The recently acquired ability to culture large numbers of human dendritic cells (DC), the most effective antigen-presenting cell for the sensitization of T lymphocytes, has provided an important resource for the formulation of active immunization strategies against cancer. The success of previous vaccine trials has probably been limited in part by the reliance on short synthetic peptide immunogens that cannot elicit CD4+ T cell help, the use of incorrectly cultured or administered DC that has failed to harness their full potential as APC, and the enrollment of patients who, because of their advanced metastatic disease and previous treatment with chemo- or radio-therapy make them inherently poor prospects for active immunotherapy. This proposed study is designed to circumvent these previous shortcomings by taking advantage of recent advances in our understanding of DC development, function, and administration, as well as the careful selection of both disease model and appropriate immunogen. High-grade ductal carcinoma in situ (DCIS) is a pre-invasive malignancy of the breast that often expresses the tumor-associated antigen her-2/neu. The proposed study will enroll her-2/neu-positive DCIS patients, who have localized disease and no previous experience with immunosuppressive therapies. These patients will receive a vaccine composed of autologous DC pulsed with multiple her-2/neu-derived peptides. These DC will be cultured in a manner proven to maximize their effectiveness in sensitizing tumor-recognizing T lymphocytes, and administered by the intra-nodal route, which has been demonstrated superior to other tested routes of delivery.
The specific aims of this study are first to determine the feasibility and safety of administering an autologous DC1 vaccine pulsed with her-2/neu peptides. Second, to determine the rate of sensitization of CD4+ and CD8+ T cells to her-2/neu after intra-nodal administration of the vaccine. Finally, the response in the peritumoral area following vaccination will be determined histopathologically and radiologically. The vaccine, if successful, will not only provide needed treatment options in addition to the current standard of care (mastectomy or lumpectomy) but may also prove useful for actually preventing invasive disease in patients judged at high risk for developing breast malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096997-03
Application #
6941356
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Xie, Heng
Project Start
2003-06-19
Project End
2007-05-31
Budget Start
2005-07-22
Budget End
2007-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$509,877
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Datta, Jashodeep; Xu, Shuwen; Rosemblit, Cinthia et al. (2015) CD4(+) T-Helper Type 1 Cytokines and Trastuzumab Facilitate CD8(+) T-cell Targeting of HER2/neu-Expressing Cancers. Cancer Immunol Res 3:455-63
Datta, Jashodeep; Berk, Erik; Cintolo, Jessica A et al. (2015) Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy. Front Immunol 6:271
Chatterjee, Abhishek; Serniak, Nicholas; Czerniecki, Brian J (2015) Sentinel lymph node biopsy in breast cancer: a work in progress. Cancer J 21:7-10
Datta, Jashodeep; Berk, Erik; Xu, Shuwen et al. (2015) Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer. Breast Cancer Res 17:71
Roses, Robert E; Datta, Jashodeep; Czerniecki, Brian J (2014) Radiation as immunomodulator: implications for dendritic cell-based immunotherapy. Radiat Res 182:211-8
Lee 4th, Major K; Xu, Shuwen; Fitzpatrick, Elizabeth H et al. (2013) Inhibition of CD4+CD25+ regulatory T cell function and conversion into Th1-like effectors by a Toll-like receptor-activated dendritic cell vaccine. PLoS One 8:e74698
Cintolo, Jessica A; Datta, Jashodeep; Mathew, Sarah J et al. (2012) Dendritic cell-based vaccines: barriers and opportunities. Future Oncol 8:1273-99

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