Trialing Engineered T Cells to Target Dormant Disseminated Tumor Cells and Prevent Metastases
Abstract
Nearly all breast cancer deaths are due to the emergence of metastatic disease, which can occur several years after primary therapy. Our understanding of how to eradicate disseminated tumor cells (DTCs) — the root of future metastases — remains limited. No therapy has been developed that takes advantage of the therapeutic window between cancer treatment and disease recurrence by selectively targeting DTCs in order to prevent metastasis. To overcome this barrier, we have worked hard over the past 3 years to uncover mediators of DTC dormancy, with a particular emphasis on signaling that sustains DTC survival and renders DTCs resistant to chemotherapy. In research catalyzed by a Breast Cancer Research Program (BCRP) Era of Hope Scholar Award, we have discovered that quiescent DTCs are not resistant to chemotherapy because they have exited the cell cycle, but because of the microenvironment that they occupy. We identified molecules within this microenvironment on the outer surface of blood vessels that sustain DTC survival in the face of chemotherapy. Targeting these interactions in combination with chemotherapy led to the depletion of 94% of DTCs from bone marrow and substantially reduced the number of mice that experienced metastatic relapse. However, this approach still requires chemotherapy, which is something that any person diagnosed with a malignancy would avoid, if possible. The question then is how we can remove chemotherapy from the equation, while still effectively and specifically targeting DTCs. The adaptive immune system has long been recognized to provide immune surveillance and maintain tumor dormancy in animal models; therefore, immunotherapies represent a promising avenue to create the first DTC-specific therapy. Most T cell-based therapies rely on antigen presentation through major histocompatibility complexes (MHC). However, we have found that dormant DTCs downregulate MHC molecules, thereby evading efficient recognition by tumor-specific T cells. Our data also suggest that upon initiating proliferation, targeting by T cells does successfully occur, providing a mechanism to prune micrometastases as they emerge. These data suggest that either: (i) a MHC-independent mechanism is necessary to target quiescent DTCs before they emerge and/or (ii) MHC-restricted interactions between emerging DTCs and T cells occur and are necessary to prevent metastasis. Before embarking on a laborious study to isolate and profile patient DTCs to determine whether DTC-specific antigens or neoantigens exist, we will perform a head-on comparison and identify the form of T cell-based immunotherapy that can effectively target DTCs. Accordingly, here we propose to use model antigens and compare T cell receptor engineered T cells, which rely on traditional MHC-mediated antigen presentation, to chimeric antigen receptor T cells, which directly bind molecules on the surface of DTCs and do not require MHC. We will determine the mode of immunotherapy that is best at eliminating DTCs and preventing metastases. In doing so, we will establish for the first time a framework for how immunotherapy can be applied for metastasis prevention in breast cancer. Importantly, this study will also guide future studies to identify DTC antigens and/or neoantigens that we can then build engineered T cells against, thereby providing a roadmap for how we can translate what are basic studies, for now, into the clinic.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910617
Entities
People
- Cyrus M Ghajar
Organizations
- Fred Hutchinson Cancer Center
- United States Army