Therapy of Radiation Injury

Transcription

1 COMMENTARY Therapy of Radiation Injury THOMAS J. MACVITTIE Key Words: Radiation accident. Therapy. Cjrtokines Transplantarion University of Maryland Cancer Center, Baltimore, Maryland, USA INTRODUCTION The International Conference on the Biological Effects of Radiation Injury held March 22-25, 1996, in Minsk focused oral presentations and discussion on the Therapy of Acute Radiation Injuries. The papers contained in this section serve to underscore the omnipresent dilemmas facing the triage and/or treatment physician as well as the limitations of current treatments. Recent history continues to document the acute and chronic health effects of radiation accidents, not only on those working with the radiation source or employed in its clean-up, but also on unsuspecting participants. For instance, the recent 1994 radiation exposure in Kiisa, Estonia, exemplifies the complexity and severity of the radiation accident scenario. An intense radiation source, stolen from a disposal site and kept at a villager s home, resulted in one death and varying degrees of radiation exposure of four other persons. A prevailing theme throughout accident scenarios is that the radiation environment is likely to be uncontrolled and ill-defmed. The radiation may vary in quality, energy, and dose rate. The exposure may be nonuniform and partial-body, depending on the location and movement of the subject in relation to the source and available shielding. The subject may also have been traumatized by thermal bums and/or wounds as well as radiation bums. This underscores a second prevailing theme of the radiation accident, i.e., the difficulty in early and accurate determination of absorbed dose, which is the basis for effective triage and medical treatment. Definition of an effective treatment strategy will depend upon the presence of associated injuries to other organ systems, development of the cutaneous radiation syndrome (CRS), and the degree of radiation-induced marrow aplasia (or, rather, the number of surviving hematopoietic stem cells capable of spontaneous regeneration). N. Duiniuk and S. Sorbu present a cogent review of the acute radiation syndrome (ARS), the hematopoietic response to radiation exposure and stem cell transplantation. The authors focus on several key points to be emphasized with regard to treatment strategy and the potential revelation of additional nonhematopoietic health consequences subsequent to successful treatment of the hematopoietic syndrome. An important consideration in treatment strategy in addition to early, reliable biodosimetry is the potential for surviving hematopoietic stem cells due to a population with enhanced radioresistance and/or the heterogeneity of the radiation exposure. If any good news is to be found in the high-dose radiation accident scenario, it is the fact that its uncontrolled nature would predict the survival of a fraction of stem cells. It is probable that surviving hematopoietic stem cells would require a therapeutic cocktail of cytokinedgrowth factors to stimulate self-renewal instead of differentiation. The authors present a potential realization associated with effective treatment and survival through the hematopoietic syndrome, e.g., the appearance of other organ effects such as the CRS or pneumonia which predominate during the subsequent intermediate and late phases after recovery from the ARS and associated myelosuppression. Duiniuk and Sorbu further suggest that the combination of severe marrow aplasia due to exposure in the high-dose range (5-12 Gy), the potential for hematopoietic stem cell survival with requisite prolonged time to engraftment, the availability of suitable growth factors, and the lack of associated injuries quahfy this group of victims for hematopoietic rescue with stem cell transplantation. Radiation Znjury and the Chernobyl Catastrophe. STEM CELLS 1997;15(suppl2): AlphaMed Press. All rights reserved.

2 264 Commenky: Therapy of Radiation Injury Further analysis of the question regarding stem cell transplantation in the accident scenario is provided by D. Densow et al. In an interesting analysis of 58 of the most severely affected patients selected from the International Computer Database for Radiation Exposure Case Histories, the authors report that of three bone marrow transplant survivors, all benefited from temporary stem cell engraftment and that subsequent to highdose exposure, stem cell transplant is an appropriate therapy option. Considering the role of associated injuries in these patients, it was noted that radiation-induced cutaneous burns and damage to gastrointestinal and lung tissue were the strongest contraindications for stem cell transplantation. It was surprising that physical trauma and thermal bums did not play a decisive role in the outcome of the transplant. The question of bone marrow transplant in the radiation accident scenario has been redefined to a certain extent in light of the relative engraftment efficacy of cytokine-mobilized peripheral blood stem cells. Both M. Bishop and A. Uss et al. report on the relative merits and limitations of stem cell transplantation for radiation accident victims. While Uss et al. show clinical results that confm the therapeutic efficacy of bone marrow compared to peripheral blood transplants, Bishop emphasizes the omnipresent problems of obtaining suitably matched, allogeneic donors regardless of stem cell source, early and accurate estimation of expe sure dose, and the narrow window of radiation exposure for therapeutic benefit of stem cell transplantation relative to optimal therapeutic enhancement due to administration of growth factors after irradiation. POTENTIAL STRATEGIES FOR TREATMENT OF ACUTE RADIATION INJURY Treatment strategies for personnel severely irradiated in accidents have been the subject of several recent conferences in addition to the ones in Houston and Minsk [I-31. Clearly, the results of biomedical research over the last decade will present physicians with a new generation of treatment modalities in addition to a continuous movement of new agents into the therapeutic pipeline in hopes of making the successful transition from bench to bedside. A dynamic area of research and a number of clinical trials have focused on defining therapeutic approaches to enhance hematopoietic recovery from radiation- or chemotherapyinduced myelosuppression, in addition to evaluating alternative sources of stem cells for short-term cellular therapy and/or long-term hematopoietic and immune reconstitution in the host with an ablated bone marrow [4]. Recent therapeutic approaches for enhancing hematopoietic recovery and reducing the obligate periods of neutropenia and thrombocytopenia associated with high-dose radiation and/or chemotherapy-induced myelosuppression have focused on evaluation of lineage-specific cytokines for thrombopoiesis, combination cytokine protocols, and/or new synthetic cytokine receptor agonists. NEW-GENERATION GROWTH FACTORS Two new-generation growth factors, the Mpl ligand (megakaryocyte growth and development factor, Amgen; Thrombopoietin, Genentech), and the synthetic interleukin 3 (IL-3) receptor agonist, Synthokine (G.D. Searle Co.), have progressed through pivotal preclinical evaluations and have recently entered clinical trials. The thrombopoietic potential of the Mpl ligand was suggested early by the magnitude of platelet production and stimulation of marrow-derived megakaryocyte-colony-forming cells in normal nonhuman primates relative to that observed for the other thrombogenic cytokines IL-3, IL-6, leukemia inhibitory factor, and IL-I1 [5]. Evaluation of the Mpl ligand in animal models of radiation- or chemotherapy-induced myelosuppression showed that it lessened or abolished the degree and duration of thrombocytopenia, and that it may have direct or indirect effects on stimulating granulopoiesis and erythropoiesis [6-81. Farese et al. [7] first reported the efficacy of recombinant human polyethylene glycol-megakaryocyte growth and development factor (PEG-rHuMGDF) alone and in combination with granulocyte colony-stimulating factor (G-CSF) in a rhesus monkey model of radiation-induced myelosuppression. It is important to note that PEG-rHuMGDF coadministered with G-CSF significantly improved all platelet recovery variables to the same degree as PEGrHuMGDF monotherapy. In addition, rhumgdf/g-csf significantly enhanced neutrophil recovery relative to G-CSF monotherapy. The rhumgdf/g-csf combination therapy showed no evidence of lineage competition, while significantly enhancing dual lineage recovery in myelosuppressed nonhuman primates.

3 MacVittie 265 Synthokine is a high-affinity IL-3 receptor agonist that was developed in response to the relatively narrow therapeutic index of endogenous or native IL-3 [9]. Synthokine, evaluated for therapeutic efficacy in a nonhuman primate model of radiation-induced myelosuppression significantly reduced the duration of thrombocytopenia, although the duration of neutropenia was unchanged [lo]. The combination of S ynthokine and G-CSF in the same model of radiation-induced myelosuppression further improved the recovery from thrombocytopenia and neutropenia relative to monotherapy with each agent [ 111. These preclinical data on the therapeutic efficacy of Mpl ligand and Synthokine suggest that each may be useful in the treatment of radiation-induced myelosuppression, and if used in combination with G-CSF, may provide the desired dual-lineage stimulus for recovery of both platelets and neutrophils. Two other thrombopoietic cytokines, IL-6 and IL-11, are progressing through clinical trials. IL-6 is in the midst of clinical evaluation as a monotherapy and in combination with G-CSF or IL-3. Phase I and I1 clinical studies of IL-11 have demonstrated thrombopoietic activity and decreased requirements for platelet transfusions. As with the Mpl ligand and Synthokine, the combination of IL-11 with G-CSF may continue to decrease platelet transfusions and accelerate recovery of neutrophils and platelets. IL-3 monotherapy, however, has proven equivocal in both preclinical and clinical studies evaluating therapeutic efficacy in producing platelets and/or neutrophils subsequent to radiation- or chemotherapy-induced myelosuppression. NOVEL CYTOKINES Synthokine, a synthetic IL-3 receptor agonist, has been combined with G-CSF or Mpl ligand to form dual functional receptor agonists called myelopoietin and promegapoietin, respectively. Myelopoietin stimulated recovery of both neutrophils and platelets in myelosuppressed nonhuman primates in a manner comparable to that noted for combined Mpl ligand and G-CSF [12]. The Promegapoietin molecule is a potent stimulus for platelet production and significantly enhanced recovery of platelets in irradiated, myelosuppressed nonhuman primates. All parameters of platelet recovery were substantially improved (J. G. Giri, personal communication). The ability to form multifunctional receptor agonists may allow for manipulation of relative cytokine/receptor binding and signal transduction in hematopoietic target cells, thereby improving their therapeutic index. STEM CELL TRANSPLANTATION Current directions in the treatment of severe radiation-induced myelosuppression or myeloablation include a renewed focus on transplantation of hematopoietic stem and progenitor cells. Transplantation of cytokine-mobilized peripheral blood stem cells (PBSCT) has resulted in rapid and durable autologous hematopoietic engraftment [ 13, 141. The noted heterogeneity and large number of hematopoietic cells mobilized by cytokine provides a marked advantage for this treatment modality in that the graft may be engineered to provide a high dose of committed progenitor cells for acceleration of short-term engraftment, while the stem cells can provide long-term reconstitution. In what may be more relevant for accidents, recent clinical studies have emphasized the successful use of allogeneic PBSCT. Cautious use of allogeneic PBSCT was based on the unknown long-term toxicity of administration of cytokines to the donors and the increased risk of acute and/or chronic graft-versus-host disease (GvHD) from the large number of T cells infused with the graft. However, early results indicated that unmanipulated allogeneic PBSCT can be performed with cytokine-mobilized cells and provide engraftment without an appreciable increase in the incidence of acute GvHD over that noted with allogeneic bone marrow transplantation [ In this regard, manipulation of the graft by CD34' immunoadsorption can concentrate the hematopoietic stem and progenitor cells while also depleting the graft of alloreactive T cells [ 181. This approach underscores the feasibility of "engineered" temporary PBSCT allografts used to bridge the period of cytopenia prior to the regeneration of surviving endogenous stem cells.

4 266 Commentary: Therapy of Radiation Injury Additional advances in stem cell transplantation will undoubtedly be derived from alternative sources such as cord blood, as well as new methodologies to enhance ex vivo expansion of stem and/or progenitor cells harvested from bone marrow, mobilized peripheral blood or cord blood. At this writing, over 200 cord blood transplants have been performed with encouraging results in related and unrelated allogeneic settings [19, 201. There are a number of advantages of cord blood as a source of stem cells. It is abundant and easy to procure without risk to mother or infant, and it can be banked for future use; it should possess fewer infectious agents than adult sources; the stem cells are of better quality than those in peripheral blood or bone marrow; and the immaturity of immunoreactive T cells may reduce the risk of GvHD. On the other hand, the number of cord blood stem cells from a single donor is limited, second access if the graft fails is not an option, and the rate of engraftment is relatively slow. The establishment of cord blood banks will increase the use of cord blood from unrelated donors. Further research into the capability of ex vivo expansion and differences in stem cell biology relative to engraftment in the adult marrow microenvironment will answer questions regarding the full engraftment potential of cord blood stem cells and the severity of GvHD relative to allogeneic marrow or peripheral blood [21]. Ex VIVO EXPANSION Selected cytokine cocktails are capable of enhancing the ex vivo expansion of stem and progenitor cells, regardless of their source. A better understanding of the growth factors involved in expanding pluripotent stem cells compared to committed progenitor cells will allow graft engineering and selec - tive emphasis on short-term recovery of platelets and neutrophils or long-term hematopoietic reconstitution. Brugger et al. [22] recently demonstrated the feasibility of hematopoietic reconstitution using autologous cytokine-mobilized peripheral-blood-derived progenitor cells generated ex vivo in cancer patients after high-dose chemotherapy. The pattern of reconstitution was identical to that in historical controls treated with unseparated mononuclear cells or with selected CD34+ cells. The new generation Mpl and flt-3 ligands, as well as myelopoietin and promegapoietin, are promising additions to the list of cytokines that may allow optimal ex vivo expansion of selected cell populations. Further research is required to define the content and quality of starting cell populations, the proper mix of cytokines to drive renewal, expansion, and/or differentiation, and the precise in vitro culture conditions for specific target cells. SUMMARY It is apparent from preclinical and clinical research to date that continued evaluation of new and alternative treatment strategies is required to eliminate the obligate periods of neutropenia and thrombocytopenia after acute high-dose irradiation. Future treatment strategies may involve new combinations of cytokines to affect hematopoietic stem cell proliferation and engineered cellular grafts to provide short-term in vivo expansion of neutrophils and platelets in an effort to bridge the cytopenic gap until endogenous or transplanted stem cells regenerate the hematopoietic and immune systems. Cytokine-mobilized peripheral blood and cord blood will provide alternative sources of allogeneic stem and progenitor cells in support of primary engraftment, delayed engraftment or secondary failure of the initial graft, as well as starting populations for various ex vivo expansion protocols. Further insights into the relative quality of stem cell populations and the factors that regulate their survival and self renewal, and the identification and roles of adhesion molecules in stem cell mobilization, engraftment, and interaction with the adult marrow microenvironment will provide the basis for future treatment strategies for the radiation-induced hematopoietic syndrome. As our ability to treat the hematopoietic syndrome improves, damage to other organ systems such as the skin, lung, and/or gastrointestinal tissue will emerge as dose-limiting. At the same time, the characterization of receptors for inflammatory cytokines, cytokine receptor antagonists, and

5 MacVittie 267 anti-endotoxin antibodies has allowed significant insights into the mechanisms and pathogenesis of sepsis. However, translation of this knowledge into a treatment modality for septic patients is precluded by the lack of any clear-cut beneficial effect from the many clinical trials. The research and clinical results presented in this volume and recent conferences reflect the body of knowledge that will lead to further developments in assessment, prophylaxis, and treatment of radiation injuries in the areas of infectious disease and the hematopoietic, gastrointestinal, and cutaneous syndromes. REFERENCES 1 The Medical Basis for Radiation Accident Preparedness II: Clinical Experience and Follow-up Since Oct., 1988, Oak Ridge, Tennessee. In: Ricks RC, Fry SA, eds. The Medical Basis for Radiation Accident Preparedness. New York: Elsevier Science Inc., First Consensus Development Conference on the Treatment of Radiation Injuries May, 1989, Washington, DC. In: Browne D, Weiss JF, MacVittie TJ et al., eds. Proceedings in Treatment of Radiation Injuries. New York: Plenum Press, Second Consensus Development Conference on the Treatment of Radiation Injuries April, 1993, Bethesda, Maryland. In: MacVittie TJ, Weiss JF, Browne D, eds. Proceedings in Advances in the Treatment of Radiation Injuries. Tarrytown, NY: Pergamon, Elsevier Science Inc., MacVittie TJ, Farese AM. Experimental approaches for therapeutic treatment of radiation-induced hematopoietic injury. In: Hendry JH, Lord BI, eds. Radiation Toxicology: Bone Marrow and Leukemia. London: Taylor and Francis, 1996: Farese AM, Hunt P, Boone TC et al. Recombinant human megakaqocyte growth and development factor (r-humgdf) stimulates megakaqocytopoiesis in normal primates. Blood 1995;86: Hokom MM, Lacey D, Kinst 0 et al. Megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice. Blood 1995 $ Farese AM, Hunt P, Grab LB et al. Combined administration of recombinant human megakaryocyte growth and development factor and granulocyte colony stimulating factor enhances multi-lineage hematopoietic reconstitution in nonhuman primates following radiation-induced marrow aplasia. J Clin Invest 1996;97: Kaushansky K, Lin NL, Grossmann A et al. Thrombopoietin expands erythroid, granulocytemacrophage, and megakaryocytic progenitor cells in normal and myelosuppressed mice. Exp Hematol 1996;24: Thomas JW, Baum CM, Hood WF et al. Potent interleukin 3 receptor agonist with selectively enhanced hematopoietic activity relative to recombinant human interleukin 3. Proc Natl Acad Sci USA 1995;92: Farese AM, Herodin F, McKeam JP et al. Acceleration of hematopoietic reconstitution with a synthetic cytokine (SC-55494) after radiation-induced bone marrow aplasia. Blood 1996;87: MacVittie TJ, Farese AM, Herodin F et al. Combination therapy for radiation-induced bone marrow aplasia in nonhuman primates using Synthokine SC and recombinant human granulocyte colony stimulating factor. Blood 1996;87: MacVittie TJ, Farese AM, Grab LB et al. Stimulation of multilineage hematopoietic recovery in a nonhuman primate, bone marrow aplasia model by a multifunctional agonist of human IL-3 and G-CSF receptors. Blood 1995;86 (suppl 1) 499a. 13 Weaver CH, Bucknmer CD, Longin K et al. Syngeneic transplantation with peripheral blood mononuclear cells collected after the administration of recombinant human granulocyte colony-stimulating factor. Blood 1993;82: Brugger W, Henschler R, Heimfeld S et al. Positively selected autologous blood CD34' cells and unseparated peripheral blood progenitor cells mediate identical hematopoietic engraftment after high dose VP16, ifosfamide, carboplatin, and epirubicin. Blood 1994;84: Korbling M, Prezepiozka D, Huh YO et al. Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: potential advantage of blood over marrow allografts. Blood 199Si85: s.

6 268 Commentary: Therapy of Radiation Injury 16 Schmitz N, Dreger P, Suttorp M et al. Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by Filgrastim (granulocyte colony stimulating factor). Blood 1995;85: Russell JA, Brown C, Bowen T. Allogeneic blood cell transplants for haematological malignancy: preliminary comparison of outcomes with bone marrow transplantation. Bone Marrow Transplant 1996; 17: Cottler-Fox M, Cipolone K, Yu M et al. Positive selection of CD34+ hematopoietic cells using an immunoaffinity column results in T- cell depletion equivalent to elutriation. Exp Hematol 1995;23: Wagner JE, Kernan NA, Steinbuch M et al. Allogeneic sibling umbilical cord blood transplantation in forty-four children with malignant and nonmalignant disease. Lancet 1995;346: Kurtzberg J, Laughlin M, Graham ML et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med 1996;335: Broxmeyer HE. Questions to be answered regarding umbilical cord blood hematopoietic stem and progenitor cells and their use in transplantation. Transplantation 1995;35: Brugger W, Heimfeld S, Berenson RJ et al. Reconstitution of hematopoiesis after high-dose chemotherapy by autologous progenitor cells generated ex vivo. N Engl J Med 1995;333: