Developing the Framework for First-in-Class Immunotherapies That Target Disseminated Tumor Cells and Prevent Breast Cancer Metastasis
Abstract
Late, distant recurrence of breast cancer is a major cause of morbidity and mortality for patients. The root of these metastases, disseminated tumor cells (DTCs), are not adequately impacted by chemotherapies. And even if they were, or could be made sensitive to chemotherapy, the patient would still be subject to all of the toxicities inherent to chemotherapy. How can we improve upon this? The ideal therapy would target the seeds of metastasis and eliminate them without affecting any other normal tissue. If such a therapy could be realized, one could envision it eventually becoming standard of care, essentially eliminating the need for chemotherapy. Immunotherapy, specifically engineered T cells, has the potential to achieve this elusive goal. But first we have to be realistic and acknowledge that there are a number of serious barriers that prevent the successful application of immunotherapies to target DTCs in breast cancer patients. The first is their rarity. DTCs are present in low frequency in organs — anywhere from 1 in 100,000, to 1 in 1,000,000 cells. And T cells directed against specific molecules expressed by DTCs are even rarer. Thus, expecting these two cell populations to interact is like expecting to win the lottery, again and again. The second is that dormant DTCs do not present molecules in a way that lets the immune system know they are foreign. So, traditional means to enhance immune function that rely on our own T cells already present in the body (e.g., vaccines, checkpoint inhibitors) may be ineffective because DTCs are invisible to them. This suggests that we need to target DTCs based on what is on their surface. But, we do not currently know what is on the surface of DTCs, or at least what distinguishes them from our normal cells. It is likely that we will need a constellation of targets to distinguish DTCs from normal cells and a means to only target these constellations in DTC-specific combinations. Can we overcome all of these barriers? It would take more than a next-generation approach; it would take a breakthrough. Making this leap is exactly what we propose to do. Specifically, we propose to engineer T cells that will overcome all of the barriers listed above. To do so, we will leverage remarkable advances in multiple fields — protein design, T cell engineering, and DTC biology — that our team has made together over the last 2 years. We will apply these advances to engineer unique chimeric antigen receptor (CAR) T cells (T cells that activate by binding molecules on the surface of cells, like an antibody) and operate via a customizable, digital series of inputs in order to activate. Once activated, these T cells will be engineered to enhance immune cell trafficking to sites harboring other, rare DTCs lying around our bodies. We will test these engineered CAR T cells in the most realistic preclinical models of dormancy and metastasis available, confirming they selectively identify DTCs and eliminate them without causing any on- or off-target toxicities elsewhere in the mouse. We believe this work will result in a true breakthrough; it will establish the framework for the first selective therapy to eradicate DTCs, which will ultimately be informed by our ongoing work to identify molecules on the surface of DTCs derived from human patients. We envision these two endeavors merging in the next 5-6 years, resulting in the development and clinical application of first-in-class immunotherapies that target DTCs and prevent metastasis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010230
Entities
People
- Stanley R Riddell
Organizations
- Fred Hutchinson Cancer Center
- United States Army