A Randomized Pilot Phase II Trial of Adjuvant Immunization With G250 Peptide andThree Different Dose Levels of IL-2 Following Surgical Resection of Locally Advanced or Metastatic Renal Cell Carcinoma

Renal cell carcinoma is a chemotherapy and radiotherapy resistant neoplasm that has a poor prognosis. Immunotherapy with the biologic agent IL-2 consistently produces a response rate of 10-15 %. Currently, for patients with locally advanced disease or patients with solitary metastases, the only treatment modality with a curative potential is surgical resection. There is presently no approved agent for use as adjuvant therapy after surgical resection to decrease the risk of recurrence. Peptide-based vaccine approaches offer an attractive treatment option.

The high prevalence of G250 in RCC, the definition of an HLA-A2-restricted epitope (the most common HLA type), and its immunogenicity makes it the most attractive candidate for peptide-based vaccine approaches in RCC therapy. The promising preclinical and clinical evidence provides the rationale for the use of IL-2 to potentiate the antitumor effects of cancer vaccines.

There is presently no conclusive data on the best dose of IL-2 to use as an adjuvant to cancer vaccines. One paradoxical finding in preclinical and clinical trials is that despite the enhancement in the antitumor effects of cancer vaccines, the number of antigen-specific CTL is not increased when IL-2 is given with a cancer vaccine 35]. In contrast, patients treated with peptide vaccines (without IL-2) in some melanoma trials had evidence of high levels of antigen-specific CTL, with no tumor regression observed 36]. Some possible explanations include capillary leak from high dose IL-2 resulting in CTL leaving the circulation and the possibility that high dose IL-2 decreases efficient T-cell priming. A more recent explanation has been proposed through advances in the mechanism of 1-cell activation. As their level of activation increases, T-cells become more susceptible to apoptosis. This phenomenon is known as activation-induced cell death (AICD) IL-2 may then have a role in the amplification and downregulation of the immune response. High dose IL-2 may help in augmenting the increase in the activation of CTL, but this may lead to increase their susceptibility to AJCD. The evidence in animal models that low doses of IL-2 were sufficient in increasing the potency of DC-based immunizations provides the rational for our study.

In our current study, the lowest dose of IL-2 (1 x 106 IU) is similar to the doses used by Yee et al. in their adoptive I cell therapy. This dose has been shown to expand and maintain CTLs in both preclinical and clinical models. The highest dose (11 x 106 IU) was chosen based on the expected toxicities from higher doses of IL-2 and our experience with this dose as a single agent in RCC.

Our hypothesis is that immunization with G250/Montanide/GM-CSF plus IL-2 can lead to an expansion of G250-specific CTL and result in killing of 0250 expressing micrometastatic RCC. We propose a dose finding study of escalating low doses of IL 2 (subcutaneous), since no prior study has specifically evaluated the use of low dose IL-2 as a cytokine adjuvant and attempted to establish a correlation between dose and immunolgic response.