Abstract 5530: Evidence for immunological pressure and escape from longitudinal analysis of the expression of and immune responses against NY-ESO-1 in a patient with metastatic melanoma
Authors: von Boehmer Lotta , Landshammer Alexandro , Nuber Natko , Bode Peter , Moch Holger , Jäger Elke , Knuth Alexander , van den Broek Maries 
Published: June 2012

Rationale: Metastatic malignant melanoma patients have a median survival of 8.5 months and a probability of surviving 5 years after the diagnosis of less than 5%. Melanoma patients have been treated with immunotherapeutic approaches including vaccination which induced durable clinical responses in a small subset of patients. Here we present a thorough characterisation of a patient living almost 10 years with metastatic melanoma, who was treated with standard therapy followed by two anti-NY-ESO-1 vaccinations, surgeries and finally Ipilimumab. The patient (ZH-311) was closely immune monitored for the expression of NY-ESO-1 in the tumor and for NY-ESO-1 specific immune response during the course of disease.

Methods: The clinical course of the patient was followed from the beginning of diagnosis (03/01) to his death in 07/10. NY-ESO-1-specific CD8+ T cell responses in peripheral blood mononuclear cells (PBMC) were analyzed by intracellular cytokine staining. Antibodies against NY-ESO-1 were monitored by ELISA. Each operated tumor and tumor site found in autopsy was analyzed for NY-ESO-1 by immunohistochemistry.

Results: The clinical course of ZH-311 is remarkable, because he lived for more than 6y with immunotherapy and 5 surgical interventions for metastases. 4 surgeries were performed due to progressing disease and the liver metastasis were stable at the time of operation. The early lesions displayed strong NY-ESO-1 expression and a very strong, polyfunctional CD8+ T-cell response against NY-ESO-1 was observed before immunotherapy, which increased upon VF vaccination. The cellular response was mirrored by the antibody response. However, the NY-ESO-1-specific CD8+ T cell response decreased upon vaccination with NY-ESO-1 protein plus CpG, whereas the antibody response remained high for one more year. Examination of later lesions revealed a loss of NY-ESO-1 expression, which is suggestive of escape as a result of immunological pressure.

Conclusion: Before and after the vaccination with NY-ESO-1 the patient had an integrated immune response with NY-ESO-1 including antibodies as well as polyfunctional CD8+ T cells. All tumors analysed after the anti-NY-ESO-1 vaccination were NY-ESO-1 negative, suggesting outgrowing escape variants. The stable liver metastases were NY-ESO-1 positive and were apparently immunologically controlled. The persisting antibody levels against NY-ESO-1 dropped after the excision of the NY-ESO-1+ liver metastasis, which suggests a correlation between antigen load and antibody titers. The study we present here provides direct clinical evidence for initial control and susbsequent sculpting of the tumor by the adaptive immune response.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5530. doi:10.1158/1538-7445.AM2011-5530