Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma

Antoni Ribas, Begoña Comin-Anduix, Bartosz Chmielowski, Jason Jalil, Pilar De La Rocha, Tara A. McCannel, Maria Teresa Ochoa, Elizabeth Seja, Arturo Villanueva, Denise K. Oseguera, Bradley R. Straatsma, Alistair J. Cochran, John A. Glaspy, Liu Hui, Francesco M. Marincola, Ena Wang, James S. Economou, Jesus Gomez-Navarro

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Purpose: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. Experimental Design: Autologous DC were pulsed with MART-126-35 peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. Results: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. Conclusion: The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.

Original languageEnglish
Pages (from-to)6267-6276
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number19
DOIs
Publication statusPublished - 1 Oct 2009
Externally publishedYes

Fingerprint

Dendritic Cells
Melanoma
Vaccination
Antigens
Blocking Antibodies
T-Lymphocytes
Immunologic Monitoring
Neoplasms
Peptides
Clinical Trials, Phase I
Neoplasm Antigens
Diarrhea
Immunity
B-Lymphocytes
Research Design
Safety
Gene Expression
Genes
tremelimumab

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ribas, A., Comin-Anduix, B., Chmielowski, B., Jalil, J., De La Rocha, P., McCannel, T. A., ... Gomez-Navarro, J. (2009). Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. Clinical Cancer Research, 15(19), 6267-6276. https://doi.org/10.1158/1078-0432.CCR-09-1254

Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. / Ribas, Antoni; Comin-Anduix, Begoña; Chmielowski, Bartosz; Jalil, Jason; De La Rocha, Pilar; McCannel, Tara A.; Ochoa, Maria Teresa; Seja, Elizabeth; Villanueva, Arturo; Oseguera, Denise K.; Straatsma, Bradley R.; Cochran, Alistair J.; Glaspy, John A.; Hui, Liu; Marincola, Francesco M.; Wang, Ena; Economou, James S.; Gomez-Navarro, Jesus.

In: Clinical Cancer Research, Vol. 15, No. 19, 01.10.2009, p. 6267-6276.

Research output: Contribution to journalArticle

Ribas, A, Comin-Anduix, B, Chmielowski, B, Jalil, J, De La Rocha, P, McCannel, TA, Ochoa, MT, Seja, E, Villanueva, A, Oseguera, DK, Straatsma, BR, Cochran, AJ, Glaspy, JA, Hui, L, Marincola, FM, Wang, E, Economou, JS & Gomez-Navarro, J 2009, 'Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma', Clinical Cancer Research, vol. 15, no. 19, pp. 6267-6276. https://doi.org/10.1158/1078-0432.CCR-09-1254
Ribas A, Comin-Anduix B, Chmielowski B, Jalil J, De La Rocha P, McCannel TA et al. Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. Clinical Cancer Research. 2009 Oct 1;15(19):6267-6276. https://doi.org/10.1158/1078-0432.CCR-09-1254
Ribas, Antoni ; Comin-Anduix, Begoña ; Chmielowski, Bartosz ; Jalil, Jason ; De La Rocha, Pilar ; McCannel, Tara A. ; Ochoa, Maria Teresa ; Seja, Elizabeth ; Villanueva, Arturo ; Oseguera, Denise K. ; Straatsma, Bradley R. ; Cochran, Alistair J. ; Glaspy, John A. ; Hui, Liu ; Marincola, Francesco M. ; Wang, Ena ; Economou, James S. ; Gomez-Navarro, Jesus. / Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 19. pp. 6267-6276.
@article{faf198b1b6a643508857d52d828558ae,
title = "Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma",
abstract = "Purpose: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. Experimental Design: Autologous DC were pulsed with MART-126-35 peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. Results: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. Conclusion: The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.",
author = "Antoni Ribas and Bego{\~n}a Comin-Anduix and Bartosz Chmielowski and Jason Jalil and {De La Rocha}, Pilar and McCannel, {Tara A.} and Ochoa, {Maria Teresa} and Elizabeth Seja and Arturo Villanueva and Oseguera, {Denise K.} and Straatsma, {Bradley R.} and Cochran, {Alistair J.} and Glaspy, {John A.} and Liu Hui and Marincola, {Francesco M.} and Ena Wang and Economou, {James S.} and Jesus Gomez-Navarro",
year = "2009",
month = "10",
day = "1",
doi = "10.1158/1078-0432.CCR-09-1254",
language = "English",
volume = "15",
pages = "6267--6276",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "19",

}

TY - JOUR

T1 - Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma

AU - Ribas, Antoni

AU - Comin-Anduix, Begoña

AU - Chmielowski, Bartosz

AU - Jalil, Jason

AU - De La Rocha, Pilar

AU - McCannel, Tara A.

AU - Ochoa, Maria Teresa

AU - Seja, Elizabeth

AU - Villanueva, Arturo

AU - Oseguera, Denise K.

AU - Straatsma, Bradley R.

AU - Cochran, Alistair J.

AU - Glaspy, John A.

AU - Hui, Liu

AU - Marincola, Francesco M.

AU - Wang, Ena

AU - Economou, James S.

AU - Gomez-Navarro, Jesus

PY - 2009/10/1

Y1 - 2009/10/1

N2 - Purpose: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. Experimental Design: Autologous DC were pulsed with MART-126-35 peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. Results: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. Conclusion: The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.

AB - Purpose: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. Experimental Design: Autologous DC were pulsed with MART-126-35 peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. Results: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. Conclusion: The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.

UR - http://www.scopus.com/inward/record.url?scp=70349680756&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349680756&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-09-1254

DO - 10.1158/1078-0432.CCR-09-1254

M3 - Article

C2 - 19789309

AN - SCOPUS:70349680756

VL - 15

SP - 6267

EP - 6276

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 19

ER -