hTERT/survivin mRNA-loaded dendritic cell vaccination combined with ex-vivo expanded T cell transfer in stage IV melanoma patients show a longer overall survival in patients with sustained immune responses against hTERT

New immunotherapy strategies have recently been developed combining peptide or dendritic cell (DC) vaccination with infusion of vaccine-primed and ex vivo expanded T cells. The hypothesis is that adoptive transfer of ex vivo expanded tumor specific T cells can improve progression-free and overall survival by restoring anti-tumor immunity. In a phase I/II clinical trial on malignant melanomas stage IV patients received DC vaccination prior to transfer of ex vivo expanded T cells. Our strategy was to target hTERT and survivin since both is highly expressed in most cancers. The vaccine consisted of autologous DCs loaded with hTERT and survivin mRNA. Prior to each DC vaccination the patients received 5 days of Temozolomide treatment to reduce the number of regulatory T cells (Treg). Following 2 monthly DC vaccinations, blood samples were tested for immune response against hTERT and survivin overlapping peptides. Immune responders were offered injection of T cells. The Elutra fraction of T cells was depleted of Treg using Dynabeads CD25 prior to expansion with Dynabeads CD3/CD28 in a WAVE bioreactor. After 10 days the beads were removed and T cells were washed. 3x1010 expanded T cells were injected fresh and DC vaccination was continued. Prior to T cell infusion, the patients received non-myeloablative conditioning with Fludarabine and Cyclophosphamide Here we present the results from three patients receiving expanded T cells. Immune response against hTERT and survivin peptides were detected in blood samples from 7 to 11 weeks of DC vaccination. After 4-7 months of DC vaccination the T cells were expanded for 10 days prior to injection. DC vaccination was continued 1 day after T cell injection. Infused T cells expanded significantly in vivo and in two of the three patients currently tested both patients showed response against hTERT and survivin peptides. Blood samples taken monthly after T cell injection demonstrated immune response against the same peptides. In one of patients the number of Treg was high (> 4%) before and during vaccination and returned to low numbers (<1%) after T cell injection. Since these findings might explain the beneficial effect of the vaccination we are currently investigating if the number of Tregs in blood show the same profile in the two other patients. Progression free survival (PFS) in the three patients was 31,20 and 11 months respectively. Patients with the shortest PFS relapsed very shortly after the T-cell infusion in spite of an objective immunresponse following the last DC vaccine. Metastatic melanoma patients included in this study given DC vaccines without T-cells had a median PFS of 7 months (3-13). We therefore conclude that dendritic cell vaccination combined with ex-vivo expanded T cell transfer can be an efficient immunotherapy strategy in melanoma patients. Disclosures: No relevant conflicts of interest to declare.

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The use of baseline tumor size to prognosticate overall survival in stage IV melanoma patients treated with the PD-1 inhibitor pembrolizumab

Annals of Translational Medicine ◽

10.21037/atm.2019.01.74 ◽

2019 ◽

Vol 7 (S1) ◽

pp. S24-S24

Author(s):

Philip Friedlander

Keyword(s):

Overall Survival ◽

Tumor Size ◽

Stage Iv ◽

Melanoma Patients ◽

Stage Iv Melanoma

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Immune gene polymorphisms predict overall survival for stage IV melanoma patients treated with biochemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.90140.7550 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 7550-7550

Author(s):

D. Liu ◽

S. J. O'Day ◽

D. Yang ◽

P. Boasberg ◽

R. Milford ◽

...

Keyword(s):

Overall Survival ◽

Gene Polymorphisms ◽

Stage Iv ◽

Immune Gene ◽

Melanoma Patients ◽

Stage Iv Melanoma

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Pretreatment Levels of Peripheral Neutrophils and Leukocytes As Independent Predictors of Overall Survival in Patients With American Joint Committee on Cancer Stage IV Melanoma: Results of the EORTC 18951 Biochemotherapy Trial

Journal of Clinical Oncology ◽

10.1200/jco.2006.09.0274 ◽

2007 ◽

Vol 25 (12) ◽

pp. 1562-1569 ◽

Cited By ~ 136

Author(s):

Henrik Schmidt ◽

Stefan Suciu ◽

Cornelis J.A. Punt ◽

Martin Gore ◽

Wim Kruit ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Factor ◽

Interleukin 2 ◽

Stage Iv ◽

Progression Free Survival ◽

Independent Prognostic Factor ◽

Short Overall Survival ◽

Leukocyte Counts ◽

Melanoma Patients ◽

Stage Iv Melanoma

Purpose An elevated count of blood neutrophils and monocytes recently was shown independently to predict short survival in patients with stage IV melanoma undergoing interleukin-2–based immunotherapy. In this study, we aimed to validate this finding in a large cohort of stage IV melanoma patients. Patients and Methods For this retrospective prognostic study, the data from the European Organisation for the Research and Treatment of Cancer 18951 study were used. Patients were randomly assigned between treatment with dacarbazine, cisplatin, and interferon alfa with or without interleukin-2. Counts of neutrophils and leukocytes were analyzed together with other known prognostic factors: serum lactate dehydrogenase, performance status, metastatic site, and sex. Two multivariate prognostic factor analyses were carried out in the model: one with leukocyte counts and one with neutrophil counts. Results A total of 363 patients were randomly assigned and baseline blood neutrophil and leukocyte counts were available from 316 and 350 patients, respectively. A high neutrophil count (> 7.5 × 109/L) was an independent prognostic factor for short overall survival (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = 0.02), and a high leukocyte count (> 10 × 109/L) was an independent prognostic factor of both short overall survival (HR, 1.7; 95% CI, 1.3 to 2.4; P = 0.0005) and short progression-free survival (HR, 1.5; 95% CI, 1.1 to 2.1; P = 0.008). Conclusion A high pretreatment count of neutrophils in blood was confirmed as an independent prognostic factor for short overall survival in stage IV melanoma patients undergoing interleukin-2–based immunotherapy. Furthermore, a high count of leukocytes was an independent prognostic factor for short overall survival and progression-free survival. Both parameters should be useful as stratification factors in clinical trials.

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