Graft—Versus—Breast Cancer Effect by Allogeneic Hematopoietic Stem-Cell Transplantation: A Possible New Frontier
Authors: Naoto T. Ueno, Elizabeth J. Shpall, Richard E. Champlin, Roy B. Jones
Journal: Journal of Clinical Oncology (2004)

Progress in the treatment of high-risk and metastatic breast cancer has come slowly, particularly for patients with estrogen receptor– or progesterone receptor–negative, or hormone-unresponsive tumors. Trastuzumab is an encouraging example of the exploitation of a newer mechanism of action, monoclonal antibody–based immunotherapy, to produce antitumor effects in patients with metastatic tumor. Numerous trials of tumor-targeted therapeutics are underway, but none have yet demonstrated the potential to increase the cure rate for this disease, as has the newer generation of hormonal agents. New ideas and approaches are critical to improve the treatment of this disease. In hematologic diseases, major developments in transplant therapy are occurring as the result of the application of reduced-intensity allogeneic transplantation. These programs are based on two observations. First, engraftment of allogeneic progenitor cells and lymphocytes has produced major antitumor effects in patients with chronic myelogenous leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, and lymphomas. This “allogeneic vaccine” can be given repeatedly until evidence of full donor T-cell chimerism, graft-versus-host disease (GVHD), or grafts-versus-tumor (GVT) effects occur. It remains unclear as to whether alloreactivity, lymphocyte reactivity against specific tumor antigens, or both, are the major therapeutic principles. Second, allogeneic engraftment can be produced using reduced-intensity immunosuppressive regimens. These regimens produce a low probability of visceral organ toxicity and GVHD when compared with fully myeloablative allogeneic transplantation. Thus, they are potentially applicable to broader patient populations, including older patients with major comorbid conditions. Full myeloablative allogeneic transplantation for breast cancer has been explored by several investigators; these studies have produced preliminary and indirect evidence for a graft– versus–breast cancer effect. More recently, reducedintensity allogeneic transplantation has been explored in patients with breast cancer and renal-cell carcinoma. In both settings, additional preliminary evidence for GVT has been reported. In addition, the use of cyclophosphamidebased immune modulation followed by infusion of tumorsensitized, ex vivo expanded autologous lymphocytes in melanoma patients has produced antitumor responses. Taken together, these observations demonstrate exciting leads for cellular immunotherapy of solid tumors. More generally, they raise the question of whether standard cytotoxic treatment could be followed quickly by lymphocyte infusions aimed at augmentation of tumor-specific immunoreactivity at a time at which the patient is usually immunosuppressed. In this issue of the Journal of Clinical Oncology, Bishop et al report the use of sibling-derived human leukocyte antigen–matched lymphocytes used as immunotherapy for patients with breast cancer. This carefully designed trial has several interesting features. An intensive regimen of cyclophosphamide and fludarabine was used to produce tumor control as well as to provide the immunosuppression required for engraftment of lymphocyte-depleted progenitor cells. T-cell– depleted peripheral blood progenitor cell allografts were also used, followed subsequently by planned donor lymphocyte infusions (DLIs) at intervals between 1 and 3 months post-transplantation. Finally, there was an independent assessment of antitumor effects during the first month (assigned causally to the chemotherapeutic regimen) and later responses (assigned causally to the DLI). It could be argued that the use of an immunosuppressive regimen lacking anti–breast cancer activity would have allowed the investigators to completely exclude chemotherapy as a JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 19 OCTOBER 1 2004