBL) were frozen and stored before and after each I-RNA treatment for later serial assay of lymphocyte-mediated tumor cytolysis (LMC). No toxicity was noted during or after I-RNA treatment. One patient with renal cell carcinoma had complete resolution of multiple pulmonary metastases, beginning 3 months and lasting 18 months after I-RNA treatment. Two other patients with visceral metastases from renal cell carcinoma demonstrated >50% regression, two patients showed stabilization of previously growing renal cell carcinoma pulmonary metastases, and one renal cell carcinoma patient and the single patient with widespread recurrent melanoma had no alteration in their rapidly progressive tumor courses. All serial PBL samples from individual patients were tested simultaneously for in vitro LMC against allogeneic renal cell carcinoma and melanoma targets. LMC was boosted in PBL samples after in vitro I-RNA treatment. Progressive increase in LMC was demonstrated in serial PBL samples harvested from patients during I-RNA therapy. Increased LMC was found in PBL samples harvested 3 to 9 months after I-RNA therapy. Statistically significant boosts in the cytolytic effect of PBL samples harvested from treated renal cell carcinoma patients were restricted to renal cell carcinoma targets. Similarly, only PBL samples harvested during I-RNA treatment of the patient with melanoma showed increased LMC on the allogeneic melanoma targets. In vitro LMC activity was clearly boosted in all treated patients regardless of their clinical course after I-RNA therapy. The relationship between the present Phase I human results and previous animal studies of adjuvant I-RNA therapy is discussed. Application of xenogeneic I-RNA to a Phase III human trial is proposed.