Abstract
The identification of responding patients early during treatment would improve the capability to develop effective new immunotherapies more rapidly. Here, we describe a bioassay that may link early T-cell-mediated immune responses to later clinical benefits. This bioassay rests upon the tenet of immunotherapy that tumor-specific effector T cells capable of invading peripheral tissue can recognize tumor antigens and exert cytotoxic functions there. To show its utility, we conducted a retrospective study of a large cohort of metastatic melanoma patients (n = 91) enrolled in dendritic cell (DC)-based vaccination protocols to examine a hypothesized correlation of posttreatment skin-infiltrating lymphocytes (SKIL) with overall survival (OS). Stringent immunologic criteria were defined to identify long-term survivors. The presence of tumor-associated antigen (TAA)-specific CD8(+) T cell populations within SKILs (criterion I) was highly predictive for long-term survival. Further restriction by selecting for the presence of TAA-specific CD8(+) T cells specifically recognizing tumor peptide (criterion II) was also associated with improved OS. Recognition of naturally processed antigen (criterion III) maximized the accuracy of the test, with a median OS of 24.1 versus 9.9 months (P = 0.001). Our results show that detailed characterization of SKILs can permit an accurate selection of metastatic melanoma patients who benefit most from DC-based vaccination. This simple and robust bioassay integrates multiple aspects of cellular functions that mediate effective immune responses, thereby offering an effective tool to rapidly identify patients who are responding to immunotherapy at an early stage of treatment.
Highlights
The focus of treatment for metastatic cancer patients is shifting from a generalized approach based on population markers, to a personalized approach based on individual tumor and host characteristics [1]
The patients were vaccinated according to the various vaccination protocols, including intranodal, intradermal, intravenous/intradermal vaccinations; mode of antigen loading of dendritic cell (DC) was either pulsing with MHC Class I or MHC Class I and II defined epitopes derived from gp100 and tyrosinase, or electroporation with mRNA encoding these tumor associated antigens [25]
To show that this procedure is feasible for large-scale clinical studies, we determined the rate of successful skin-infiltrating lymphocytes (SKIL) cultures and their yield (Table 1). 329 out of 410 (80%) cultures yielded sufficient numbers of cells to allow further analysis, which results appear to be independent of the vaccination protocol (Table 1)
Summary
The focus of treatment for metastatic cancer patients is shifting from a generalized approach based on population markers, to a personalized approach based on individual tumor and host characteristics [1]. Immunotherapy is intrinsically a personalized treatment modality, as it acts via the patients' own immune system to induce anticancer immunity. Recent trials have underscored the potential of immunotherapy in metastatic cancers, especially in melanoma [2]. Owing to their unique immune stimulatory properties, dendritic cells. Authors' Affiliations: 1Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, 2Department of Medical Oncology, 3Laboratory of Medical Immunology, and 4Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, and 5Department of Medical Oncology, Academic Medical Centre, Amsterdam, The Netherlands. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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