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Originally published as JCO Early Release 10.1200/JCO.2004.06.922 on August 16 2004 © 2004 American Society of Clinical Oncology.
Graft—Versus—Breast Cancer Effect by Allogeneic Hematopoietic Stem-Cell Transplantation: A Possible New FrontierDepartments of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, TX 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.1 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.2-5 More recently, reduced-intensity allogeneic transplantation has been explored in patients with breast cancer6,7 and renal-cell carcinoma.7-12 In both settings, additional preliminary evidence for GVT has been reported. In addition, the use of cyclophosphamide-based immune modulation followed by infusion of tumor-sensitized, ex vivo expanded autologous lymphocytes in melanoma patients has produced antitumor responses.13 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 al14 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 cause of late tumor shrinkage. This study design, however, would not allow for the delay of 1 to 3 months, which is required for the DLI to expand in vivo, resulting in antitumor effects. The patients included in this study had advanced tumor with an average of four prior treatment regimens, and most patients had liver or lung metastases. Without intensive pretransplant chemotherapy, most would have developed progressive tumor and been removed from study before any GVT effect could occur. It is notable that, even with this treatment, the two patients experiencing a partial response attributed to a DLI effect developed progressive tumor before responding. Overall, the investigators present persuasive data that the DLI produced anti–breast cancer effects as a result of multiple infusions and the withdrawal of cyclosporine immunosuppression. Further, steroid treatment of GVHD was temporally associated with tumor relapse, consistent with a steroid-induced lympholytic effect. Allogeneic transplantation is associated with life-threatening risk, expense, and GVHD-associated morbidity, which militate against any near-term use of this strategy for routine treatment of breast cancer. The novel mechanism of action of DLI, however, suggests that it may be additive or synergistic with more standard treatment strategies. Some investigators have demonstrated that preparative regimens of less intensity than those used by Bishop et al can produce successful donor engraftment without causing severe neutropenia or thrombocytopenia. Alternatively, investigators have shown that more intensive preparative regimens than those used by Bishop et al can produce successful donor engraftment and GVT effect against breast cancer by rapid achievement of 100% donor engraftment without the need for DLI.1 These techniques could be studied in patients with less advanced cancer (minimal metastatic disease or stage IV patients whose tumor can be controlled with surgery or radiation) in which short-term tumor progression is unlikely, less toxicity and GVHD morbidity will result from the treatment,1 and immunotherapy will have a more profound effect because of the lower volume of tumor. Additionally, these patients would not be expected to have rapid tumor progression, and the 2- to 4-month treatment-free interval required to allow the GVT effect to occur would be more acceptable. Finally, a deeper understanding of the cellular basis and mechanism for the GVT effect produced by both autologous and allogeneic lymphocytes will emerge from ongoing laboratory investigations. Cytotoxic treatments have always had the theoretical limitation, in that they suppress any potential for native antitumor immunity that might eradicate minimal tumor. The results of the Bishop et al study points to exciting new leads for the chemoimmunotherapy of solid tumors. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Richard E. Champlin, Berlex, Cellerant, Amgen. Research Funding: Naoto T. Ueno, Sysmex Corp. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue. REFERENCES 1. Champlin R, Khouri I, Anderlini P, et al: Nonmyeloablative preparative regimens for allogeneic hematopoietic transplantation: Biology and current indications. Oncology (Huntingt) 17:94-107, 2003
2. Eibl B, Schwaighofer H, Nachbaur D, et al: Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. Blood 88:1501-1508, 1996 3. Ueno NT, Rondon G, Mirza NQ, et al: Allogeneic peripheral blood progenitor cell transplantation for poor-risk patients with metastatic breast cancer. J Clin Oncol 16:986-993, 1998[Abstract] 4. Ben-Yosef R, Or R, Nagler A, et al: Graft-versus-tumour and graft-versus-leukaemia effect in patient with concurrent breast cancer and acute myelocytic leukaemia. Lancet 348:1242-1243, 1996[Medline] 5. Oblon DJ, Paul S, Yankee R: Allogeneic transplantation after a conditioning regimen with ifosfamide, carboplatin and etoposide (ICE). Bone Marrow Transplant 20:421-423, 1997[CrossRef][Medline]
6. Bregni M, Dodero A, Peccatori J, et al: Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer. Blood 99:4234-4236, 2002
7. Ueno NT, Cheng YC, Rondon G, et al: Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. Blood 102:3829-3836, 2003
8. Childs R, Chernoff A, Contentin N, et al: Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 343:750-758, 2000 9. Rini BI, Zimmerman TM, Gajewski TF, et al: Allogeneic peripheral blood stem cell transplantation for metastatic renal cell carcinoma. J Urol 165:1208-1209, 2001[CrossRef][Medline] 10. Pedrazzoli P, Da Prada GA, Giorgiani G, et al: Allogeneic blood stem cell transplantation after a reduced-intensity, preparative regimen: A pilot study in patients with refractory malignancies. Cancer 94:2409-2415, 2002[CrossRef][Medline]
11. Rini BI, Zimmerman T, Stadler WM, et al: Allogeneic stem-cell transplantation of renal cell cancer after nonmyeloablative chemotherapy: Feasibility, engraftment, and clinical results. J Clin Oncol 20:2017-2024, 2002 12. Hentschke P, Barkholt L, Uzunel M, et al: Low-intensity conditioning and hematopoietic stem cell transplantation in patients with renal and colon carcinoma. Bone Marrow Transplant 31:253-261, 2003[CrossRef][Medline]
13. Dudley ME, Wunderlich PF, Robbins JC, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850-854, 2002
14. Bishop MR, Fowler DH, Marchigiani D, et al: Allogenic Lymphocytes Induce Tumor Regression of Advanced Metastatic Breast Cancer. J Clin Oncol 22:3886-3892, 2004
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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