Effects of Granulocyte Colony-Stimulating Factor and Stem Cell Factor, Alone and in Combination, on the Mobilization

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Effects of Granulocyte Colony-Stimulating Factor and Stem Cell Factor, Alone and in Combination, on the Mobilization of Peripheral Blood Cells That Engraft Lethally Irradiated Dogs

By Thierry de Revel, Frederick R. Appelbaum, Rainer Storb, Friedrich Schuening, Richard Nash, Joachim Deeg, Ian McNiece, Robert Andrews, and Theodore Graham

The effects of recombinant canine granulocyte colony-stimu- with 1 x 10' PBMC/kg collected without pretreatment died lating factor (rcG-CSF) and recombinant canine stem cell with marrow aplasia 11 to 29 days after TB1 as did animals factor (rcSCF), a c-kitligand, on the circulation of hematopoi- treated with only low-dose SCF before cell collection. In con- etic progenitor and stem cells were studied in a canine trast, all animals given PBMC collected after G-CSF, high- model. Administration of rcG-CSF (10 pglkg) for 7 days led dose SCF, or a combination of G-CSF plus low-dose SCF to a 5.4-fold increase in CFU-GM/mL of blood, while 7 days recovered granulocyte function. Recovery to 500 granulo- of rcSCF (200 pglkg) led to an 8.2-fold increase. Although cytes/pL after transplant took 17, 18.8, and 13.6 days, re- treatment with low-dose rcSCF (25 pg/kg) had no effect on spectively, (P= .056 for the difference between the combina- the level of peripheral blood progenitors, 7-day exposureto tion G-CSF-SCF group and the other two groups). In both a combination of G-CSF plus low dose SCF led to a 21.6-fold the G-CSF and SCF groups, 4 of 5 animals completely recov- increase (P = .03). To assess the ability of these factors to ered while 1 of 5 in each group died with prolonged throrn- Downloaded from http://ashpublications.org/blood/article-pdf/83/12/3795/614678/3795.pdf by guest on 27 September 2021 increase the circulation of cells capableof rescuing animals bocytopenia. In thecombination group, all 5 animals became after lethal total body irradiation ITBI). 1 x 10' peripheral long-term survivors. These studies demonstrate that both blood mononuclear cells (PBMC)/kgwere collected and cryo- G-CSF and SCF dramatically increase the level of peripheral preserved from animals after 7 days of treatment with G- blood hematopoietic progenitor and stem cells andsupport CSF,SCF or a combination of the two. One month later, the view that these factors can act synergistically. animals were exposed to 9.2 Gy TB1 and transplanted with 0 1994 by The Americm Society of Hffm8tology. the previously collected cells. Control animals transplanted

N BOTH ANIMAL models and humans, hematopoietic collected after G-CSF and SCF administration, given alone and in I stem cells and committed progenitors normally are pres- Combination. ent at low levels in the peripheral blood,14 but dramatically Animals were administered hematopoietic growth factors for 7 increase during recovery from cytotoxic the rap^^.^ or after days following which leukapheresis was performed. The timing of leukapheresis was chosen based preliminary studies in dogs sug- treatment with hematopoietic growth factors.7x8Mobilized OR gesting maximal mobilization of CFU-GM after 6 to 10 days of progenitors are able to rescue lethally irradiated recipients, administration of either G-CSF or SCF. A total of 1 X 10' PBMCl providing sustained hematopoietic eng~1ftment.6.~ kg were collected and cryopreserved. Animals were allowed to rest Granulocyte colony-stimulating factor (G-CSF) and stem for 28 days, after which a single dose of 920 cGy total body irradia- cell factor (SCF) both stimulate hematopoiesis in vitro and tion (1,200 R) from opposing 'Vobalt sources, at 7 cGy (9.3 R) per in vivo and after in vivo administration increase the number minute was administered. Cryopreserved autologous PBMC were of colony-forming cells (CFC) as well as CD34' cells in the thawed and infused after completion of the TBI. Oral antibiotics for peripheral blood.'0"6 Previous laboratory and clinical studies gut decontamination were started 5 days before total body irradiation showed that G-CSF mobilized peripheral blood mononuclear (TBI) and continued until granulocyte recovery. Fluid support, and cells provide engraftment and long-term survival after lethal red cell and platelet transfusions were administered as needed until complete clinical recovery. No posttransplant growth factors were irradiation or high-dose chem~therapy.'~~'~Similarly, SCF administered. mobilized progenitors rescue baboons after otherwise lethal Growth factors administration. Both recombinant canine SCF irradiati~n.'~,'~In this study we have examined the abilities (rcSCF) and recombinant canine G-CSF (rcG-CSF) were provided of G-CSF and SCF alone and in combination to mobilize by Amgen (Thousands Oaks, CA) and were diluted, respectively, in peripheral blood progenitor cells as determined by in vitro dextrose 5% and NaClO.9% with 0.1% normal dog serum and stored assays. In addition, we have measured the capacity of mobi- at 4°C until injection. lized progenitors to rescue lethally irradiated animals. Three groups of five animals were treated either with SCF (200

MATERIALSAND METHODS From The Fred Hutchinson Cancer Research Center and the Uni- Animals. Twenty one dogs (beagles) of both sexes were housed versity of Washington School of Medicine, Seattle; and Amgen, Inc, at the Fred Hutchinson Cancer Research Center (FHCRC) under Thousand Oaks, CA. conditions approved by the American Association for Accreditation Submitted November 9, 1993; accepted February 11. 1994. of Laboratory Animal Care. The housing area was maintained at 70 Supported, in part, by Grants No. CA18105, AI33484, DK42716, _t 2°F with 50% +- 10% relative humidity and on a 12 hours light/ and CA31 787 fromthe National Institutes of Health, and by Amgen, dark lighting cycle. All the dogs were provided with commercial Inc. dog chow and chlorinated tap water ad libitum. All animals were Address reprint requests to Frederick R. Appelbaum, MD, Fred dewormed and vaccinated for rabies, leptospirosis, hepatitis, and Hutchinson Cancer Research Center, 1124 Columbia St, Room parvovirus. The protocol of this study was approved by the Internal M227, Seattle, WA 98104-2092. Animal Use Committee of the FHCRC. The publication costs of this article were defrayed in part by page Study design. Previous studies demonstrated that lethally irradi- charge payment. This article must therefore be hereby marked ated dogs administered 1 X IO8 peripheral blood mononuclear cells "advertisement" in accordance with I8 U.S.C. section 1734 soleiy to PBMCkg collected at steady state invariably die with marrow indicate this fact. In this study the ability of this normally insufficient dose 0 1994 by The American Society of Hematology. of cells to rescue irradiated animals was determined when cells were 0006-4971/94/8312-0014$3.00/0

Blood, Vol83, No 12 (June 15), 1994 pp 3795-3799 3795 3796 DE REVEL ET AL pg/kg/d), G-CSF (10 pgkgld), or the combination of G-CSF and Table 1. Frequency of the CFC in the Peripheral Blood Before low dose (LD) SCF (25 pg/kg/d). The 25 pg/kg/d dose level for (Day 0) and After Administration of Growth Factors (Day 8) low-dose SCF was based on the observation that this may approxi- Day 0 Day 8 mate the maximum tolerated dose in humans." One group of three dogs was treated with LD-SCF and one control group of three dogs Animal CFU-GM BFU-E CFU-GEMMCFU-GM BFU-E CFU-GEMM was not administered any growth factor. All factors were adminis- Control tered subcutaneously in divided doses every 12 hours, No toxicities D449 5.3 0.3 0 attributable to growth factor administration were observed. D454 4.3 0 0 D62 1 3.6 0 0 Leukapheresisand cryopreservation of peripheral blood cells. LD SCF Blood was collected by phlebotomy and the buffy-coat was collected (25 bglkgl using centrifugation at 1,800 rpm. Excess red blood cells and plasma D647 11.5 1 0 9 1 0 were recovered by re-spinning the buffy-coat. D654 6.3 1.6 0 8.6 2 0 D670 4.6 0 0 7.3 1 0 A predetermined dose of PBMC (1 X 108/kg) was diluted in SCF (200 freezing solution containing 10% dimethylsulfoxide (DMSO) and w/kd cooled at 1°C per minute until -80°C using a controlled rate freezer, D592 7.3 0.3 0 0.332.6 5.3 and then stored in a liquid nitrogen freezer. D617 5 0.6 0 62 3 1

D618 12 0 0 49 3 0 Downloaded from http://ashpublications.org/blood/article-pdf/83/12/3795/614678/3795.pdf by guest on 27 September 2021 CFC assay. The CFC assays were carried out on peripheral D626 10.3 0.6 0 51.3 2 1.3 blood on the day before growth factor administration and (after 7 D62726 0.3 5 1.3 2 0.6 days of growth factors) on the day of leukapheresis. In addition, G-CSF CFC assays were performed directly on the leukapheresis product (10 dkgi D496 5 0.6 0 9 2 0 before cryopreservation. D593 9.3 1.6 0 27.3 6.3 0.6 PBMC were separated over a Ficoll-Hypaque gradient and were D594 8.3 1 0 0.324 2.3 cultured at I .O X 1O5 cells per 35 mm plastic culture dish in a two- D622 4 1.3 0 1.3 20 4.6 layer agar culture as described previo~sly.'~~~'The lower layer (1.0 D625 5.6 0.6 0 40.6 4.0 0 G-CSF + mL) consisted of a medium in I% (wthol) agar (FMC, Rockland, CD SCF ME) supplemented with 25% fetal bovine serum (FBS; Hyclone, D579 5.6 1 0 45.6 4.3 06 Logan, UT), 2% (wthol) bovine serum albumin (BSA; Fraction V; D607 7 1 0 50 5.6 1 Sigma, St Louis, MO) and gentamicin sulfate 100 pg/mL. Also D674 6.3 0.6 0 43.6 3.6 0.6 D676 6.3 2 0 29.6 2 0 included were recombinant canine growth factors rcSCF (100 ngl D663 7 1 0 55 6.3 1 mL), rcGM-CSF (100 nglmL), rcG-CSF (100 ng/mL) kindly pro- The numbers are mean of triplicate for lo5 MNC per plate. vided by Amgen and human recombinant erythropoietin (hrEpo) (4 IUlmL). After the lower layer had gelled, cells in 0.5 mL of culture medium as described above with 0.6% agar were layered on the top. Cultures in triplicate were incubated at 37°C in a 5% O,, 5% CO2 to G-CSF resulted in a 21.6-fold increase of CFU-GM and humidified incubator. CFU-GM, Cm-GEMM, and BFU-E were 18-fold increase of BFU-E per milliliter of blood. We found enumerated at day 14 of culture using an inverted microscope. 4,488 (2,090 to 9,502) CFU-GM and 659 (207-1,960) BFU- Sratisticulmethods. Length of leukopenia, neutropenia, and thrombocytopenia were defined as the number of days from TB1 E per milliliter of blood, which is statistically significantly until recovery to a white blood cell count (WBC) of l,OOO/~L,a more than found with every other group (P = .03). granulocyte count of 500/pL, and a platelet count of 20,00O/pL. The apheresis product infused consisted of 1 X lo* Groups of dogs were compared with regard to length of cytopenia PBMCkg resulting in a mean of 0.66 X IO4 CFU-Gh4kg using the log rank test. and 0.94 X lo4 CFU-GWkg for the control group and the LD-SCF group, respectively. The same number of PBMC RESULTS contained 3.6 X lo", 2.4 X lo", and 5.0 X lo4 CFU-GM/kg SCF and G-CSF mobilize CFC in the peripheral blood for the SCF, G-CSF, and combination groups, respectively. (Tables I and 2). Peripheral blood (PB) hematopoietic pro- Thus, for the same number of PBMC stored, the CFU-GM genitors measured before administration of growth factors yields were, respectively, 5.45,3.63, and 7.72 times greater occurred with a mean number of 6.63 (4-12) CFU-GM and than the control group. 0.77 (0-1.6) BFU-E per lo5 mononuclear cells in culture; Hematopoietic recovery from irradiation afterinfusion of' CFU-GEMM were not detected. The mean absolute number 1 X lo8 PBMC/kg (Table 3). None of the three animals of of PB progenitors was 329 CFU-GM (150-578) and 39 BFW- the control group recovered marrow function after infusion E (0-91) per milliliter of PB with our culture technique. of 1 X lo8 PBMCkg and all three died between day 11 and By day 7 of treatment with growth factors, a dramatic day 29 from sepsis and hemorrhage. Bone marrow biopsies increase of both relative and absolute numbers of CFC was postmortem showed marrow aplasia. Similarly, the three observed. The relative numbers of progenitors per lo5PBMC dogs given PBMC collected after treatment with low-dose are presented in Table 1. Absolute values are presented in SCF alone failed to recover. Table 2. For high-dose SCF the mean absolute number was After infusion of the same number of PBMC collected 2,704 (1,456 to 4,414) CFU-GM and 181 (112 to 318) BFU- after SCF, G-CSF, or the combination G-CSF plus low- E per milliliter of blood, representing an 8.2-fold and 4.6- dose SCF treatment, all animals recovered WBC counts. The fold increase. After G-CSF treatment, mean absolute num- mean interval from transplantation to recovery of more than bers of colonies were 2,240 (878 to 3,050) CFU-GM and 1,000 WBCs and more than 500 polymorphonuclear cells 373 (195 to 604) BFU-E per milliliter of blood resulting in (PMNs)/pL of blood for all three groups combined was 16.2 a 5.4- and 5.7-fold increase. Although low-dose SCF alone and 16.4 days, respectively. did not increase the peripheral CFC (see Table 2), its addition The kinetics of WBC recovery appeared similar between STEM CELL MOBILIZATION WITH G-CSF AND SCF 3797

the SCF and G-CSF groups with amean period of 18.8 Table 2. Absolute Number of CFC in the Peripheral Blood (SW) and 17 (G-CSF) days after irradiation to obtain 500 and in the Apheresis Product PMNs/pL. While the dogs transplanted with PBMC col- Apheresis Product lected after low-dose SCF did not engraft, the dogs trans- Blood lCFU/mL) (CFU ~104) planted with the same number of PBMC collected after the Animal Day 0 Day 8 Per kg infusedTotal combination treatment appeared to recover PMN more rap- SCF group idly than the dogs of either the SCF or G-CSF groups. The CFU-GM mean intervals were 14.4 days to obtain 1000 WBC and D617 3,224 172 4.4 37 13.6 days to obtain 500 granulocytes/pL. Despite the small D618 616 2,445 4.4 54.5 number in each group, the difference in granulocyte recovery D626 578 4,414 3.75 31.5 between the combination group and the G-CSF alone or SCF D627 1,456 285 1.9 20 alone groups approaches statistical significance (P = .056). 346 1,980 3.56 39.9 D592 As suggested by the CFU-C studies, the combination of G- BFU-E D617 23 2 156 0.46 CSF and low-dose SCF appears to be synergistic in the D618 05 147 0.4 ability of such primed PBMC to rescue dogs from otherwise Downloaded from http://ashpublications.org/blood/article-pdf/83/12/3795/614678/3795.pdf by guest on 27 September 2021 D626 403.6 172 0.4 lethal TBI. D627 18 1.4 112 0.13 Although PMN recovery occurred rapidly for each dog of D592 146.8 318 0.6 the three study groups, 1 of 5 dogs in both the SCF and the G-CSF group G-CSF groups died due to hemorrhagic complications as CFU-GM assessed by autopsy, despite platelet transfusions. All five D496 313 878 1.36 14.7 dogs in the combination group recovered. The platelet recov- D622 2,352 230 1.63 26.4 ery was slow in each group, the delay to reach more than D625 3,050 277 1.66 16.6 20,000 platelets/pL being 46 days (SCF), 42 days (G-CSF), D593 530 2,620 4.53 49.8 D594 728 2,304 2.7 29.2 and 37 days (G-CSF plus LD SCF). There was a trend, albeit BFU-E not significant, for amore rapid platelet recoveryin the D496 41 195 1 10 combination group. D622 76 548 3.3 54 D625 32 300 1.3 13 D593 91 105 604 9.3 Table 3. Engraftment and Outcome of Dogs After Transplantation D594 88 220 5 56 G-CSF + LD SCF Granulocytes/ CFU-GM Leucocytedpl PL ~ Platelets/ D607 5,600 287 7.46 56 Animal >500 >1,000 >l00 >500 pL >20,000 Survival D579 232 2,181 5.86 67.4 Control D674 214 2,467 4.3 31.4 D449 NR NR D676 9,502 208 2.96 24.8 NR Died dl1 D663 252 2,090 4.5 45 D454 NR NR NR Died dl7 BFU-E D621 NR NR NR Died d29 D607 41 627 1.33 10 LD SCF (25 pg/kg) D579 41 262 0.53 6.1 D670 NR NR NR NR NR Died dl3 D674 22 207 22 0.36 3.2 D647 NR NR NR NR NR Died dl5 D676 66 1,960 0.2 1.6 D654 dl7 NR NR NR NR Died d29 D663 36 239 0.8 8 LD SCF group SCF (200 pg/kg) CFU-GM D617 dl2 d22 dl3 d22 d50 D670 158 227 0.7 10.3 D618 dl1 dl5 dl1 dl5 d33 D647 464 333 1.5 11.4 D626 dl0 dl3 d9 dl2 d55 D654 27 1 395 0.63 5.9 D627 dl2 d21 dl4 d21 d47 BFU-E D592 dl3 dl6 dl3 d24 NR Died d35 D670 0 31 0 0 G-CSF (IO pglkg) D647 40 37 0.16 1.2 D496 dl6 d23 dl6 d23 d41 D654 69 92 0.16 1.5 D622 dl0 dl4 dl1 dl4 d 46 Control group D625 dl3 dl5 dl3 dl5 NR CFU-GM Died d25 D593 dl4 dl6 dl3 dl6 d41 D449 233 0.83 9.1 D594 dl4 dl6 dl4 dl7 d40 D454 288 0.4 38 D621 7.1 150 0.76 G-CSF + LD SCF BFU-E D607 dl0 dl5 dl0 dl2 d42 D449 14 0 0 D579 dl1 dl6 dl1 dl5 d38 D454 0 0 0 D674 dl0 dl1 dl0 dl1 d27 1 71.5 0.06 0.65 0.06 71.5 D62 1 D676 dl4 dl9 dl3 dl9 d45 The numbers of CFC are calculated by the formula: [CFC per lo5 D663 d9 dl1 dl0 dl1 d32 cells X total MNC per mL of blood x IO5]. Abbreviations: NR, never recovered; d. day of event 3798 DE REVEL ET AL

Despite a relationship between the rate of myeloid recov- humans than in mice, dogs, or baboons. In the initial trial ery and the content of progenitor cells in the apheresis prod- reported by Crawford et al, doses above 25 pgkgld were uct of each group, we did not observe an individual relation- not tolerated because of urticaria, angioedema, and throat ship within each group. tightness.34Accordingly, we studied SCF at a low dose alone All long-term survivors displayed constant hematologic and combined with full-dose G-CSF. SCF at a low dose did recovery without secondary decreases of the WBC or plate- not mobilize cells capable of engraftment, but its combina- lets with follow-up up to 180 days. tion with G-CSF had a synergistic effect on the yield of CFC in the peripheral blood compared with G-CSF alone. This DISCUSSION was associated with more rapid hematopoietic recovery after Hematopoietic growth factors have been used extensively irradiation using the same number of PBMC infused, proba- in clinical settings for shortening hematopoietic recovery bly secondary to a higher number of progenitors in the apher- following chemotherapy or bone marrow tran~plantation,'~-*~ esis product. and more recently for their ability to mobilize hematopoietic Platelet recovery after ABMT is often delayed and does progenitors in the peripheral Mobilized progenitors not seem to be influenced by administration of G-CSF or are able to hasten engraftment when used with bone marrow GM-CSF posttransplant.11.23Several studies reported a bene- Downloaded from http://ashpublications.org/blood/article-pdf/83/12/3795/614678/3795.pdf by guest on 27 September 2021 tran~plantation'~*'~and more recently have been substituted ficial effect of G-CSF mobilized PBMC when added to bone for Further, mobilized progenitors are of great marro~,'~,~~despite a lack of effect in vitro on megakaryocy- interest as targets for gene the rap^.'^ topoiesis. Time to platelet recovery has been correlated to Our experimental model is designed to evaluate the en- the yield of CFU-GM infused which may, in part, explain grafting potential of peripheral blood progenitors by using the best recovery in the combination group where the number a low-dose of PBMC, which allows for differences between of CFlJ-GM per lo8PBMCkg was significantly higher than cell populations to be seen. Since both SCF and G-CSF have in the two other groups. While SCF does not have prolifera- been reported to mobilize progenitors, we were interested in tive effects on megakaryocyte progenitors, it does have a comparing them when used individually and in combination marked synergistic effect in vitro when combined with cyto- in our canine model. kines acting on early stages of megakaryocytopoiesis such G-CSF has been used for several years to mobilize hema- as IL-3.33Given our results demonstrating in vivo a benefit of topoietic progenitors in the peripheral blood. Molineux et a1 the combination of SCF and G-CSF in mobilizing peripheral described first in the mouse model the ability of G-CSF blood progenitors, it seems attractive in future trials to ex- mobilized progenitors to rescue recipients after irradiation? plore other combinations which may include IL-3 or IL-6 to With our quantitative model we demonstrate that a yield of try to achieve even greater mobilization. PBMC, otherwise unable to engraft, can rescue recipients if collected after G-CSF administration. While one major activ- REFERENCES ity of G-CSF is its action on late progenitors of granulo- 1. Barnes DWH, Loutit JF: Haematopoietic stem cells in the pe- poiesi~,~'it also has an effect on multipotential progenitors.3i ripheral blood. Lancet 2: 1138, 1967 2. Goodman JW, Hodgson GS: Evidence of stem cells in the CD34 positive cells have been shown to rise in the peripheral peripheral blood of mice. Blood 10:702, 1962 blood after treatment by G-CSF as assessed by FACS analy- 3. 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