A Phase I Trial of Vaccination of CA9-Derived Peptides for HLA-A24-Positive Patients with Cytokine-Refractory Metastatic Renal Cell Carcinoma

Abstract

Purpose: A phase I peptide vaccination trial was done in patients with progressive cytokinerefractory metastatic renal cell carcinoma (RCC) to assess both the toxicity and capability to induce immune responses of three peptides (CA9p219-227, p288-296, and p323-331) derived from CA9, a tumor-associated antigen ubiquitously expressed in RCC. Experimental Design: Twenty-three patients positive for human leukocyte antigen (HLA)-A24 with histologically confirmed RCC were enrolled. Eligibility included progressive disease after standard cytokine therapy with interleukin-2 and/or IFN-a. Patients were vaccinated s.c. with the three peptides emulsified in incomplete Freund's adjuvant at 2-week intervals. Pre-and postvaccination blood samples were obtained for toxicity assessment and immunologic studies. Patients were monitored for clinical responses on a 3-monthly basis. Results: Vaccinations were well tolerated without any major adverse event. Most of the patients developed peptide-specific CTLs and/or immunoglobulin G reactive to the peptides after the 6th or 9th vaccination, followed by a gradual increase in both CTL frequency and levels of peptidereactive serum IgG. Three patients with multiple lung metastases showed partial responses with disappearance and shrinking of metastatic lesions. Additionally, stable disease for >6 months was observed in six patients (median duration, 12.2 months). Moreover, the median survival time of all patients who were progressive at trial enrollment after failing immunotherapy was 21.0 months (5-35 months). Conclusions:These results suggest that vaccination of these peptides is safe and recommended for further trials for HLA-A24-positive metastatic RCC patients.

Massive expansion of regulatory T-cells following interleukin 2 treatment during a phase I-II dendritic cell-based immunotherapy of metastatic renal cancer

“…Furthermore, directing the immune response to recently identified tumor-associated antigens such as MUC1 (38), carbonic anhydrase IX-G250MN (CA9) (60) or survivin (61) in RCC cancer patients should also be progressed in order to improve the efficacy of such cell therapy strategies. Our data also prompt to consider re-evaluating the use of IL-2 in gene and cell therapies of cancer.…”

The tumor antigens RHAMM and G250/CAIX are expressed in head and neck squamous cell carcinomas and elicit specific CD8+ T cell responses

“…Furthermore, HLA-A * 0201 restricted T cell epitopes derived from G250/CAIX were identified, eliciting peptide-specific CTLs both in vitro and in vivo (19,48). Clinical phase I/II vaccination trials with G250/CAIX-derived peptides for patients with advanced renal cell carcinoma revealed to be safe and feasible with no gastrointestinal hepatic toxicity observed despite CAIX expression in large bile duct epithelium and gastric mucosal cells (49,50). In the study of Uemura et al, most of the patients developed peptide specific CTLs and/or immunoglobulin G reactive to the peptides and showed clinical responses (49).…”

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

“…Nevertheless, both interferon alpha and IL-2 are toxic, and the large majority of individuals who receive them derive no benefit. Efforts to develop more sophisticated immunotherapy platforms for this disease, including newer cytokine therapy (Alatrash et al, 2004), vaccine therapy (Uemura et al, 2006;Ernstoff et al, 2007), and nonmyeloablative transplantation (Childs et al, 2000;Artz et al, 2004;Rini et al, 2006), have been reported. Although these approaches have demonstrated tantalising indications of efficacy in a small group of individuals, they have not reached the threshold of therapeutic efficacy or safety.…”