Skin-derived tumor specific T cells predict clinical outcome in dendritic cell vaccination studies in both stage III and IV melanoma patients

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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Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients

Journal of Translational Medicine ◽

10.1186/1479-5876-11-135 ◽

2013 ◽

Vol 11 (1) ◽

pp. 135 ◽

Cited By ~ 40

Author(s):

Laura Ridolfi ◽

Massimiliano Petrini ◽

Anna Granato ◽

Giusy Gentilcore ◽

Ester Simeone ◽

...

Keyword(s):

T Cells ◽

Dendritic Cell ◽

Regulatory T Cells ◽

Low Dose ◽

Advanced Melanoma ◽

Dendritic Cell Vaccination ◽

Melanoma Patients

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Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients

OncoImmunology ◽

10.1080/2162402x.2016.1191732 ◽

2016 ◽

Vol 5 (7) ◽

pp. e1191732 ◽

Cited By ~ 12

Author(s):

Steve Boudewijns ◽

Kalijn F. Bol ◽

Gerty Schreibelt ◽

Harm Westdorp ◽

Johannes C. Textor ◽

...

Keyword(s):

Dendritic Cell ◽

Immune Responses ◽

Stage Iii ◽

Dendritic Cell Vaccination ◽

Melanoma Patients ◽

Stage Iii Melanoma

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In situ detection of antigen-specific T cells in cryo-sections using MHC class I tetramers after dendritic cell vaccination of melanoma patients

Cancer Immunology Immunotherapy ◽

10.1007/s00262-007-0304-5 ◽

2007 ◽

Vol 56 (10) ◽

pp. 1667-1676 ◽

Cited By ~ 20

Author(s):

I. J. M. De Vries ◽

M. R. Bernsen ◽

W. L. van Geloof ◽

N. M. Scharenborg ◽

W. J. Lesterhuis ◽

...

Keyword(s):

T Cells ◽

Dendritic Cell ◽

Mhc Class I ◽

Class I ◽

Dendritic Cell Vaccination ◽

Melanoma Patients ◽

In Situ Detection

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

OncoImmunology ◽

10.1080/2162402x.2015.1057673 ◽

2015 ◽

Vol 5 (1) ◽

pp. e1057673 ◽

Cited By ~ 38

Author(s):

Kalijn F Bol ◽

Erik H J G Aarntzen ◽

Florentien E M in 't Hout ◽

Gerty Schreibelt ◽

Jeroen H A Creemers ◽

...

Keyword(s):

Overall Survival ◽

Dendritic Cell ◽

Stage Iii ◽

Dendritic Cell Vaccination ◽

Melanoma Patients ◽

Stage Iii Melanoma

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Immunomonitoring Tumor-Specific T Cells in Delayed-Type Hypersensitivity Skin Biopsies After Dendritic Cell Vaccination Correlates With Clinical Outcome

Journal of Clinical Oncology ◽

10.1200/jco.2005.06.478 ◽

2005 ◽

Vol 23 (24) ◽

pp. 5779-5787 ◽

Cited By ~ 142

Author(s):

I. Jolanda M. de Vries ◽

Monique R. Bernsen ◽

W. Joost Lesterhuis ◽

Nicole M. Scharenborg ◽

Simon P. Strijk ◽

...

Keyword(s):

T Cells ◽

Clinical Outcome ◽

Stage Iv ◽

Keyhole Limpet Hemocyanin ◽

Delayed Type Hypersensitivity ◽

Dendritic Cell Vaccination ◽

Dc Vaccine ◽

Novel Approach ◽

Hypersensitivity Skin ◽

Melanoma Patients

Purpose Tumor-specific immunomonitoring is essential to evaluate the efficacy of vaccination against cancer. In this study, we investigated the predictive value of the presence or absence of antigen-specific T cells in biopsies from delayed-type hypersensitivity (DTH) sites. Patients and Methods In our ongoing clinical trials, HLA-A2.1+ melanoma patients were vaccinated with mature dendritic cells (DC) pulsed with melanoma-associated peptides (gp100 and tyrosinase) and keyhole limpet hemocyanin. Results After intradermal administration of a DTH challenge with gp100- and tyrosinase peptide-loaded DC, essentially all patients showed a positive induration. In clinically responding patients, T cells specific for the antigen preferentially accumulated in the DTH site, as visualized by in situ tetramer staining. Furthermore, significant numbers of functional gp100 and tyrosinase tetramer-positive T cells could be isolated from these DTH biopsies, in accordance with the applied antigen in the DTH challenge. We observed a direct correlation between the presence of DC vaccine-related T cells in the DTH biopsies of stage IV melanoma patients and a positive clinical outcome (P = .0012). Conclusion These findings demonstrate the potency of this novel approach in the monitoring of vaccination studies in cancer patients.

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