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Li R, Zhang D, Ren B, Cao S, Zhou L, Xiong Y, Sun Q, Ren X. Therapeutic effect of haploidentical peripheral blood stem cell treatment on relapsed/refractory ovarian cancer. Bull Cancer 2023; 110:285-292. [PMID: 36739242 DOI: 10.1016/j.bulcan.2022.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 02/05/2023]
Abstract
The traditional immunotherapy is limited on relapsed/refractory metastatic ovarian cancer because tumors cause immunosuppression. Since new therapeutic strategies to improve clinical outcomes for patients with relapsed/refractory metastatic ovarian carcinoma are needed, the aim of this study was to evaluate the therapeutic effect of haploidentical peripheral blood stem cells (haplo-PBSCs) adoptive treatment on relapsed/refractory ovarian cancer. Thirteen patients with advanced stage of ovarian cancer and refractory history after surgery and chemotherapy were treated with interleukin-2 activated haplo-PBSCs donated by their parents or children. Clinical outcomes including therapeutic response by measuring tumor size changes using CT scanning, CA-125 levels and survival times were evaluated. T and NK cell population in patients before and after treatment was detected by flow cytometry analysis. The median follow-up time after haplo-PBSCs adoptive treatment was 14 months. At the time of the last follow-up, the median overall survival after haplo-PBSCs adoptive treatment was 9.1 months. Ten patients (76.9%) achieved a relief of symptoms, including abdominal distention, ache, fatigue, and poor appetite. During the first 2 months after treatment, CA125 levels decreased in 10 patients (76.9%). Five patients (38.5%) had a stable disease and 1 patient (8%) had partial response. T cell population (CD3+CD4+ and CD3+CD8+) and CD3-CD16+CD56+ NK cells were increased in patients after haplo-PBSCs adoptive treatment. Our study reveals that haplo-PBSCs adoptive treatment is associated with an anti-tumor effect and increasing immune responses in patients with relapsed/refractory ovarian cancer.
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Affiliation(s)
- Runmei Li
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Dong Zhang
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Baozhu Ren
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Shui Cao
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Li Zhou
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yanjuan Xiong
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Qian Sun
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xiubao Ren
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; National Clinical Research Center for Cancer-Translational Research Center for Cell Immunotherapy, Department of Cancer Immunology and Immunotherapy, Tianjin Cancer Hospital Airport Hospital, Tianjin, China.
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Şahin U, Demirer T. Graft-versus-cancereffect and innovative approaches in thetreatment of refractory solid tumors. Turk J Med Sci 2020; 50:1697-1706. [PMID: 32178508 PMCID: PMC7672351 DOI: 10.3906/sag-1911-112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/14/2020] [Indexed: 12/23/2022] Open
Abstract
Background/aim Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been used for the treatment of various refractory solid tumors during the last two decades. After the demonstration of graft-versus-leukemia (GvL) effect in a leukemic murine model following allo-HSCT from other strains of mice, graft-versus-tumor (GvT) effect in a solid tumor after allo-HSCT has also been reported in a murine model in 1984. Several trials have reported the presence of a GvT effect in patients with various refractory solid tumors, including renal, ovarian and colon cancers, as well as soft tissue sarcomas [1]. The growing data on haploidentical transplants also indicate GvT effect in some pediatric refractory solid tumors. Novel immunotherapy-based treatment modalities aim at inducing an allo-reactivity against the metastatic solid tumor via a GvT effect. Recipient derived immune effector cells (RDICs) in the antitumor reactivity following allo-HSCT have also been considered as an emerging therapy for advanced refractory solid tumors. Conclusion This review summarizes the background, rationale, and clinical results of immune-based strategies using GvT effect for the treatment of various metastatic and refractory solid tumors, as well as innovative approaches such as haploidentical HSCT, CAR-T cell therapies and tumor infiltrating lymphocytes (TIL).
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Affiliation(s)
- Uğur Şahin
- Hematology Unit, Yenimahalle Education and Research Hospital, Yıldırım Beyazıt University, Ankara, Turkey
| | - Taner Demirer
- Department of Hematology, School of Medicine, Ankara University, Ankara, Turkey
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Wiener DC, Bravo-Iñiguez CE, Trien-Vihn Ho V, Qian X, Jaklitsch MT. Graft-Versus-Tumor Effect in Adenocarcinoma of the Lung. Ann Thorac Surg 2018; 105:e145-e147. [PMID: 29571344 DOI: 10.1016/j.athoracsur.2017.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 10/20/2017] [Accepted: 11/05/2017] [Indexed: 10/17/2022]
Abstract
Donor T cells after allogeneic hematopoietic cell transplantation can give rise to the graft-versus-tumor (GVT) effect in hematologic malignancies. GVT effect has been reported previously to cause regression of some solid tumors. However, none have reported a documented case of GVT effect leading to complete resolution of adenocarcinoma of the lung. Here, we present the case of complete regression of a pathologically proven adenocarcinoma of the lung in a patient undergoing myeloablative-matched unrelated donor peripheral blood stem cell transplantation for the treatment of acute myelogenous leukemia.
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Affiliation(s)
- Daniel C Wiener
- Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
| | | | - Vincent Trien-Vihn Ho
- Department of Adult Oncology, Center for Hematologic Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts
| | - Xiaohua Qian
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Michael T Jaklitsch
- Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts
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Risk Factors for Subsequent Central Nervous System Tumors in Pediatric Allogeneic Hematopoietic Cell Transplant: A Study from the Center for International Blood and Marrow Transplant Research (CIBMTR). Biol Blood Marrow Transplant 2017; 23:1320-1326. [PMID: 28411175 DOI: 10.1016/j.bbmt.2017.04.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 04/04/2017] [Indexed: 11/22/2022]
Abstract
Survivors of hematopoietic cell transplantation (HCT) are at risk of subsequent solid tumors, including central nervous system (CNS) tumors. The risk of CNS tumors after HCT in pediatric HCT recipients is not known. We evaluated the incidence and risk factors for CNS tumors in pediatric recipients of allogeneic HCT reported to the Center for International Blood and Marrow Transplant Research between 1976 and 2008. A case control design was used. There were no CNS tumors in the nonmalignant cohort (n = 4543) or in those undergoing HCT for solid tumors (n = 26). There were 59 CNS tumors in 8720 patients transplanted for hematologic malignancies. In comparison with the general population, pediatric HCT recipients with hematologic malignancies had a 33 times higher than expected rate of CNS tumors (95% confidence interval, 22.98 to 45.77; P < .0001). The cumulative incidence of subsequent CNS tumors was 1.29% (95% confidence interval .87 to 1.87) at 20 years after HCT. Significant risk factors in the entire cohort were having an unrelated donor (HR, 3.35; P = .0002) and CNS disease before HCT for both acute lymphoblastic leukemia (HR, 8.21; P = .0003) and acute myeloid leukemia (HR, 6.21; P = .0174). Analysis of the matched cohort showed having an unrelated donor transplant (HR, 4.79; P = .0037), CNS disease before HCT (HR, 7.67; P = .0064), and radiotherapy exposure before conditioning (HR, 3.7; P = .0234) to be significant risk factors. Chronic graft-versus-host disease was associated with a lower risk (HR, .29; P = .0143). Survivors of HCT for nonmalignant diseases did not show an increased incidence of CNS tumors, whereas survivors of hematologic malignancies have a markedly increased incidence of CNS tumors that warrants lifelong surveillance.
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Karadurmus N, Sahin U, Basgoz BB, Arpaci F, Demirer T. Review of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in solid tumors excluding breast cancer. World J Transplant 2016; 6:675-681. [PMID: 28058217 PMCID: PMC5175225 DOI: 10.5500/wjt.v6.i4.675] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 11/01/2016] [Accepted: 11/22/2016] [Indexed: 02/05/2023] Open
Abstract
Solid tumors in adults constitute a heterogeneous group of malignancy originating from various organ systems. Solid tumors are not completely curable by chemotherapy, even though some subgroups are very chemo-sensitive. Recently, oncologists have focused on the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reduced intensity conditioning (RIC) for the treatment of some refractory solid tumors. After the demonstration of allogeneic graft-versus-leukemia effect in patients with hematological malignancies who received allo-HSCT, investigators evaluated this effect in patients with refractory metastatic solid tumors. According to data from experimental animal models and preliminary clinical trials, a graft-versus-tumor (GvT) effect may also be observed in the treatment of some solid tumors (e.g., renal cell cancer, colorectal cancer, etc.) after allo-HSCT with RIC. The use of RIC regimens offers an opportunity of achieving full-donor engraftment with GvT effect, as well as, a reduced transplant-related mortality. Current literature suggests that allo-HSCT with RIC might become a choice for elderly and medically fragile patients with refractory metastatic solid tumors.
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Omazic B, Remberger M, Barkholt L, Söderdahl G, Potácová Z, Wersäll P, Ericzon BG, Mattsson J, Ringdén O. Long-Term Follow-Up of Allogeneic Hematopoietic Stem Cell Transplantation for Solid Cancer. Biol Blood Marrow Transplant 2015; 22:676-681. [PMID: 26740375 DOI: 10.1016/j.bbmt.2015.12.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 12/19/2015] [Indexed: 01/25/2023]
Abstract
We wanted to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) may result in long-term survival in patients with solid cancer. HSCT was performed in 61 patients with solid cancer: metastatic renal carcinoma (n = 22), cholangiocarcinoma (n = 17), colon carcinoma (n = 15), prostate cancer (n = 3), pancreatic adenocarcinoma (n = 3), or breast cancer (n = 1). Liver transplantation was performed for tumor debulking in 18 patients. Median age was 56 years (range, 28 to 77). Donors were either HLA-identical siblings (n = 29) or unrelated (n = 32). Conditioning was nonmyeloablative (n = 23), reduced (n = 36), or myeloablative (n = 2). Graft failure occurred in 13 patients (21%). The cumulative incidence of acute graft-versus-host disease (GVHD) of grades II to IV was 47%, and that of chronic GVHD was 32%. Treatment-related mortality was 21%. At 5 years cancer-related mortality was 63%. Currently, 6 patients are alive, 2 with renal cell carcinoma, 1 with cholangiocarcinoma, and 3 with pancreatic carcinoma. Eight-year survival was 12%. Risk factors for mortality were nonmyeloablative conditioning (HR, 2.95; P < .001), absence of chronic GVHD (HR, 3.57; P < .001), acute GVHD of grades II to IV (HR, 2.90; P = .002), and HLA-identical transplant (HR, 5.00; P = .03). With none of these risk factors, survival at 6 years was 50% (n = 6). Long-term survival can be achieved in some patients with solid cancer after HSCT.
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Affiliation(s)
- Brigitta Omazic
- Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden; Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden
| | - Mats Remberger
- Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden
| | - Lisbeth Barkholt
- Division of Therapeutic Immunology, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden
| | - Gunnar Söderdahl
- Department of Transplantation Surgery, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden
| | - Zuzana Potácová
- Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden
| | - Peter Wersäll
- Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden
| | - Bo-Göran Ericzon
- Department of Transplantation Surgery, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden
| | - Jonas Mattsson
- Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden; Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden
| | - Olle Ringdén
- Division of Therapeutic Immunology, Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden.
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Espinoza-Delgado I, Childs RW. Nonmyeloablative transplantation for solid tumors: a new frontier for allogeneic immunotherapy. Expert Rev Anticancer Ther 2014; 4:865-75. [PMID: 15485320 DOI: 10.1586/14737140.4.5.865] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The failure of conventional chemotherapy to improve survival in a large percentage of patients with advanced solid tumors has prompted the development of alternative anticancer approaches. Conventional allogeneic hematopoietic stem cell transplantation (HSCT) relies on myeloablative conditioning to eradicate the underlying disease, as well as suppress the patient's immune response, allowing engraftment of the donor's lymphohematopoietic system. Such preparative regimens are frequently associated with serious hematologic and nonhematologic toxicities, resulting in substantial morbidity and mortality. A significant curative component of allogeneic HSCT is the immune-mediated graft-versus-tumor (GVT) effect. Nonmyeloablative preparative regimens were designed to suppress host immunity to allow for sufficient engraftment of the donor immune system for the subsequent generation of GVT effects. These relatively low-dose preparative regimens are generally well tolerated and are associated with a reduction in the risk of transplant-related mortality. Nonmyeloablative HSCT provides a safer platform to explore the efficacy of allogeneic HSCT in patients with solid tumors. Initial reports have demonstrated that GVT may occur against several different solid tumors, including renal cell carcinoma, ovarian cancer, breast cancer and others. Based on these preliminary encouraging results, further exploration of nonmyeloablative HSCT for solid tumors is clearly warranted. The development of strategies to decrease graft-versus-host disease while enhancing post-transplant antitumor immunity will hopefully be forthcoming in the near future.
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Affiliation(s)
- Igor Espinoza-Delgado
- National Institute on Aging, Section of Hematology-Oncology, 5600 Nathan Shock Drive, Room 4C10, Baltimore, MD 21224, USA.
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Roigas J, Johannsen M, Ringsdorf M, Massenkeil G. Allogeneic stem cell transplantation for patients with metastatic renal cell carcinoma. Expert Rev Anticancer Ther 2014; 6:1449-58. [PMID: 17069529 DOI: 10.1586/14737140.6.10.1449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Allogeneic stem cell transplantation and donor lymphocyte infusions are currently under clinical investigation as an innovative therapeutic option for patients with metastatic renal cell carcinoma. A variety of trials have proven the clinical efficacy of allogeneic stem cell transplantation using reduced-intensity conditioning protocols and donor lymphocyte infusions, as demonstrated by the induction of objective remissions in metastatic renal cell carcinoma patients. However, despite clinical remissions, reduced-intensity conditioning protocols and donor lymphocyte infusions were associated with a high treatment-related mortality rate of approximately 17%. The disproportion between clinical efficacy and treatment-related mortality may mainly be caused by the selection of patients that had often been heavily pretreated, with a large tumor burden and rapidly progressing tumors. The improvement of efficacy with the preservation of a powerful graft-versus-tumor effect while reducing the toxicity, is the major experimental and clinical challenge of allogeneic stem cell transplantation in the treatment of metastatic renal cancer and other solid tumors. Recently, there has been a revolutionary development of molecular-targeted agents in metastatic renal cancer. These inhibitors of angiogenesis and signal-transduction pathways have demonstrated clinical efficacy and significant survival prolongation in the first- and second-line settings, while causing moderate toxicity. Some of these agents have already been approved by the US FDA and will probably replace standard cytokines, such as interferon-alpha2 and interleukin-2, in metastatic renal cancer. In the context of these innovative clinical developments, allogeneic stem cell transplantation clearly has to be regarded an investigational clinical treatment approach. Therefore, patients should only be treated at centers that are experienced in clinical trials, and patient selection remains a critical factor for a successful transplant procedure.
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Affiliation(s)
- Jan Roigas
- Charité-Universitätsmedizin Berlin, Department of Urology, Campus Mitte, Charitéplatz 1, D-10117 Berlin, Germany.
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Blaise D, Mohty M, Faucher C, Olive D, Chabannon C. Current update on reduced intensity regimens for allogeneic stem cell transplantation. Hematology 2013; 10 Suppl 1:64-5. [PMID: 16188639 DOI: 10.1080/10245330512331389971] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Affiliation(s)
- Didier Blaise
- Institut Paoli-Calmettes, 232 Boulevard de ste. Marguerite, 13273, Marseille, Cedex, France
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Carvallo C, Childs R. Nonmyeloablative stem cell transplantation as immunotherapy for kidney cancer and other metastatic solid tumors. Cytotechnology 2011; 41:197-206. [PMID: 19002956 DOI: 10.1023/a:1024839225920] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Over the past few decades, great strides have been made to advance the field of allogeneic hematopoietic stem cell transplantation. The donor immune mediated graft-vs-tumor effect that follows the procedure is now widely accepted as the most effective form cancer immunotherapy available for patients with a variety of advanced hematological malignancies. Recognition that a transplanted immune system could cure patients with treatment refractory leukemia led to the development of ;low-intensity' conditioning regimens, which have improved the safety of the procedure and broadened the application of allogeneic immunotherapy to a growing list of neoplastic diseases. Here we discuss the investigational use of allogeneic transplantation as immunotherapy for patients with metastatic, treatment-refractory solid tumors.
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Affiliation(s)
- Cristian Carvallo
- Urologic Oncology Branch, National Cancer Institute, Hematology Branch, National Heart Lung and Blood Institute, National Institutes for Health, Bethesda, MD, U.S.A
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Abstract
Cancer immunotherapy consists of approaches that modify the host immune system, and/or the utilization of components of the immune system, as cancer treatment. During the past 25 years, 17 immunologic products have received regulatory approval based on anticancer activity as single agents and/or in combination with chemotherapy. These include the nonspecific immune stimulants BCG and levamisole; the cytokines interferon-α and interleukin-2; the monoclonal antibodies rituximab, ofatumumab, alemtuzumab, trastuzumab, bevacizumab, cetuximab, and panitumumab; the radiolabeled antibodies Y-90 ibritumomab tiuxetan and I-131 tositumomab; the immunotoxins denileukin diftitox and gemtuzumab ozogamicin; nonmyeloablative allogeneic transplants with donor lymphocyte infusions; and the anti-prostate cancer cell-based therapy sipuleucel-T. All but two of these products are still regularly used to treat various B- and T-cell malignancies, and numerous solid tumors, including breast, lung, colorectal, prostate, melanoma, kidney, glioblastoma, bladder, and head and neck. Positive randomized trials have recently been reported for idiotype vaccines in lymphoma and a peptide vaccine in melanoma. The anti-CTLA-4 monoclonal antibody ipilumumab, which blocks regulatory T-cells, is expected to receive regulatory approval in the near future, based on a randomized trial in melanoma. As the fourth modality of cancer treatment, biotherapy/immunotherapy is an increasingly important component of the anticancer armamentarium.
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Affiliation(s)
- Robert O Dillman
- Hoag Cancer Institute of Hoag Hospital , Newport Beach, California 92658, USA.
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Takeuchi A, Eto M, Yamada H, Tatsugami K, Naito S, Yoshikai Y. A reduction of recipient regulatory T cells by cyclophosphamide contributes to an anti-tumor effect of nonmyeloablative allogeneic stem cell transplantation in mice. Int J Cancer 2011; 130:365-76. [DOI: 10.1002/ijc.26009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Accepted: 01/10/2011] [Indexed: 01/01/2023]
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Morse MA, Secord AA, Blackwell K, Hobeika AC, Sinnathamby G, Osada T, Hafner J, Philip M, Clay TM, Lyerly HK, Philip R. MHC class I-presented tumor antigens identified in ovarian cancer by immunoproteomic analysis are targets for T-cell responses against breast and ovarian cancer. Clin Cancer Res 2011; 17:3408-19. [PMID: 21300761 DOI: 10.1158/1078-0432.ccr-10-2614] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The purpose of this study is to test whether peptide epitopes chosen from among those naturally processed and overpresented within MHC molecules by malignant, but not normal cells, when formulated into cancer vaccines, could activate antitumor T-cell responses in humans. EXPERIMENTAL DESIGN Mixtures of human leukocyte antigen A2 (HLA-A2)-binding ovarian cancer-associated peptides were used to activate naive T cells to generate antigen-specific T cells that could recognize ovarian and breast cancers in vitro. Combinations of these peptides (0.3 mg of each peptide or 1 mg of each peptide) were formulated into vaccines in conjunction with Montanide ISA-51 and granulocyte monocyte colony stimulating factor which were used to vaccinate patients with ovarian and breast cancer without evidence of clinical disease in parallel pilot clinical trials. RESULTS T cells specific for individual peptides could be generated in vitro by using mixtures of peptides, and these T cells recognized ovarian and breast cancers but not nonmalignant cells. Patient vaccinations were well tolerated with the exception of local erythema and induration at the injection site. Nine of the 14 vaccinated patients responded immunologically to their vaccine by inducing peptide-specific T-cell responses that were capable of recognizing HLA-matched breast and ovarian cancer cells. CONCLUSION Mixtures of specific peptides identified as naturally presented on cancer cells and capable of activating tumor-specific T cells in vitro also initiate or augment immune responses toward solid tumors in cancer patients.
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Affiliation(s)
- Michael A Morse
- Department of Medicine, Duke University Medical Center, Durham, North Carolina 27410, USA.
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Lodi D, Iannitti T, Palmieri B. Stem cells in clinical practice: applications and warnings. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:9. [PMID: 21241480 PMCID: PMC3033847 DOI: 10.1186/1756-9966-30-9] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 01/17/2011] [Indexed: 12/11/2022]
Abstract
Stem cells are a relevant source of information about cellular differentiation, molecular processes and tissue homeostasis, but also one of the most putative biological tools to treat degenerative diseases. This review focuses on human stem cells clinical and experimental applications. Our aim is to take a correct view of the available stem cell subtypes and their rational use in the medical area, with a specific focus on their therapeutic benefits and side effects. We have reviewed the main clinical trials dividing them basing on their clinical applications, and taking into account the ethical issue associated with the stem cell therapy.
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Affiliation(s)
- Daniele Lodi
- Department of Nephrology, Dialysis and Transplantation, University of Modena and Reggio Emilia Medical School, Modena, Italy
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De Somer L, Sprangers B, Fevery S, Rutgeerts O, Lenaerts C, Boon L, Waer M, Billiau AD. Recipient lymphocyte infusion in MHC-matched bone marrow chimeras induces a limited lymphohematopoietic host-versus-graft reactivity but a significant antileukemic effect mediated by CD8+ T cells and natural killer cells. Haematologica 2010; 96:424-31. [PMID: 21109687 DOI: 10.3324/haematol.2010.035329] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Challenge of MHC-mismatched murine bone marrow chimeras with recipient-type lymphocytes (recipient lymphocyte infusion) produces antileukemic responses in association with rejection of donor chimerism. In contrast, MHC-matched chimeras resist eradication of donor chimerism by recipient lymphocyte infusion. Here, we investigated lymphohematopoietic host-versus-graft reactivity and antileukemic responses in the MHC-matched setting, which is reminiscent of the majority of clinical transplants. DESIGN AND METHODS We challenged C3H→AKR radiation chimeras with AKR-type splenocytes (i.e. recipient lymphocyte infusion) and BW5147.3 leukemia cells. We studied the kinetics of chimerism using flowcytometry and the mechanisms involved in antileukemic effects using in vivo antibody-mediated depletion of CD8(+) T and NK cells, and intracellular cytokine staining. RESULTS Whereas control chimeras showed progressive evolution towards high-level donor T-cell chimerism, recipient lymphocyte infusion chimeras showed a limited reduction of donor chimerism with delayed onset and long-term preservation of lower-level mixed chimerism. Recipient lymphocyte infusion chimeras nevertheless showed a significant survival benefit after leukemia challenge. In vivo antibody-mediated depletion experiments showed that both CD8(+) T cells and NK cells contribute to the antileukemic effect. Consistent with a role for NK cells, the proportion of IFN-γ producing NK cells in recipient lymphocyte infusion chimeras was significantly higher than in control chimeras. CONCLUSIONS In the MHC-matched setting, recipient lymphocyte infusion elicits lymphohematopoietic host-versus-graft reactivity that is limited but sufficient to provide an antileukemic effect, and this is dependent on CD8(+) T cells and NK cells. The data indicate that NK cells are activated as a bystander phenomenon during lymphohematopoietic T-cell alloreactivity and thus support a novel type of NK involvement in anti-tumor responses after post-transplant adoptive cell therapy.
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Affiliation(s)
- Lien De Somer
- Laboratory of Experimental Transplantation, University of Leuven, Belgium
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16
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Zhang Y, Hosaka N, Cui Y, Shi M, Ikehara S. Effects of allogeneic hematopoietic stem cell transplantation plus thymus transplantation on malignant tumors: comparison between fetal, newborn, and adult mice. Stem Cells Dev 2010; 20:599-607. [PMID: 20672991 DOI: 10.1089/scd.2010.0230] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We have recently shown that allogeneic intrabone marrow-bone marrow transplantation + adult thymus transplantation (TT) is effective for hosts with malignant tumors. However, since thymic and hematopoietic cell functions differ with age, the most effective age for such intervention needed to be determined. We performed hematopoietic stem cell transplantation (HSCT) using the intrabone marrow method with or without TT from fetal, newborn, and adult B6 mice (H-2(b)) into BALB/c mice (H-2(d)) bearing Meth-A sarcoma (H-2(d)). The mice treated with all types of HSCT + TT showed more pronounced regression and longer survival than those treated with HSCT alone in all age groups. Those treated with HSCT + TT showed increased numbers of CD4(+) and CD8(+) T cells but decreased numbers of Gr-1/Mac-1 myeloid suppressor cells and decreased percentages of FoxP3 cells in CD4(+) T cells, compared with those treated with HSCT alone. In all mice, those treated with fetal liver cell (as fetal HSCs) transplantation + fetal TT or with newborn liver cell (as newborn HSCs) transplantation (NLT) + newborn TT (NTT) showed the most regression, and the latter showed the longest survival. The number of Gr-1/Mac-1 cells was the lowest, whereas the percentage of CD62L(-)CD44(+) effector memory T cells and the production of interferon γ (IFN-γ) were highest in the mice treated with NLT + NTT. These findings indicate that, at any age, HSCT + TT is more effective against cancer than HSCT alone and that NLT + NTT is most effective.
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Affiliation(s)
- Yuming Zhang
- First Department of Pathology, Kansai Medical University, Osaka, Japan
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Bay JO, Cabrespine-Faugeras A, Tabrizi R, Blaise D, Viens P, Ehninger G, Bornhauser M, Slavin S, Rosti G, Peccatori J, Demirer T, Bregni M. Allogeneic hematopoietic stem cell transplantation in ovarian cancer-the EBMT experience. Int J Cancer 2010; 127:1446-52. [PMID: 20049839 DOI: 10.1002/ijc.25149] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Although preliminary results suggest that allogeneic hematopoietic stem cell transplantation (allo HCT) for ovarian cancer (OC) is a feasible procedure, the low patient number in previous studies had limited ability to evaluate the true benefit of allo HCT in OC. This retrospective multicenter study included 30 patients with OC allografted between 1995 and 2005 to determine the outcome of patients with OC treated with allo HCT. Prior to allo HCT, patients were in complete response (n = 1), partial response (n = 7), stable disease (n = 11) or had progressive disease (n = 13). An objective response (OR) was observed in 50% (95% CI, 33-67) of patients. Three patients of responding patients had an objective response following the development of acute graft-versus-host disease (aGvHD). The cumulative incidence of chronic GvHD (cGVHD) was 34% (95% CI, 18-50). Transplant relative mortality rates were 7 and 20% on day 100 and 1 year, respectively. With a median follow-up of 74.5 months (range 16-148), median progression free survival (PFS) was 6 months and median overall survival (OS) was 10.4 months. Patients who developed cGvHD following allo HCT had a significant OS improvement compared to those who did not (17.6 months vs. 6.5 months, p = 0.042). However, PFS was not similarly significantly improved in patients who developed cGvHD (12 months versus 3.7 months, p = 0.81). Allo HCT in OC may lead to graft-versus-OC effects. Their clinical relevance remains to be shown.
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Affiliation(s)
- Jacques-Olivier Bay
- Cellular Therapy and Clinic Hematology Unit, Hôtel-Dieu, Clermont-Ferrand, France.
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Kawakami T, Takimoto M, Soma Y. Late appearance of an acute graft-vs.-host disease reaction subsequent to a graft-vs.-tumor effect induced by bone marrow transplantation in a refractory ovarian carcinoma patient. Int J Dermatol 2010; 49:308-10. [PMID: 20465671 DOI: 10.1111/j.1365-4632.2009.04261.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Tamihiro Kawakami
- Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
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Abstract
Since the 1950s, the overall survival of children with cancer has gone from almost zero to approaching 80%. Although there have been notable successes in treating solid tumors such as Wilms tumor, some childhood solid tumors have continued to elude effective therapy. With the use of megatherapy techniques such as tandem transplantation, dose escalation has been pushed to the edge of dose-limiting toxicities, and any further improvements in event-free survival will have to be achieved through novel therapeutic approaches. This article reviews the status of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for many pediatric solid tumor types. Most of the clinical experience in transplant for pediatric solid tumors is in the autologous setting, so some general principles of autologous HSCT are reviewed. The article then examines HSCT for diseases such as Hodgkin disease, Ewing sarcoma, and neuroblastoma, and the future of cell-based therapies by considering some experimental approaches to cell therapies.
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Abstract
During the past three decades, allogeneic stem cell transplantation (ASCT) has developed from being an experimental therapy in patients with endstage leukemia into a well-established therapy in patients with a range of disorders of the immunohematopoietic system. Graft-versus-host disease (GVHD), acute or chronic, attacking host tissue is a major threat. However, donor immunocompetent T cells have a potent graft-versus-leukemia effect. A combination of calcineurin inhibitors and methotrexate is the standard therapy to prevent GVHD. Modulation of the immunosuppressive regimen may induce mild acute and mild chronic GVHD, reduce the risk of relapse, and improve long-term survival. Natural killer cells also play a role in this context. Killer cell immunoglobulin-like receptor incompatibility between recipient and donor may reduce the risk of relapse in patients with myeloid leukemia. Relapse of leukemia is a major cause of death after ASCT. Minimal residual disease and recipient leukemia lineage-specific chimerism are sensitive techniques for early detection of leukemic relapse. Donor lymphocyte infusions can enhance the antitumor effect, especially for patients with molecular relapse. The allogeneic graft-versus-cancer effect has been demonstrated in patients with metastatic breast, renal, colorectal, ovarian, prostatic, and pancreatic carcinoma. Mesenchymal stem cells have immunomodulatory properties and may be used for immunomodulation of GVHD and tissue repair. All things considered, the future looks promising for ASCT.
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Affiliation(s)
- Olle Ringdén
- Division of Clinical Immunology, Karolinska Institutet, Karolinska University, Hospital, Huddinge, SE-141 86 Stockholm, Sweden
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Ringdén O, Karlsson H, Olsson R, Omazic B, Uhlin M. The allogeneic graft-versus-cancer effect. Br J Haematol 2009; 147:614-33. [PMID: 19735262 DOI: 10.1111/j.1365-2141.2009.07886.x] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Allogeneic haematological stem cell transplantation (HSCT) has developed into immunotherapy. Donor CD4+, CD8+ and natural killer (NK) cells have been reported to mediate graft-versus-leukaemia (GVL) effects, using Fas-dependent killing and perforin degranulation to eradicate malignant cells. Cytokines, such as interleukin-2, interferon-gamma and tumour necrosis factor-alpha potentiate the GVL effect. Post-transplant adoptive therapy of cytotoxic T-cells (CTL) against leukaemia-specific antigens, minor histocompatibility antigens, or T-cell receptor genes may constitute successful approaches to induce anti-tumour effects. Clinically, a significant GVL effect is induced by chronic rather than acute graft-versus-host disease (GVHD). An anti-tumour effect has also been reported for myeloma, lymphoma and solid tumours. Reduced intensity conditioning enables HSCT in older and disabled patients and relies on the graft-versus-tumour effect. Donor lymphocyte infusions promote the GVL effect and can be given as escalating doses with response monitored by minimal residual disease. A high CD34+ cell dose of peripheral blood stem cells increases GVL. There is a balance between effective immunosuppression, low incidence of GVHD and relapse. For instance, T-cell depletion of the graft increases the risk of relapse. This paper reviews the current knowledge in graft-versus-cancer effects. Future directions, such as immunotherapy using leukaemia-specific CTLs, allo-depleted T-cells and suicide gene manipulated T-cells, are presented.
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Affiliation(s)
- Olle Ringdén
- Centre for Allogeneic Stem Cell Transplantation and Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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Kamiryo Y, Eto M, Yamada H, Yajima T, Harano M, Takeuchi A, Tatsugami K, Hamaguchi M, Naito S, Yoshikai Y. Donor CD4 T cells are critical in allogeneic stem cell transplantation against murine solid tumor. Cancer Res 2009; 69:5151-8. [PMID: 19491277 DOI: 10.1158/0008-5472.can-08-2517] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Nonmyeloablative allogeneic stem cell transplantation (SCT) has been used for various malignancies, although detailed mechanisms of antitumor effects remain unclear. We showed that a nonmyeloablative allogeneic SCT regimen, which consists of mixed chimerism induced by an injection of donor spleen and bone marrow cells followed by cyclophosphamide treatment and a donor lymphocyte infusion (DLI), exerted antitumor effects on established murine bladder tumor, MBT-2. An expansion of donor CD4 T cells accompanied by transient but vigorous IFN-gamma production was detected shortly after DLI. In vivo neutralization of IFN-gamma or depletion of CD4 T cells from DLI abolished the antitumor effects, indicating an indispensable role of donor CD4 T cells producing IFN-gamma. Donor as well as host CD8 T cells accumulated in the tumor region with time. Importantly, depletion of CD8 T cells from DLI did not reverse the suppression of tumor growth, indicating that CD4 T cells play a more essential role in mediating early antitumor effects. Furthermore, tumor-specific response of host CD8 T cells was suggested. These results not only provide the first evidence of nonmyeloablative allogeneic SCT for the treatment of bladder tumor but also elucidate detailed mechanisms of antitumor effects provoked by DLI.
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Affiliation(s)
- Yoriyuki Kamiryo
- Division of Host Defense, Research Center for Prevention of Infectious Disease, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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Improved survival and preserved antiviral responses after combination therapy with daclizumab and infliximab in steroid-refractory graft-versus-host disease. J Pediatr Hematol Oncol 2009; 31:456-61. [PMID: 19648797 DOI: 10.1097/mph.0b013e31819daf60] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Patients with steroid-refractory acute graft-versus-host disease (aGVHD) have a high mortality due to infections and progressive aGVHD. We investigated the combined use of 2 monoclonal antibodies (Mabs), daclizumab and infliximab in steroid-refractory aGVHD to selectively control the proliferation of alloreactive T cells and to target 2 different points in the cytokine cascade responsible for this complication. Twenty-two consecutive children who developed 25 episodes of steroid-refractory aGVHD after hematopoietic stem cell transplantation at our institution between September 2002 and July 2007 were treated with combination Mab therapy. Nineteen out of 22 patients responded, with a median response time of 15 days from the start of Mab therapy. Seven patients developed recurrent GVHD, 3 of whom received a second course of Mabs. Seven out of 22 patients developed chronic GVHD. There were 13 episodes of viral reactivations, 4 patients developed probable fungal infections. Impressively, however, there were only 2 infection-related deaths. Interferon-gamma enzyme-linked immunospot assays on selected patients showed preservation of responses to cytomegalovirus and Epstein-Barr virus and the ability to mount de novo responses to these pathogens after Mab therapy. At a median follow-up of 31 months, 15 of the 22 (68%) children are alive. The causes of death were progressive GVHD (3), obliterative bronchiolitis (2), and sepsis (2). These data suggest that combination treatment with daclizumab and infliximab is an effective therapeutic option for patients with steroid-refractory GVHD and seems to be associated with a low infection-related mortality compared with previous therapies.
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24
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Ingersoll SB, Patel S, Caballero L, Ahmad S, Edwards D, Holloway RW, Edwards JR. Synergistic cytotoxicity of interferonalpha-2b and interleukin-2 in combination with PBMC against ovarian cancer: development of an experimental model for cellular therapy. Gynecol Oncol 2008; 112:192-8. [PMID: 18995891 DOI: 10.1016/j.ygyno.2008.09.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2008] [Revised: 09/11/2008] [Accepted: 09/13/2008] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Current therapies for ovarian cancer (OC) patients have a modest impact on long-term survival justifying the need for novel treatment strategies. We developed in vitro and in vivo systems to test the effects of cytokines in combination with peripheral blood mononuclear cells (PBMC) on OC cells. METHODS Two OC cell-lines were transfected with a plasmid encoding Red Fluorescent Protein (SKOV3-RFP and CAR3-RFP). Proliferation of these lines in the presence of cytokines alone and in combination was assayed. Cytotoxicity of SKOV3-RFP cells mediated by PBMC and cytokines was determined by lactate dehydrogenase release. Mice were injected intraperitoneally (IP) with SKOV3-RFP cells; solid tumor and ascitic fluid were collected, analyzed, and cell lines were established. Tumor-derived cell lines were re-injected to produce a more tumorigenic line. RESULTS IFNalpha-2b showed an inhibitory effect on OC cell proliferation. The remaining cytokines, either alone or in combination, showed no significant effect. PBMC in combination with IL-2 showed clear dose-dependent cytotoxicity against SKOV3-RFP. IFNalpha-2b had a synergistic effect with IL-2 and PBMC increasing the cytotoxicity by an average of 20%. Using an animal model, SKOV3-RFP cells continue to express RFP when harvested from the peritoneum and are more tumorigenic when re-injected into mice. CONCLUSION These observations justify the use of IL-2, IFNalpha-2b, and PBMC in a xenograph animal model of OC to determine if combination cytokine and cellular therapy has an anti-tumor effect in vivo. This approach may prove useful as an in vivo system of IP cytokines administered in combination with cellular therapy.
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Affiliation(s)
- Susan B Ingersoll
- Cellular Therapy Laboratory, Florida Hospital Cancer Institute, Orlando, FL 32804, USA.
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25
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Adoptive transfer of allogeneic tumor-specific T cells mediates effective regression of large tumors across major histocompatibility barriers. Blood 2008; 112:4746-54. [PMID: 18799724 DOI: 10.1182/blood-2008-07-169797] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Graft-versus-tumor effects can be achieved after allogeneic bone marrow transplantation in patients with malignancies of the kidney or hematopoietic system but are often accompanied by severe graft-versus-host-disease (GVHD). We sought to maximize graft-versus-tumor while minimizing GVHD using tumor-specific allogeneic effector T cells rather than open-repertoire T cells. We transferred allogeneic CD8(+) pmel-1 or CD4(+) TRP-1 T cells specific for the melanoma-associated antigens, glycoprotein 100 (gp100) and tyrosinase-related protein-1 (TRP-1), respectively, into B16-melanoma-bearing mice. Mice receiving a preparative regimen of nonmyeloablating (5 Gy) total body irradiation experienced the rapid rejection of tumor-specific allogeneic lymphocytes with no impact on tumor growth. However, when mice were given more intense total body irradiation conditioning regimens combined with autologous bone marrow transplantation, adoptively transferred allogeneic tumor-specific T lymphocytes persisted at detectable levels for several weeks and mediated significant regression of large, vascularized tumors. We found that the risk of GVHD was low when tumor-specific T cells were transferred and significant toxicity was observed only when substantial numbers of open repertoire allogeneic naive T cells were mixed with the tumor-specific lymphocytes. Taken together, these data indicate that the use of tumor-specific allogeneic CD8(+) T cells or CD4(+) can result in significant antitumor effects in the absence of measurable GVHD.
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Har-Noy M, Zeira M, Weiss L, Slavin S. Completely mismatched allogeneic CD3/CD28 cross-linked Th1 memory cells elicit anti-leukemia effects in unconditioned hosts without GVHD toxicity. Leuk Res 2008; 32:1903-13. [PMID: 18565579 DOI: 10.1016/j.leukres.2008.05.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2008] [Revised: 05/06/2008] [Accepted: 05/12/2008] [Indexed: 12/27/2022]
Abstract
Fully allogeneic CD3/CD28 cross-linked Th1 cells were found to elicit host-mediated anti-leukemia effects without GVHD toxicity. Mice inoculated with a lethal dose of BCL1 leukemia demonstrated significantly enhanced survival after allogeneic Th1 treatment. Cure rates of 12.5% with a single allogeneic cell infusion and 31.25% with multiple infusions were demonstrated. Cured mice were able to reject rechallenge with a lethal dose of tumor without further treatment. These results suggest that use of intentionally mis-matched, Th1 memory cells infused with cross-linked CD3/CD28 could represent a novel clinical approach to eliciting potent anti-tumor effects in patients without conditioning and without GVHD toxicity.
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Affiliation(s)
- M Har-Noy
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
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27
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Attar R, Attar E. Use of hematopoietic stem cells in obstetrics and gynecology. Transfus Apher Sci 2008; 38:245-51. [DOI: 10.1016/j.transci.2008.04.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Transplantation of allogeneic hematopoietic stem cells: an emerging treatment modality for solid tumors. ACTA ACUST UNITED AC 2008; 5:256-67. [PMID: 18398414 DOI: 10.1038/ncponc1104] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2007] [Accepted: 12/11/2007] [Indexed: 01/15/2023]
Abstract
Allogeneic transplantation of hematopoietic cells from an HLA-compatible donor has been used to treat hematologic malignancies. Allogeneic transplantation not only replaces the marrow affected by the disease, but exerts an immune graft-versus-tumor (GVT) effect mediated by donor lymphocytes. The development of nonmyeloablative conditioning regimens before allogeneic transplantation has allowed this therapy to be used in elderly and disabled patients. An allogeneic GVT effect is observed in a proportion of patients with renal, breast, colorectal, ovarian, and pancreatic cancer treated with allogeneic transplantation. In general, the tumor response is associated with the development of acute and chronic graft-versus-host disease. Further improvements will depend on the identification of the antigen targets of GVT, and on reduction of the toxicity of the procedure. Targeted therapies may complement the immune effect of allogeneic transplantation. We present updated results from the literature and data recently placed on file at the European Bone Marrow Transplantation Solid Tumors Working Party.
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29
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Yu J, Ren X, Cao S, Li H, Hao X. Beneficial effects of fetal–maternal microchimerism on the activated haplo-identical peripheral blood stem cell treatment for cancer. Cytotherapy 2008; 10:331-9. [DOI: 10.1080/14653240802061146] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Blaise D, Viens P. Immunothérapie allogénique des tumeurs solides: état actuel et futur. ONCOLOGIE 2007. [DOI: 10.1007/s10269-007-0787-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Gottlieb DJ, Micklethwaite K, Bradstock KF, Li YCH. Rapid expansion of tumor-reactive cells from HLA-matched siblings for adoptive immunotherapy of melanoma. Cytotherapy 2007; 9:133-43. [PMID: 17453965 DOI: 10.1080/14653240601145231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND Administration of expanded tumor-infiltrating lymphocytes in association with lymphodepleting chemotherapy is effective in some patients with advanced malignant melanoma. However, obtaining lymphocytes and subsequent expansion is labor intensive, making it impractical for broad clinical application. Allogeneic transplantation may have anti-melanoma efficacy because of a graft vs. tumor effect. The disappointing tumor control observed post-transplant suggests that adoptive immunotherapy using melanoma-reactive cells will be essential for sustained responses. METHODS Melanoma cell lines were grown from two patients with advanced disease. High-level CD80 and CD86 expression was obtained in the tumor lines using a retroviral vector for gene transfer. Transduced melanoma and controls were cultured with mononuclear cells from HLA-identical sibling donors. RESULTS Expression of CD80 and CD86, particularly the former, promoted marked expansion of lymphocytes from HLA-matched sibling donors. Proliferation of up to 300-fold after 4 weeks of culture was observed. Lymphocytes from cultures stimulated with CD80 demonstrated cytotoxicity against recipient-untransfected melanoma (45-75% specific lysis at an E:T ratio of 50:1). Although expanded lymphocytes were predominantly CD4(+), cytotoxicity was greatest in the numerically smaller CD8(+) subpopulation. Both CD4(+) and CD8(+) cells secreted IFN-gamma (but not IL-4) on exposure to untransduced stimulator melanoma cells. DISCUSSION Our strategy generates a large number of melanoma-reactive lymphocytes from HLA-identical siblings using a 4-week culture strategy. Lymphocytes expanded in this way offer an alternative to tumor-infiltrating lymphocytes for allogeneic cellular immunotherapy after stem cell transplantation in young patients.
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Affiliation(s)
- D J Gottlieb
- Leukaemia Research Laboratory, Westmead Hospital, University of Sydney, Sydney, Australia.
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32
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Busca A, Novarino A, de Fabritiis P, Picardi A, Zeuli M, Locatelli F, Bertetto O, Falda M. Nonmyeloablative allogeneic blood stem cell transplantation in patients with metastatic solid tumors. ACTA ACUST UNITED AC 2007; 11:171-7. [PMID: 17325957 DOI: 10.1080/10245330600775253] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
BACKGROUND The aim of the study was to evaluate the feasibility and efficacy of a non-myeloablative regimen to achieve complete donor chimerism after stem cell transplantation (SCT) in patients with metastatic solid tumors. PATIENTS AND METHODS Seven patients with renal cell carcinoma (RCC), 3 with colorectal carcinoma and 1 with soft tissue sarcoma received an allogeneic SCT after fludarabine (90 mg/m2) and TBI 200 cGy. RESULTS At day 30, median donor chimerism was 94%. Regression of tumor metastases has been observed in 1 patient with RCC. Overall, 8 patients (73%) died from progressive disease (median progression-free survival 3.7 months) and 1 (9%) from treatment-related complications; 2 patients were alive 152 and 862 days after transplantation. CONCLUSIONS Our preliminary results suggest that non-myeloablative SCT for metastatic solid tumors is feasible, although may lead to durable responses in a minority of patients. Careful patient selection seems to be mandatory in this transplant setting.
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Affiliation(s)
- Alessandro Busca
- Bone Marrow Transplant Unit, Ospedale San Giovanni Battista, Turin, Italy.
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Shapira MY, Hai AA, Tsirigotis P, Resnick IB, Or R, Slavin S. Hematopoietic stem cell therapy for malignant diseases. Ann Med 2007; 39:465-73. [PMID: 17852026 DOI: 10.1080/07853890701472323] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Allogeneic bone marrow or blood stem cell transplantation (SCT) has changed its face in the last two decades. The introduction of nonmyeloablative conditioning regimens has reduced procedure toxicity and allowed the application of SCT in patients and conditions in which SCT was not offered in the past. In this review we will summarize the changes and accomplishments achieved in the past years in the field of stem cell transplantation for malignant disorders.
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Affiliation(s)
- Michael Y Shapira
- Department of Bone Marrow Transplantation & Cancer Immunotherapy, Hadassah University Hospital, Jerusalem 91120, Israel.
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Ohashi M, Kobayashi A, Hara H, Miura Y, Yoshida K, Kushida M, Ikarashi Y, Mandai M, Kitajima M, Yoshida T, Aoki K. Allogeneic MHC gene transfer enhances antitumor activity of allogeneic hematopoietic stem cell transplantation without exacerbating graft-versus-host disease. Clin Cancer Res 2006; 12:2208-15. [PMID: 16609036 DOI: 10.1158/1078-0432.ccr-05-2657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Enhancement of the specific antitumor activity of allogeneic hematopoietic stem cell transplantation (alloHSCT) against solid cancers is a major issue in the clinical oncology. In this study, we examined whether intratumoral allogeneic MHC (alloMHC) gene transfer can enhance the recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. In minor histocompatibility antigen-mismatched alloHSCT (DBA/2-->BALB/c: H-2(d)) recipients, alloMHC gene (H-2K(b)) was transduced directly into a s.c. tumor of CT26 colon cancer cells. Because CT26 cells have an aggressive tumorigenicity in syngeneic BALB/c mice, an H-2K(b) gene transfer provides only a limited antitumor effect after syngeneic (BALB/c-->BALB/c) HSCT. By contrast, the H-2K(b) gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors without gene transduction. In vitro cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to the H-2K(b) gene transfer. Graft-versus-host disease was not exacerbated serologically or clinically in the treated mice, demonstrating that alloMHC gene transfer enhances the antitumor effects of alloHSCT without exacerbating graft-versus-host disease. This combination strategy has important implications for the development of therapies for human solid cancers.
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Affiliation(s)
- Masaki Ohashi
- Genetics Division, National Cancer Center Research Institute, Department of Surgery, Keio University School of Medicine Tokyo, Japan
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Gottlieb DJ, Li YC, Lionello I, Tanzarella S, Marangolo M, Bradstock KF, Russo V, Traversari C. Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma. Br J Cancer 2006; 95:181-8. [PMID: 16819544 PMCID: PMC2360612 DOI: 10.1038/sj.bjc.6603243] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Lymphodepletion and infusion of autologous expanded tumour-infiltrating lymphocytes is effective therapy for patients with malignant melanoma. Antitumour responses are likely to be mediated by HLA class I- and II-restricted immune responses directed at tumour antigens. We assessed whether the peripheral blood of normal HLA-matched siblings of patients with melanoma could be used to generate lymphocytes with antimelanoma activity for adoptive immunotherapy after allogeneic blood or marrow transplantation. Melanoma cell lines were derived from two donors and were used to stimulate the mononuclear cells of three HLA-identical siblings. CD4(+) clones dominated cultures. Of these, approximately half were directly cytotoxic towards recipient melanoma cells and secreted interferon-gamma in response to tumour stimulation. More than half of the noncytotoxic clones also secreted interferon-gamma after melanoma stimulation. No CD4(+) clones responded to stimulation with recipient haemopoietic cells. The majority of CD8(+) clones directly lysed recipient melanoma, but did not persist in long-term culture in vitro. No crossreactivity with recipient haemopoietic cells was observed. The antigenic target of one CD4(+) clone was determined to be an HLA-DR11-restricted MAGE-3 epitope. Antigenic targets of the remaining clones were not elucidated, but appeared to be restricted through a non-HLA-DR class II molecule. We conclude that the blood of allogeneic HLA-matched sibling donors contains melanoma-reactive lymphocyte precursors directed at tumour-associated antigens. Adoptive immunotherapy with unselected or ex vivo-stimulated donor lymphocytes after allogeneic stem cell transplantation has a rational basis for the treatment of malignant melanoma.
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Affiliation(s)
- D J Gottlieb
- Leukaemia Research Laboratory, University of Sydney, Westmead Hospital, Sydney NSW 2145, Australia.
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Conrad R, Remberger M, Cederlund K, Hentschke P, Sundberg B, Ringdén O, Barkholt L. Inflammatory cytokines predominate in cases of tumor regression after hematopoietic stem cell transplantation for solid cancer. Biol Blood Marrow Transplant 2006; 12:346-54. [PMID: 16503504 DOI: 10.1016/j.bbmt.2005.10.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2005] [Accepted: 10/31/2005] [Indexed: 10/25/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (SCT) has recently been presented as promising immunotherapy against renal cell, colon, ovarian, breast, and primary liver cancer. Because clinical results demonstrate a variable effect on metastases, we studied whether there is an association between the clinical response and free cytokines in serum. Two patients with metastatic colorectal and 4 with renal cell cancer underwent allogeneic SCT. Conditioning included fludarabine (30 mg/m2) for 3 or 5 days, using sibling or matched unrelated donors, respectively, followed by 2 Gy total body irradiation (n=5) or cyclophosphamide (60 mg/kg) for 2 days (n=1). Antithymoglobuline (4 mg/kg) was given to patients with matched unrelated donors (n=3). Immunosuppression was cyclosporin A, combined with mycophenolate mofetil (n=5) or methotrexate (n=1). The tumor load was examined by computer tomography of the thorax and abdomen before and 3, 6, 9, and 12 months after SCT. Free cytokines in serum were analyzed using enzyme-linked immunosorbent assay. In each patient, the ratio between inflammatory (I) and anti-I cytokines was calculated. No statistical significance was found between the cytokine ratio in correlation to the tumor load according to international response evaluation criteria in solid tumors criteria. In contrast, tumor regression was found to correlate with dominating I cytokine levels in 5/7 occasions, compared with 1/12 of cases with anti-I cytokines using our local method focusing on metastases in lungs, lymph nodes, and liver (P=.01). Thus, an increased level of I cytokines possibly mirrors tumor killing induced by type 1 T-cell response. Furthermore, anti-I cytokines might inhibit cytotoxic cells from exerting the antitumor effect of allogeneic SCT.
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Affiliation(s)
- Réka Conrad
- Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
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Barkholt L, Bregni M, Remberger M, Blaise D, Peccatori J, Massenkeil G, Pedrazzoli P, Zambelli A, Bay JO, Francois S, Martino R, Bengala C, Brune M, Lenhoff S, Porcellini A, Falda M, Siena S, Demirer T, Niederwieser D, Ringdén O. Allogeneic haematopoietic stem cell transplantation for metastatic renal carcinoma in Europe. Ann Oncol 2006; 17:1134-40. [PMID: 16648196 DOI: 10.1093/annonc/mdl086] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND An allogeneic antitumour effect has been reported for various cancers. We evaluated the experience of allogeneic haematopoietic stem cell transplantation (HSCT) for renal cell carcinoma (RCC) in 124 patients from 21 European centres. PATIENTS AND METHODS Reduced intensity conditioning and peripheral blood stem cells from an HLA-identical sibling (n = 106), a mismatched related (n = 5), or an unrelated (n = 13) donor were used. Immunosuppression was cyclosporine alone, or combined with methotrexate or mycophenolate mofetil. Donor lymphocyte infusions (DLI) were given to 42 patients. The median follow-up was 15 (range 3-41) months. RESULTS All but three patients engrafted. The cumulative incidence of moderate to severe, grades II-IV acute GVHD was 40% and for chronic GVHD it was 33%. Transplant-related mortality was 16% at one year. Complete (n = 4) or partial (n = 24) responses, median 150 (range 42-600) days post-transplant, were associated with time from diagnosis to HSCT, mismatched donor and acute GVHD II-IV. Factors associated with survival included chronic GVHD (hazards ratio, HR 4.12, P < 0.001), DLI (HR 3.39, P < 0.001), <3 metastatic sites (HR 2.61, P = 0.002) and a Karnofsky score >70 (HR 2.33, P = 0.03). Patients (n = 17) with chronic GVHD and given DLI had a 2-year survival of 70%. CONCLUSION Patients with metastatic RCC, less than three metastatic locations and a Karnofsky score >70% can be considered for HSCT. Posttransplant DLI and limited chronic GVHD improved the patient survival.
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Affiliation(s)
- L Barkholt
- Division of Clinical Immunology and Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden
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Ballen KK, Colvin G, Dey BR, Porter D, Westervelt P, Spitzer TR, Quesenberry PJ. Cellular immune therapy for refractory cancers: novel therapeutic strategies. Exp Hematol 2006; 33:1427-35. [PMID: 16338484 PMCID: PMC1986765 DOI: 10.1016/j.exphem.2005.06.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2005] [Revised: 06/10/2005] [Accepted: 06/29/2005] [Indexed: 01/27/2023]
Abstract
OBJECTIVE Allogeneic stem cell transplantation is curative for certain cancers, but the high doses of chemotherapy and radiotherapy may lead to toxicity. This review summarizes the field of cellular immune therapy using very-low-dose conditioning for refractory cancers. METHODS In our initial study, we treated 25 patients with refractory cancers with 100 cGy total body irradiation followed by allogeneic, nonmobilized peripheral blood cells. Eighteen patients received sibling and seven patients received unrelated cord blood stem cells. RESULTS None of the 13 patients with solid tumors achieved donor chimerism or had a sustained response. Twelve patients with hematologic malignancies were treated, 1 received a cord blood transplant and 11 received sibling donor cells. Nine of these 11 patients achieved donor chimerism, ranging from 5% to 100%. Four patients had sustained complete remission of their cancers. The patients who received cord blood transplants did not respond. Development of chimerism correlated with total previous myelotoxic chemotherapy (p < 0.001). We review additional studies in this area, including data in the haploidentical and unrelated donor setting. The data presented comprises studies performed at the four institutions represented by the authors, and a review of other pertinent studies in this area. CONCLUSIONS Cellular immune therapy is an emerging application of transplantation therapy, which may be appropriate for refractory cancers. New studies in solid tumors, and with alternative donors, will expand the application of this new and promising treatment.
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Affiliation(s)
- Karen K Ballen
- Division of Hematology/Oncology, Massachusetts General Hospital, Boston, 02114, USA.
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Carnevale-Schianca F, Ricchiardi A, Capaldi A, Bucci AR, Grignani G, Rota-Scalabrini D, Fizzotti M, Aliberti S, Aglietta M. Allogeneic hemopoietic stem cell transplantation in solid tumors. Transplant Proc 2006; 37:2664-6. [PMID: 16182778 DOI: 10.1016/j.transproceed.2005.06.050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The existence of a graft versus tumor (GVT) effect of donor-derived T cells after allogeneic hematopoietic stem cell transplantation is well established as a critical component for the success of the procedure in several hematologic malignancies. Although it has been suggested that a GVT effect might also be generated in patients affected by refractory solid tumors, the morbidity of conventional allogeneic hematopoietic stem cell transplantation has limited its investigation in these diseases. Recently introduced allogeneic nonmyeloablative regimens have greatly decreased morbidity and mortality related to transplants which retain a powerful GVT. On this basis, it has become possible to explore the existence of alloreactivity toward solid tumors. The present article reviews the early clinical results of this novel immunotherapeutic approach for solid tumors.
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Affiliation(s)
- F Carnevale-Schianca
- Medical Oncology, Department of Oncological Sciences, University of Turin Medical School, Institute for Cancer Research and Treatment (I.R.C.C.), Candiolo, Turin, Italy
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Abstract
Although myeloablative conditioning can cytoreduce or debulk malignancies, the curative antitumor effects of allogeneic hematopoietic stem cell transplantation (HCT) are mostly mediated by transplanted donor immune cells. A heightened awareness and appreciation of the immune-mediated anticancer effects that occur after allogeneic transplantation has led to the increasing use of reduced-intensity stem cell transplantation (RIST) approaches to treat advanced malignancies. The graft-versus-leukemia effects that occur against hematologic cancers after RIST have recently attracted oncologists to explore the therapeutic potential of allogeneic HCT for treatment-refractory solid tumors. Delayed tumor regression after RIST in a subset of patients with metastatic renal cell, breast, ovarian, pancreatic, and colon carcinoma has recently been reported, confirming the existence of a graft-versus-tumor effect in solid tumors. Advanced disease states, rapidly growing tumors, and accrual of patients with extremely short survival are factors that have been identified to limit the efficacy of allogeneic immunotherapy. This review discusses results of allogeneic HCT for solid tumors and the development of newer transplant strategies to optimize the potential of the graft-versus-tumor effect.
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Affiliation(s)
- Andreas Lundqvist
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1652, USA
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Kanda Y, Komatsu Y, Akahane M, Kojima S, Asano-Mori Y, Tada M, Oshima K, Isayama H, Ogawa S, Motokura T, Chiba S, Ohtomo K, Omata M, Hirai H. Graft-versus-Tumor Effect Against Advanced Pancreatic Cancer after Allogeneic Reduced-Intensity Stem Cell Transplantation. Transplantation 2005; 79:821-7. [PMID: 15818325 DOI: 10.1097/01.tp.0000153507.94980.a5] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The prognosis of advanced pancreatic cancer is extremely poor and therefore a novel treatment strategy is desired. The authors thus started a prospective study of allogeneic reduced-intensity hematopoietic stem cell transplantation (RIST) for patients with advanced pancreatic cancer to evaluate the feasibility and efficacy of this approach for such patients. METHODS Only patients with pathologically proven pancreatic cancer that was locally advanced or metastatic and not amenable to curative resection were included. The conditioning regimen consisted of gemcitabine, fludarabine, and busulfan. RESULTS In the first stage of this study, the authors treated seven patients. Treatment-related mortality before day 100 was observed in one patient. The median survival after RIST was 229 days. An objective response on computed tomographic scan was observed in two patients and another had a tumor marker response. Marked tumor shrinkage was observed in one of the remaining patients after donor lymphocyte infusion. These antitumor effects appeared after the effect of the conditioning regimen had disappeared. In addition, some of these responses were associated with an increase in the serum anticarcinoembryonic antigen antibody level. CONCLUSIONS Pancreatic cancer appeared to be sensitive to a graft-versus-tumor effect; therefore, a larger clinical study with a refined strategy is warranted.
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Affiliation(s)
- Yoshinobu Kanda
- Department of Cell Therapy & Transplantation Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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Abstract
The graft-versus-leukaemia (GVL) reaction that occurs after allogeneic haematopoietic cell transplantation (HCT) can cure patients with a variety of haematological malignancies. A heightened appreciation of the GVL effect has resulted in the development of reduced intensity transplant approaches, where antitumour effects occur predominantly as a consequence of the transplanted donor immune system. The recent success of these transplants in patients with acute and chronic leukaemias has led to trials investigating for graft-versus-tumour (GVT) effects in patients with treatment-refractory metastatic solid tumours. This review discusses evidence that immune replacement following allogeneic HCT is a potent form of cancer immunotherapy for patients with haematological and non-haematological malignancies.
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Affiliation(s)
- Sakti Chakrabarti
- National Heart, Lung, and Blood Institute, Hematology branch, 9000 Rockville Pike, Bethesda, Maryland 20892, USA
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Roigas J, Massenkeil G. Nonmyeloablative allogeneic stem cell transplantation in metastatic renal cell carcinoma: a new therapeutic option or just a clinical experiment? World J Urol 2005; 23:213-20. [PMID: 15685446 DOI: 10.1007/s00345-004-0480-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 11/15/2004] [Accepted: 11/15/2004] [Indexed: 01/02/2023] Open
Abstract
Nonmyeloablative stem cell transplantation (NST) and donor lymphocyte infusions (DLI) are currently under clinical investigation as an innovative therapeutic option for patients with metastatic renal cell carcinoma (RCC). The underlying concept, adopted from patients with hematologic malignancies, aims at a reduction of conditioning toxicity and exploits the graft versus malignancy effect of donor T-lymphocytes after transplantation. Clinical data from more than 100 patients treated worldwide have been published so far. The data provide evidence that NST is feasible with a very low rate of engraftment failure. Objective remissions in these heterogenous studies were observed in 23% of the patients overall. Remissions after NST developed only after complete engraftment of donor lymphoid cells had occurred. Objective responses were almost always accompanied by graft versus host disease (GvHD) after withdrawal of immunosuppression and/or DLI. GvHD and infections were the main contributors to a substantial transplant related morbidity and mortality, the major drawback of allogeneic stem cell transplantation. Therefore, clinical studies are necessary to further investigate and improve the selection of patients with metastatic RCC or other solid tumors for NST and to reduce post-transplant complications. This article reviews the results, side effects and potential future developments of NST in the treatment of solid tumors.
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Affiliation(s)
- Jan Roigas
- Department of Urology, Campus Mitte, Charité-University Medicine Berlin, 10098, Berlin, Germany.
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Kojima R, Kami M, Hori A, Murashige N, Ohnishi M, Kim SW, Hamaki T, Kishi Y, Tsutsumi Y, Masauzi N, Heike Y, Mori SI, Kobayashi K, Masuo S, Tanosaki R, Takaue Y. Reduced-intensity allogeneic hematopoietic stem-cell transplantation as an immunotherapy for metastatic colorectal cancer. Transplantation 2005; 78:1740-6. [PMID: 15614146 DOI: 10.1097/01.tp.0000146194.36297.4e] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Allogeneic stem-cell transplantation (allo-SCT) can induce curative graft-versus-leukemia reactions for hematologic malignancies through allogeneic immunity. Because the gastrointestinal tract is a target of graft-versus-host disease (GvHD), colorectal cancer might be a candidate for allo-SCT. METHODS Four patients with metastatic colorectal cancer underwent reduced-intensity stem-cell transplantation (RIST) in the National Cancer Center Hospital between July 2002 and February 2003. Three patients received transplants from an human leukocyte antigen (HLA)-identical related donor, and the remaining patient received selected CD34-positive cells from a two-loci HLA-mismatched donor. The basis of preparative regimen was busulfan 4 mg/kg for 2 days and fludarabine 25 mg/kg for 6 days. RESULTS All the patients tolerated the preparative regimen and achieved engraftment without significant toxicities. All developed acute or chronic GvHD. Although serum levels of CA19-9 and carcinoembryonic antigen were transiently elevated after RIST in all the patients, the levels subsequently decreased below the levels from before RIST in all but one patient. Three had measurable lesions before RIST, one achieved partial response, and the others stable disease, which was durable for 120 and 60 days. Three patients died; the causes of death were progressive disease, GvHD, and accident. Postmortem examination was obtained for two patients; in one patient, the peritoneal metastatic lesions macroscopically disappeared, and in the other patient, the supraclavicular lymph node disappeared while the other measurable lesions remained stable. CONCLUSIONS All the patients showed some evidence suggesting the presence of a graft-versus-tumor effect for colorectal cancer, which should be confirmed in a future prospective trial.
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Affiliation(s)
- Rie Kojima
- Hematopoietic Stem Cell Transplant Unit, the National Cancer Center Hospital, Tokyo, Japan
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Mohty M, Faucher C, Blaise D. Immunothérapie par transplantation de cellules souches hématopoïétiques allogéniques : actualités et perspectives. Rev Med Interne 2005; 26:33-40. [DOI: 10.1016/j.revmed.2004.05.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2004] [Accepted: 05/07/2004] [Indexed: 11/24/2022]
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Nieto Y, Jones RB, Shpall EJ. Stem-cell transplantation for the treatment of advanced solid tumors. SPRINGER SEMINARS IN IMMUNOPATHOLOGY 2004; 26:31-56. [PMID: 15368078 DOI: 10.1007/s00281-004-0160-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2004] [Accepted: 04/18/2004] [Indexed: 01/21/2023]
Abstract
Over the past two decades, high-dose chemotherapy (HDC) with autologous stem-cell transplantation (ASCT) has been explored for a variety of solid tumors in adults, particularly breast cancer, ovarian cancer and non-seminomatous germ-cell tumors. The results of prospective phase II studies seemed superior in many cases to the outcome expected with standard-dose chemotherapy (SDC). The value of HDC for adult solid tumors remains, in most instances, a controversial issue, currently under the scrutiny of randomized phase III trial evaluation. ASCT pursuing an immune graft-versus-tumor effect has been evaluated in recent years for patients with advanced and refractory solid malignancies. This article reviews the results of the main phase II and III studies of HDC with ASCT, as well as the preliminary experience using allogeneic transplantation for solid tumors.
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Affiliation(s)
- Yago Nieto
- University of Colorado Health Sciences Center, 4200 East Ninth Avenue, B-190, Denver, CO 80262, USA.
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Bregni M, Bernardi M, Ciceri F, Peccatori J. Allogeneic stem cell transplantation for the treatment of advanced solid tumors. ACTA ACUST UNITED AC 2004; 26:95-108. [PMID: 15378271 DOI: 10.1007/s00281-004-0164-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2004] [Accepted: 04/21/2004] [Indexed: 10/26/2022]
Abstract
Allogeneic stem cell transplantation has emerged as a potentially curative treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, an immune mechanism mediated by the donor immune system, is an important component of the therapeutic effect of allogeneic transplantation. Recent data from experimental animal models and from preliminary clinical experience suggest that a graft-versus-tumor effect, analogous to the graft-versus-leukemia effect, may be generated against solid tumors such as renal cell cancer, breast cancer, and other malignancies. The use of non-myeloablative, immunosuppressive conditioning regimens offers the opportunity to achieve a full-donor engraftment with reduced transplant-related complications and mortality, enabling also patients of advanced age and with co-morbidities to receive an allografting. Advanced renal cell cancer, an essentially incurable disease, has emerged from pilot studies as a disease susceptible to the graft-versus-tumor effect. Future studies will demonstrate if the tumor responses observed after allografting will translate into a clinically meaningful survival advantage. Other tumors in which tumor responses have been observed are: breast cancer, ovarian cancer, colorectal cancer, soft-tissue sarcoma, and others. Advanced melanoma may not be amenable to graft-versus-tumor effect. Future studies will point to the identification, isolation and cloning of target antigen(s) of graft-versus-tumor effect, to further reduce toxicities and to achieve a selective cell-mediated immunotherapy.
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Affiliation(s)
- Marco Bregni
- Division of Hematology and Bone Marrow Transplantation, Istituto H San Raffaele, Via Olgettina 60, 20132 Milano, Italy.
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Nakagawa T, Kami M, Hori A, Kim SW, Murashige N, Hamaki T, Kishi Y, Fujimoto H, Matsuoka N, Okajima E, Komiyama M, Tobisu KI, Wakayama T, Uike N, Tajima K, Makimoto A, Mori S, Tanosaki R, Takaue Y, Kakizoe T. Allogeneic hematopoietic stem cell transplantation with a reduced-intensity conditioning regimen for treatment of metastatic renal cell carcinoma: single institution experience with a minimum 1-year follow-up. Exp Hematol 2004; 32:599-606. [PMID: 15246155 DOI: 10.1016/j.exphem.2004.04.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2003] [Revised: 03/31/2004] [Accepted: 04/20/2004] [Indexed: 11/20/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the safety and efficacy of allogeneic hematopoietic stem cell transplantation with a reduced-intensity conditioning regimen (RIST) for interferon-alpha-refractory metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS Of 26 patients referred to the National Cancer Center Hospital for possible RIST between June 2000 and April 2002, an HLA-identical relative was identified for 12 patients. Nine patients underwent RIST. The conditioning regimen consisted of fludarabine 180 mg/m2 or cladribine 0.66 mg/kg, plus busulfan 8 mg/kg and rabbit antithymocyte globulin 5 mg/kg. Graft-vs-host disease (GVHD) prophylaxis was cyclosporine alone. RESULTS All patients achieved engraftment without grade III to IV nonhematologic regimen-related toxicity. All patients achieved complete donor-type chimerism without donor lymphocyte infusion by day 60. Four patients developed acute GVHD, and four developed chronic GVHD. One patient (11%) achieved partial response. As of July 2003, six patients were alive at median follow-up of 681 days. The actuarial overall survival rate was 89% at 1 year and 74% at 2 years. The overall survival rate tended to be higher in the 12 patients with a matched donor than in the other 14 patients without a matched donor (p = 0.088). CONCLUSION Our RIST procedure is feasible without severe toxicity. The efficacy of RIST for RCC should be confirmed in phase II/III clinical trials.
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Affiliation(s)
- Tohru Nakagawa
- Urology Division, National Cancer Center Hospital, Tokyo, Japan
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