The translational goal of this project is to evaluate the adoptive transfer of tunnor-specific T cells derived or engineered from central memory cells to treat breast cancer. The immune system is designed to distinguish diseased from normal cells with exquisite specificity and sensitivity, and there is increasing evidence that tumor development and progression is restrained by adaptive host T cell responses to tumor-associated antigens. However, harnessing this activity to provide therapeutic benefit in breast cancer requires identifying antigens that are expressed by tumor cells and can be safely targeted, and developing methods to achieve potent and durable T cell immunity in patients. Many candidate tumor associated antigens have been discovered in breast cancer and we have focused on targeting the HER-2 oncoprotein and NY-BR-1. We have pursued the adoptive transfer of T cells specific for these antigens because this approach should allow for control ofthe specificity, function, and magnitude ofthe antitumor response, and could overcome obstacles that limit the endogenous host response, or T cell responses elicited by vaccination. The efficacy of adoptive T cell therapy in clinical trials for other human malignancies has been limited by the inability of tumor-specific effector cells that have been expanded in vitro to persist at high levels in vivo after adoptive transfer. Studies in our lab have demonstrated that the survival of adoptively transferred T cells is correlated with the differentiation state of the precursor T cell from which the T cells are derived. Effector cells isolated from central memory but not effector memory T cells provide persistent engraftment, migrate to memory T cell niches, function in vivo after adoptive transfer, and can be sustained at remarkably high levels by a short course of IL-15. This project will build on these findings and evaluate the adoptive transfer of T cells derived or engineered from central memory cells to treat breast cancer.
The specific aims are: 1. To perform a phase I trial of adoptive T cell therapy with TcM-derived HER-2/neu (HER-2)-specific T cells following in vivo priming with a HER-2 peptide vaccine in patients with advanced HER-2 breast cancer 2. To engineer CD45RO* CD62L* TCM derived effector T cells through T cell receptor (TCR) gene transfer to express a TCR that targets NY-BR-1. 3. To perform a phase I study of adoptive T cell therapy with TCR modified TCMIO target NY-BR-1 in patients with advanced NY-BR-I breast cancer

Public Health Relevance

There is evidence breast cancer is detected by the immune system, but the development of immunotherapy that improves the outcome for patients has been challenging. The proposed studies will evaluate new approaches to the immunotherapy for breast cancer in which cells of the immune system that have the capacity to survive long term, will be isolated, programmed to target and kill tumor cells and transferred back to the patient. The results of these studies will provide insights into the potential utility of adoptive T cell therapy for breast cancer, and for the broader application of this approach in human malignancy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Wangerin, Kristen A; Muzi, Mark; Peterson, Lanell M et al. (2017) A virtual clinical trial comparing static versus dynamic PET imaging in measuring response to breast cancer therapy. Phys Med Biol 62:3639-3655
Amornsiripanitch, Nita; Nguyen, Vicky T; Rahbar, Habib et al. (2017) Diffusion-weighted MRI characteristics associated with prognostic pathological factors and recurrence risk in invasive ER+/HER2- breast cancers. J Magn Reson Imaging :
Balakrishnan, Ashwini; Goodpaster, Tracy; Randolph-Habecker, Julie et al. (2017) Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues. Clin Cancer Res 23:3061-3071
Sommermeyer, D; Hudecek, M; Kosasih, P L et al. (2016) Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30:492-500
Busch, Dirk H; Fräßle, Simon P; Sommermeyer, Daniel et al. (2016) Role of memory T cell subsets for adoptive immunotherapy. Semin Immunol 28:28-34
Paszkiewicz, Paulina J; Fräßle, Simon P; Srivastava, Shivani et al. (2016) Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J Clin Invest 126:4262-4272
Liu, Lingfeng; Sommermeyer, Daniel; Cabanov, Alexandra et al. (2016) Inclusion of Strep-tag II in design of antigen receptors for T-cell immunotherapy. Nat Biotechnol 34:430-4
Rahbar, Habib; Parsian, Sana; Lam, Diana L et al. (2016) Can MRI biomarkers at 3 T identify low-risk ductal carcinoma in situ? Clin Imaging 40:125-9
Rahbar, Habib; McDonald, Elizabeth S; Lee, Janie M et al. (2016) How Can Advanced Imaging Be Used to Mitigate Potential Breast Cancer Overdiagnosis? Acad Radiol 23:768-73
Robinson, Michael A; Graham, Daniel J; Morrish, Fionnuala et al. (2016) Lipid analysis of eight human breast cancer cell lines with ToF-SIMS. Biointerphases 11:02A303

Showing the most recent 10 out of 52 publications