Innate Anti-Breast Cancer Activity of -T cells: A Novel Biological and Clinical Approach to the Treatment of Relapsed or Refractory Breast Cancer

摘要

We initially identified a specific signaling pathway which inhibits apoptosis in human -T cells. We have exploited this pathway to develop the methodologies allowing the large-scale ex vivo expansion of viable apoptosis- resistant -T cells. Importantly, we have shown that apoptosis-resistant human - T cells retain significant innate (MHC-unrestricted) cytotoxicity against a wide variety of tumor cell lines, including human breast cancer cell lines. In this project, we have focused upon testing the hypothesis that -T cells - by virtue of their innate ability to recognize and kill epithelial-derived malignancies - play an important role in regulating the initial growth or spread of breast cancer in vivo and may also be of therapeutic utility. In this report, we summarize the findings we have made during the course of this project. In both the human pre-clinical work and in the mouse models, we have made the important discovery that -T cells are severely impaired in tumor- bearing hosts (human and mouse) compared to healthy controls - this possibly limiting our ability to use patient-derived (autologous) -T cells for therapy. However, data derived from animal studies clearly show that using -T cells derived from healthy donors (syngeneic or allogeneic) offers a feasible and rationale alternative approach when patient-derived (autologous) -T cells cannot be expanded for use clinically. This represents a significant conceptual advance and is the basis for new studies.