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

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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

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ribas, A., Comin-Anduix, B., Chmielowski, B., Jalil, J., De La Rocha, P., McCannel, T. A., Ochoa, M. T., Seja, E., Villanueva, A., Oseguera, D. K., Straatsma, B. R., Cochran, A. J., Glaspy, J. A., Hui, L., Marincola, F. M., Wang, E., Economou, J. S., & 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