A small subset of patients with metastatic renal cell carcinoma (RCC) will achieve durable complete responses to treatment with immunostimulatory agents such as cytokines or vaccines. We have conducted a study to determine if a common HLA genotype exists among these good-outcome patients.

The study population consisted of 80 patients with metastatic RCC who received cytokine therapy. The “good-outcome” cohort was composed of ten patients who had achieved a clinical or surgical complete response, and had a disease-free survival of at least 40 months (median disease-free survival, 77 months). DNA extracted from peripheral blood mononuclear cells was used for high-resolution typing of HLA A, B, C, DRB1, DQA1, and DQB1 alleles.

The results of the HLA typing revealed that 60% of the class II alleles from the good-outcome cohort were components of two haplotypes: DRB1*0301/DQA1*0501/DQB1*0201 and DRB1*1501/DQA1*0102/DQB1*0602. The frequency of hetero- or homozygosity for these alleles was significantly higher in the good-outcome cohort than in those patients whose disease progressed through therapy. Hetero- or homozygosity at these loci was also associated with a significant prolongation of survival.

We conclude that hetero- or homozygosity for the class II haplotypes DRB1*0301/DQA1*0501/DQB1*0201 and DRB1*1501 /DQA1*0102/DQB1*0602 is associated with durable response and survival in metastatic RCC patients treated with cytokine therapy. Given that both haplotypes are associated with autoimmune disease, we propose that RCC patients who carry these haplotypes are prone to autoimmunity, and that the immune stimulation provided by immunotherapy is sufficient to trigger its development. We hypothesize that in these patients, the autoimmune mechanisms are directed against tumor antigens, producing a clinical antitumor response. Future research will focus an autoimmune mechanisms of cytokine-induced anti-tumor activity in RCC patients and an the predictive power of HLA class II typing for outcomes of patients with either advanced or early stage disease.