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.
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.
| Galluzzi, Lorenzo; Bravo-San Pedro, José Manuel; Demaria, Sandra et al. (2017) Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat Rev Clin Oncol 14:247-258 |
| Demaria, Sandra; Formenti, Silvia C (2016) Can abscopal effects of local radiotherapy be predicted by modeling T cell trafficking? J Immunother Cancer 4:29 |
| Kwa, Maryann; Plottel, Claudia S; Blaser, Martin J et al. (2016) The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer. J Natl Cancer Inst 108: |
| Demaria, Sandra; Coleman, C Norman; Formenti, Silvia C (2016) Radiotherapy: Changing the Game in Immunotherapy. Trends Cancer 2:286-294 |
| Demaria, Sandra; Golden, Encouse B; Formenti, Silvia C (2015) Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA Oncol 1:1325-32 |
| Vanpouille-Box, Claire; Pilones, Karsten A; Wennerberg, Erik et al. (2015) In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment. Vaccine 33:7415-7422 |
| Golden, Encouse B; Formenti, Silvia C (2015) Radiation therapy and immunotherapy: growing pains. Int J Radiat Oncol Biol Phys 91:252-4 |
| Vatner, Ralph E; Formenti, Silvia C (2015) Myeloid-derived cells in tumors: effects of radiation. Semin Radiat Oncol 25:18-27 |
| 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 |
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