Successful treatment of metastasis continues to be the main challenge in cancer. Local chest wall recurrences of breast cancer often occur in the context of metastatic disease, presenting the challenge of treating both. In this setting, salvage chemotherapy/hormone therapy result in overall response rates of only 20-30%, warranting novel treatment strategies. Our group has demonstrated that local ionizing radiation therapy (RT) can be successfully combined with immunotherapy (IT) strategies to generate an anti-tumor immune response, enabling not only rejection of the treated tumor, but also of metastases outside the irradiated field (abscopal effects). Imiquimod (IMQ) is a small molecule immune response modifier which triggers immune activation via toll-like receptor (TLR)-7 and is FDA approved, based on its clinical activity against a variety of skin cancers. In preclinical models of breast cancer, the syngeneic murine tumors TSA and 4T1, we have shown that the combination of local RT with topical IMQ successfully delayed both primary tumor growth and metastases. We propose a clinical trial that translates the preclinical experience of combining topical imiquimod and local radiotherapy to the setting of metastatic breast cancer patients who also have chest wall recurrences. The strategy is that of vaccinating patients against their own tumor to generate an immune response that, if successful, can be detected outside the field of local therapies.
The specific aims are to: 1. Determine the safety and therapeutic efficacy of topical IMQ and concurrent local RT in breast cancer patients with cutaneous metastases. 2. Determine the effects of TLR7 agonist IMQ and RT on tumor-specific T cell immunity and tumor immune signature. The selection of breast cancer patients with chest wall recurrences is based on the following rationale: 1) the accessibility of the lesions to topical agent (imiquimod) and to radiotherapy;2) the ease to visually monitor local response and to perform Fine Needle Aspiration biopsies for mechanistic studies. A Phase I/II trial will be conducted to evaluate the safety of the combination of RT and IMQ, topically applied to skin metastases of breast cancer. Efficacy is measured with respect to local tumor regression as well as systemic responses (outside the field of combined therapy), as a demonstration of an effective anti-tumor immune response. Immunomonitoring will consist of an analysis of tumor-specific T cell immunity and an assessment of immune signatures in the tumor, to learn whether the proposed treatment induces tumor- specific T cell responses and generates a tumor immune signature consistent with immunological rejection. The proposed studies will create the basis for a potential paradigm shift with direct clinical implications: harnessing a novel combination to effectively immunize the patient to her own tumor, and thereby achieving a response of the systemic disease.

Public Health Relevance

Breast cancer that has recurred to the chest wall is often concomitant with visceral metastases and does not respond readily to standard therapy. In a clinical trial that tests the novel combination of two local therapies, radiotherapy (RT) and topical drug imiquimod (IMQ), we propose to generate (and monitor) an anti-tumor immune response, capable to reject and control the disease locally as well as at distant metastatic sites. This combination has shown efficacy in a mouse model of breast cancer by harnessing the immunostimulatory effects of RT and those of IMQ, a FDA approved biologic agent for topical treatment of skin tumors. In this model immunized animals also rejected lung metastases. If successful, this strategy could be translated to other metastatic tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA161891-03S1
Application #
8761378
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Song, Min-Kyung H
Project Start
2013-12-03
Project End
2015-12-02
Budget Start
2013-12-03
Budget End
2015-12-02
Support Year
3
Fiscal Year
2014
Total Cost
$206,156
Indirect Cost
$82,070
Name
New York University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Golden, Encouse B; Frances, Derek; Pellicciotta, Ilenia et al. (2014) Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology 3:e28518
Adams, Sylvia; Gray, Robert J; Demaria, Sandra et al. (2014) Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32:2959-66
Adams, Sylvia; Novik, Yelena; Oratz, Ruth et al. (2014) Clinical trial evidence of the antitumor activity of topical imiquimod for breast cancer skin metastases. J Clin Oncol 32:3204-5
Singh, Jasmeet; Novik, Yelena; Stein, Stacey et al. (2014) Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer. Breast Cancer Res 16:R32
Adams, Sylvia; Gray, Robert J; Demaria, Sandra et al. (2014) Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32:2959-67
Demaria, Sandra; Pilones, Karsten A; Vanpouille-Box, Claire et al. (2014) The optimal partnership of radiation and immunotherapy: from preclinical studies to clinical translation. Radiat Res 182:170-81
Formenti, Silvia C; Demaria, Sandra (2013) Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst 105:256-65