Abstract 2398: Intra-lymph node DNA vaccination as a platform for safe and effective immunotherapy of cancer
Authors: Zhiyong Qiu, Kent A. Smith, Raymond Wong, Victor Tam, Begonya Comin-Anduix, Anthony Ribas, Darlene Rosario, Mihail Obrocea, Adrian Bot
Journal: Cancer Research (2010)

Abstract The purpose of this study was to advance a novel immunotherapy platform technology that would achieve objective clinical response and allow subsequent elucidation of immune correlates of clinical responses. To this aim, we tested an immunotherapy approach encompassing sequential intra-lymph node administration of DNA vectors and peptide analogues to elicit multivalent CD8+ T cell immunity against cancer cell and stromal antigens. This included the assessment of safety, immune response and clinical outcome following treatment with two investigational regimens in patients with metastatic solid tumors such as melanoma, prostate, and renal clear cell carcinoma. Strikingly, T cell transcriptomal analysis by gene array and flow cytometry analysis in a preclinical model showed that DNA vaccination induced a distinct immunophenotype, compared to peptide vaccination. DNA vaccine-primed CD8+ T cells showed a coordinated, lower expression of co-inhibitory molecule PD-1 and retention of the lymph node homing molecule CD62L, leading to a significant persistence of antigen-specific T cells, cellular expansion and functional conversion to effector cells, upon peptide boosting. Secondly, both objective tumor regression and elevation of antigen-specific T cells were observed in immunized patients, although there was no strict correlation between these two outcomes. Instead, there was a disease stage dependency of the presence of T cells specific for Melan A / MART-1 in melanoma patients, with all stage IV M1a (lymphatic metastatic disease) patients exhibiting pre-existing T cells and responding to treatment through durable tumor regression. Significantly, T cells specific for both immunizing antigens, Melan A/MART-1 and Tyrosinase, were identifiable within regressing tumor lesions in these M1a patients. In contrast, the preponderance of pre-existing Melan A/MART-1 T cells in melanoma patients with visceral metastatic disease was less than 50% and no apparent tumor regression upon administration was observed. In a second parallel trial, co-immunization against PRAME and PSMA generated clinical response through disease stabilization in several patients with carcinoma and was mirrored by a persisting T cell immunity. In summary, these results lead to three major conclusions: first, design of synthetic active immunotherapies affording objective tumor regression is possible, thereby refuting the paradigm that such approaches can be effective only in earlier disease stage; second, a systemic, hypothesis-generating approach must be employed to uncover appropriate biomarker correlates; and third, DNA-based vaccination has the potential of being translated to safe and effective therapies for cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2398.