Prolonged Survival of Dendritic Cell–Vaccinated Melanoma Patients Correlates With Tumor-Specific Delayed Type IV Hypersensitivity Response and Reduction of Tumor Growth Factor β-Expressing T Cells

2009 ◽  
Vol 27 (6) ◽  
pp. 945-952 ◽  
Author(s):  
Mercedes N. López ◽  
Cristian Pereda ◽  
Gabriela Segal ◽  
Leonel Muñoz ◽  
Raquel Aguilera ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Disease Progression ◽  
Stage Iv ◽  
Stage Iii ◽  
Type Iv ◽  
Melanoma Patients

PurposeThe aim of this work was to assess immunologic response, disease progression, and post-treatment survival of melanoma patients vaccinated with autologous dendritic cells (DCs) pulsed with a novel allogeneic cell lysate (TRIMEL) derived from three melanoma cell lines.Patients and MethodsForty-three stage IV and seven stage III patients were vaccinated four times with TRIMEL/DC vaccine. Specific delayed type IV hypersensitivity (DTH) reaction, ex vivo cytokine production, and regulatory T-cell populations were determined. Overall survival and disease progression rates were analyzed using Kaplan-Meier curves and compared with historical records.ResultsThe overall survival for stage IV patients was 15 months. More than 60% of patients showed DTH-positive reaction against the TRIMEL. Stage IV/DTH-positive patients displayed a median survival of 33 months compared with 11 months observed for DTH-negative patients (P = .0014). All stage III treated patients were DTH positive and remained alive and tumor free for a median follow-up period of 48 months (range, 33 to 64 months). DTH-positive patients showed a marked reduction in the proportion of CD4+ transforming growth factor (TGF) β+ regulatory T cells compared to DTH-negative patients (1.54% v 5.78%; P < .0001).ConclusionOur findings strongly suggest that TRIMEL-pulsed DCs provide a standardized and widely applicable source of melanoma antigens, very effective in evoking antimelanoma immune response. To our knowledge, this is the first report describing a correlation between vaccine-induced reduction of CD4+TGFβ+ regulatory T cells and in vivo antimelanoma immune response associated to improved patient survival and disease stability.

Characteristics and probability of survival for patients with advanced melanoma who live five or more years after initial treatment with immune checkpoint blockade (ICB).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9534-9534
Author(s):  
Kimberly Loo ◽  
Debra A. Goldman ◽  
Katherine Panageas ◽  
Margaret K. Callahan ◽  
Paul B. Chapman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Failure ◽  
Disease Progression ◽  
Stage Iii ◽  
Late Relapse ◽  
Unresectable Stage ◽  
Melanoma Patients ◽  
Long Term Survivors

9534 Background: A subset of melanoma patients treated with ICB (ipilimumab [ipi], nivolumab [nivo], pembrolizumab [pembro] or nivo+ipi) will experience durable responses. While five-year survival rates have been reported for patients treated with ICB on clinical trials, little is known about the clinical characteristics, survival past five years, and patterns of late relapse of long-term survivors. Methods: We retrospectively reviewed all patients treated at Memorial Sloan Kettering for unresectable stage III/IV melanoma who survived at least five years following their first dose of ICB (N = 151). Demographics, disease characteristics, and nature of progression were examined. Overall survival (OS) was calculated from 5 years post-ICB. Time to Treatment failure (TTF) was calculated conditionally from 5 years out until next therapy, progression, or death. Results: Of the 151 long-term survivors, median age at first ICB treatment was 62 years (range 22-83), with 101 (66.9%) male and 50 (33.1%) female patients. Stage at first ICB treatment was unresectable stage III (26, 17.2%), M1a (21,13.9%), M1b (39, 25.8%), M1c (52, 34.4%), M1d (13, 8.6%). Melanoma subtype was cutaneous (122, 80.8%), unknown primary (24, 15.9%), mucosal (3, 2%), and acral (2, 1.3%). First ICB was ipi (108, 71.5%), PD-1 (nivo or pembro) (5, 3.3%), and nivo+ipi (37, 24.5%). The best overall response to first ICB was CR (76, 50.3%), PR (27, 17.9%), SD (16, 10.6%) and PD (32, 21.2%). Of the patients who progressed after initial ICB, 38 received subsequent systemic treatment as follows: PD-(L)1 in 20 (53%), BRAF ± MEK in 9 (23.7%), ipi in 7 (18.4%), and chemotherapy in 2 (5.3%). Median duration of follow-up among survivors (N = 138) was 93 months (range 60-192). From 5 years post-ICB, 85% (95% CI: 73-92%) survived an additional 5 years. In those who made it to 5 years without treatment failure (N = 72), the probability of remaining failure-free was 92% (95% CI: 86-99%) at 7 years. Of the 151 patients, only 4 patients (2.6%) experienced disease progression after 5 years. Three patients had radiographic or pathologic disease progression in the lymph nodes and one in the subcutaneous tissue. No patients progressed in the lungs, visceral organs, or CNS after 5 years. At time of analysis, 13 (8.6%) patients died after 5 years post ICB, none died of progressive melanoma. 6 patients died of unknown causes, 2 died of other causes, and 5 died of other non-melanoma cancer-related causes. Conclusions: Patients who survive five years after their initial immunotherapy have excellent overall survival and treatment failure-free survival. Given the anxiety surrounding survivorship and late progression, long-term survivors should be reassured of their excellent prognosis. These data suggest that aggressive follow-up schedules and imaging of melanoma patients after 5 years of survival may not be required.

scholarly journals Serum CEACAM1 Correlates with Disease Progression and Survival in Malignant Melanoma Patients

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Sapoznik Sivan ◽  
Faranesh Suzan ◽  
Ortenberg Rona ◽  
Hamburger Tamar ◽  
Barak Vivian ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Malignant Melanoma ◽  
Metastatic Melanoma ◽  
Disease Progression ◽  
Skin Test ◽  
Metastatic Disease ◽  
Prognostic Value ◽  
Serum Samples ◽  
Melanoma Patients

The search for melanoma biomarkers is crucial, as the incidence of melanoma continues to rise. We have previously demonstrated that serum CEACAM1 (sCEACAM1) is secreted from melanoma cells and correlates with disease progression in metastatic melanoma patients. Here, we have used a different cohort of melanoma patients with regional or metastatic disease (N=49), treated with autologous vaccination. By monitoring sCEACAM1 in serum samples obtained prior to and after vaccination, we show that sCEACAM1 correlates with disease state, overall survival, and S100B. The trend of change in sCEACAM1 following vaccination (increase/decrease) inversely correlates with overall survival. DTH skin test is used to evaluate patients’ anti-melanoma immune response and to predict response to vaccination. Importantly, sCEACAM1 had a stronger prognostic value than that of DTH, and when sCEACAM1 decreased following treatment, this was the dominant predictor of increased survival. Collectively, our results point out the relevance of sCEACAM1 in monitoring melanoma patients.

scholarly journals THE MAIN PARAMETERS OF CELLULAR IMMUNITY IN PATIENTS WITH TRIPLE-NEGATIVE BREAST CANCER: RELATIONSHIP WITH EFFICIENCY OF CHEMOTHERAPY

2018 ◽  
Vol 20 (5) ◽  
pp. 667-680 ◽  
Author(s):  
A. I. Chertkova ◽  
E. G. Slavina ◽  
E. K. Shoua ◽  
L. G. Zhukova ◽  
M. A. Okruzhnova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Overall Survival ◽  
T Cells ◽  
Disease Progression ◽  
Triple Negative ◽  
Lymphocyte Subsets ◽  
Nkt Cells ◽  
Peripheral Blood Lymphocytes ◽  
Initial State

Chemotherapy is among the primary methods of treating advanced breast cancer. It was shown that clinical efficacy of various chemotherapeutic agents in many cases depends not only on their direct cytostatic and/or cytotoxic effect upon tumor cells, but also on their ability to modulate phenotype of the tumor cells and to influence anti-tumor immune response. Initial state of the immune system and its response to treatment is crucial. Antitumor response involves cells of innate and adaptive immunity (NK, NKT, T cells). These populations are heterogeneous and contain, e.g., cells with antitumor activity and regulatory (suppressor) cells that suppress immune response and promote tumor progression. The aim of this work was to determine the relationship between the initial state of cellular immunity of patients suffering from locally advanced breast cancer with triple negative phenotype, and clinical effect of chemotherapy (cisplatin + doxorubicin/paclitaxel), and studying effects of the therapy upon subpopulation profiles of peripheral blood lymphocytes in the patients. We registered the terms of the disease progression as well as overall survival and progression-free survival. The disease progressed in 25 of 53 cases (47.2%) whereas 28 of 53 patients (52.8%) remained progression-free. The observation period was 35.5 months. Laboratory examination of the patients included immunophenotyping of peripheral blood lymphocytes and determination of NK cell cytotoxic activity before and after chemotherapy. Percentages of effectors and regulatory lymphocyte populations were determined. The results obtained showed that, for some lymphocyte subsets, the pre-treatment differences of cell percentage deviations from control were found between the progression-free groups and patients with progression of the disease. The differences in percentages of NKT cells and lymphocytes expressing CD25 activation marker proved to be most significant. Decreased number of NKT cells and activated CD25+ lymphocytes prior to chemotherapy was associated with increased probability of disease progression. Reduced percentage of NKT cells against control was observed in 56% of patients from the progression group (PD), and only 21.4% in the group free of disease progression (DF). [OR = 4.6 (95% CI 1.4 to 15.4)]. Percentage of CD25+ lymphocytes was decreased from 68.2% in the PD group, and 28.6% for DF patients [OR = 5.4 (95% CI 1.6-18.1)]. We studied relationships between the overall survival (OS) and percentage of perforin-containing NK, NKT, and T cells, and mean perforin fluorescence density (PFD) in these lymphocyte subsets in 26 of the 53 patients before treatment. A statistically significant positive correlation was revealed between OS and perforin PFD in all the three cell populations under study. Normalization of the parameters altered before treatment, and an increase of T cell numbers was observed in the disease-free patients.

Adjuavnt tyrosinase peptide vaccination in patients with resected stage III/IV melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2570-2570
Author(s):  
A. Letsch ◽  
C. Scheibenbogen ◽  
M. Fluck ◽  
A. Asemissen ◽  
D. Nagorsen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Clinical Efficacy ◽  
Ex Vivo ◽  
T Cell Response ◽  
Stage Iii ◽  
Effector Memory ◽  
Rapid Progression ◽  
Melanoma Patients

2570 Background: This phase II study was undertaken to evaluate the immunogenicity and clinical efficacy of vaccination with tyrosinase peptides as adjuvant treatment in melanoma patients after multiple relapses. Methods: Stage III/IV melanoma patients after complete resection of relapses were vaccinated with tyrosinase peptides together with GM-CSF and KLH. Vaccination was given bi-weekly times 4, followed by monthly times 8 in absence of relevant disease progression. Tyrosinase-specific T cells were quantitated and characterized ex vivo by intracellular cytokine flow cytometry. Results: 44 patients were accrued with a median of 5.8 (range 2–25) previous relapses at cutaneous /s.c. only (n = 11), ln (n = 30) and/or visceral sites (n = 7). 11 patients received less than 6 vaccinations due to rapid progression. Of 32 patients evaluable for immunological response 16 (50%) displayed pre-vaccine spontaneous tyrosinase-specific T cells (median 0.32%). In 7 of the 15 patients without pre-existing T cells tyrosinase-specific T cells were induced after 6 vaccinations (median 0.08% CD3+CD8+ T cells) and in 10 of 12 patients after 12 vaccinations (median 0.36%, p = 0.03 compared to 6 vaccinations). Similarly, in 9 of the 16 patients with pre-existing T cell responses the frequency of tyrosinase-specific T cells did increase after 6 cycles (median 0.43 %), but in none of 10 patients with pre-existing T cells an increase was observed after 12 vaccinations (median 0.20%). Both, the spontaneous and the vaccine-induced T cells were predominantly of effector and effector-memory phenotype. With respect to clinical efficacy vaccination was terminated after 3 to 9 cycles due to disease progression in 19 of 44 patients. Of the remaining 25 patients receiving all 12 vaccinations 7 (16% of all 44 enrolled) had a favourable clinical course with cessation of recurrences. Conclusions: Taken together, this study shows high immunogenicity of the vaccine in patients with limited tumor burden associated with clinical efficacy. In case of a spontaneous pre-existing T cell response to the vaccine peptides, however, this could not, or only transiently be augmented. No significant financial relationships to disclose.

scholarly journals Digital Immunophenotyping Predicts Disease Free and Overall Survival in Early Stage Melanoma Patients

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 422
Author(s):  
Francesco De Logu ◽  
Francesca Galli ◽  
Romina Nassini ◽  
Filippo Ugolini ◽  
Sara Simi ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Cd8 T Cells ◽  
Early Stage ◽  
High Density ◽  
Stage Ii ◽  
Prognostic Impact ◽  
Training Cohort ◽  
Melanoma Patients ◽  
Disease Free

Background: the prognostic significance of tumor infiltrating lymphocytes (TILs) in intermediate/thick primary cutaneous melanoma (PCM) remains controversial, partially because conventional evaluation is not reliable, due to inter-observer variability and diverse scoring methods. We aimed to assess the prognostic impact of the density and spatial distribution of immune cells in early stage intermediate/thick PCM. Materials and Methods: digital image acquisition and quantitative analysis of tissue immune biomarkers (CD3, CD4, CD8, CD68, PD-L1, CD163, FOX-P3, and PD-1) was carried out in a training cohort, which included patients with primary PCM ≥ 2 mm diagnosed, treated, and followed-up prospectively in three Italian centers. Results were validated in an independent Italian cohort. Results: in the training cohort, 100 Stage II–III melanoma patients were valuable. At multivariable analysis, a longer disease free survival (DFS) was statistically associated with higher levels of CD4+ intratumoral T-cells (aHR [100 cell/mm2 increase] 0.98, 95%CI 0.95–1.00, p = 0.041) and CD163+ inner peritumoral (aHR [high vs. low] 0.56, 95%CI 0.32–0.99, p = 0.047). A statistically significant longer DFS (aHR [high-high vs. low-low] 0.52, 95%CI 0.28–0.99, p = 0.047) and overall survival (OS) (aHR [high-high vs. low-low] 0.39, 95%CI 0.18–0.85, p = 0.018) was found in patients with a high density of both intratumoral CD8+ T-cells and CD68+ macrophages as compared to those with low density of both intratumoral CD8+ T-cells and CD68+ macrophages. Consistently, in the validation cohort, patients with high density of both intratumoral CD8+ and CD3+ T-cells were associated to a statistically better DFS (aHR[high-high vs. low-low] 0.24, 95%CI 0.10–0.56, p < 0.001) and those with high density of both intratumoral CD8+ and CD68+ were associated to a statistically longer OS (aHR[high-high vs. low-low] 0.28, 95%CI 0.09–0.86, p = 0.025). Conclusion: our findings suggest that a specific preexisting profile of T cells and macrophages distribution in melanomas may predict the risk of recurrence and death with potential implications for the stratification of stage II–III melanoma patients.

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