Skin-Test Infiltrating Lymphocytes Early Predict Clinical Outcome of Dendritic Cell–Based Vaccination in Metastatic Melanoma

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 tumorspecific 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 ¼ 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 þ 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 þ 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 ¼ 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. Cancer Res; 72(23); 6102-10. Ó2012 AACR.

Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination

“…27,28 However, the presence of tumor-specific T cells after DC vaccination might also represent the patients with a more potent immune system and therefore longer survival regardless of treatment. In this study we demonstrate that in melanoma patients with regional metastasis the presence of functional tumor-specific T cells after adjuvant DC vaccination is also positively correlated with survival, which provides further evidence that activation of the immune system against melanoma cells by DC vaccination plays a pivotal role in its clinical efficacy.…”

“…This is further substantiated by the finding that functional tumor-specific T cells are more frequently found in melanoma patients with regional metastasis (71%), in comparison to patients with distant metastasis (23%). 27 This might partially be explained by that the patients with regional metastasis received more vaccinations and more delayed-type hypersensitivity (DTH) skin tests. Additionally, the greater efficacy of DC vaccination in the adjuvant setting, eradicating residual micrometastasis if present, and higher frequencies of function tumor-specific T cells may also be caused by less tumor burden and therefore less tumor-mediated immune suppression compared to metastatic disease.…”

“…45 Skin-test infiltrating lymphocyte analyses Skin tests were performed within two weeks after each vaccination cycle as described previously. 27,28 Briefly, DCs loaded with either gp100, tyrosinase or both epitopes were injected intradermally in the skin of the back of the patient. After 48 h, punch biopsies (6 mm) were taken.…”

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

“…In a phase III trial in prostate cancer, DC vaccination induced antibody and T-cell responses in the majority of patients, and their presence correlated with survival (19,40). Although correlation of T-cell responses with clinical outcome is shown more often (41)(42)(43)(44), measuring T-cell responses remains notoriously difficult and laborious and assays are not validated in prospective clinical trials. Correlation with survival might become more accurate by broadening the immune cells analyzed, for example, with NK cell activation markers or tumor-specific antibodies (45)(46)(47).…”

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

“…DC-based immunotherapy exploits this property of DCs: tumor antigen-loaded DCs are injected into cancer patients to stimulate T cells and initiate tumor eradication (2,3). In clinical trials, this approach resulted in effective immunologic responses that coincided with favorable clinical outcomes (4,5). However, the number of objective clinical responses is limited, hampering its implementation as standard treatment.…”