HER-2/neu expression in breast cancers (HER-2/neu phenotype and Luminal B) is associated with poor prognosis high risk breast cancers. Targeting HER-2/neu in early breast cancer using vaccine approaches may eliminate this high risk phenotype and create estrogen receptorpos HER-2/neuneg (Luminal A) phenotypes that are more amenable to current standard treatments. In our previous funding period, we developed novel type I polarized dendritic cells (DC1) activated using toll like receptor agonists with the capacity for high level second burst interleukin-12 production. These DC1 pulsed with MHC class I and class II peptides derived from HER-2/neu administered in a neoadjuvant trial to patients with ductal carcinoma in situ (DCIS) resulted in near uniform sensitization of HER-2/neu specific CD4, and CD8 T cells, induction of complement fixing antibodies, and in half the patients accumulation of T and B cells in the breast. These immune responses appear to be long lasting. In addition, there was significant reductions in HER-2/neu expressing DCIS in about 50% of patients with apparent clinical reductions in the extent of disease. The latter results strongly suggest evidence for a paradigm we have identified as targeted immunoediting. In targeted immunoediting a more aggressive phenotype is targeted for elimination to create a more favorable phenotype, the reverse of natural immunediting. We have also made the striking observation as a result of our initial trial that HER-2/neu expression in DCIS appears to be highly associated with the development of invasive breast cancer. Therefore targeting HER-2/neu prior to development or in early disease settings may prevent the development of a significant number of invasive breast cancers. In the initial funding period we focused on developing an adaptive immune response by administering DC in a remote intranodal location however, the DC1 generated produce large quantities of cytokines and chemokines that can be taken advantage of to attract both innate and antigen specific effectors into the breast if administered into the region of cancer. Given the early success of this DC1 vaccination there is tremendous opportunity to explore the development of DC1 vaccines for the treatment of DCIS and the prevention of invasive breast cancer. In the current application we will extend our initial observations from the previous application to (1) Determine whether combined intranodal and intralesional HER-2/neu pulsed DC1 vaccinations will increase the clinical response rates by delivering innate immune effectors into the breast to increase the accumulation of both the innate (NK cells) and adaptive effectors into the area of DCIS this will be assessed in a randomized clinical trial using 3 routes of administration, intralesional, intranodal or both sites. (2), Determine the mechanism by which the DC1 vaccination induces clinical responses and immunoedits DCIS. This will be accomplished by evaluation of the immune response including cytokine chemokine production in the locoregional area including sentinel nodes and DCIS lesions and systemic peripheral blood, and perform a molecular profile of the edited DCIS lesions. It is anticipated that this program will identify the requirements for successful anti-cancer vaccine strategies in general and develop the groundwork for utilizing HER-2/neu vaccines for the treatment of early breast cancer. Success of the project may lead to new immunotherapies that can be utilized with existing standrard treatments for breast cancer, but more importantly pave the way for developing vaccines for breast cancer prevention.

Public Health Relevance

HER-2/neu over-expressing DCIS represents a group of patients with significant risk for development of invasive breast cancer. In this proposal we will continue to evaluate the development of type I polarized DC for the treatment of DCIS by evaluating whether further improvements in therapeutic response can be achieved by intralesional administration of HER-2/neu pulsed DC1 compared with intranodal administration. It is anticipated that the production of chemokines and cytokines by DC1 will lead to accelerated accumulation of specific and non-specific effectors in the area of DCIS and further clinical responses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096997-07
Application #
8196751
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Song, Min-Kyung H
Project Start
2002-07-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
7
Fiscal Year
2012
Total Cost
$497,125
Indirect Cost
$181,490
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Datta, Jashodeep; Fracol, Megan; McMillan, Matthew T et al. (2016) Association of Depressed Anti-HER2 T-Helper Type 1 Response With Recurrence in Patients With Completely Treated HER2-Positive Breast Cancer: Role for Immune Monitoring. JAMA Oncol 2:242-6
Nocera, Nadia F; Lee, M Catherine; De La Cruz, Lucy M et al. (2016) Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention. Front Pharmacol 7:356
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; 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; 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
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
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
Sharma, Anupama; Koldovsky, Ursula; Xu, Shuwen et al. (2012) HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ. Cancer 118:4354-62

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