Use of Hematopoietic Growth Factors to Control Myelosuppression Caused by Radioimmunotherapy1

[CANCER RESEARCH (SUPPL.) 50. I003s-1007s. February 1. 1990) Use of Hematopoietic Growth Factors to Control Myelosuppression Caused by Radioimmunotherapy1

R. D. Blumenthal, R. M. Sharkey, L. M. Quinn, and D. M. Goldenberg2

Center for Molecular Medicine and Immunology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

Abstract man peripheral T-lymphoid cells (14). In vivo studies demon strated that IL-1 administration could increase survival time of Therapeutically efficacious doses of I31l-antibody result in a loss in mice following ionizing radiation (15). In a report by Schwartz circulating white blood cells; the granulocyte population is suppressed by 80-85% and the agranulocytes by 60-65% following 2 mCi of I31I- et al. (16), pretreatment of mice with IL-1 prior to lethal irradiation resulted in more erythroid colony-forming units, antibody in hamsters. The administration of 100,000 units of human erythroid burst-forming units, granulocyte-macrophage colony- recombinant interleukin 1 24 h prior to radioantibody can prevent the loss in WBC from 1 mCi of radioantibody and reduce the loss from 2 forming cells, and spleen colony-forming units than in saline- mCi of antibody. Recombinant murine granulocyte-macrophage colony- treated controls. IL-1-dependent increases in survival following stimulating factor is also a potent stimulator of myelopoiesis and may irradiation can be correlated with increases in the total number also be useful as a method of reducing radioantibody-induced myelo- of colony-forming units as well as increases in bone marrow suppression. The tumor uptake of radioantibody in animals treated with and peripheral blood cellularity (17). We have recently shown recombinant interleukin 1 is reduced by 30% 1 day after injection of that pre- or posttreatment with IL-1 can be an effective method radioantibody but returns to levels seen in animals not treated with the to prevent or reverse radioantibody-induced myelosuppression, cytokine at 96 and 168 h. Therapeutic efficacy is not compromised by respectively (18). GM-CSF is another cytokine that induces doses of interleukin 1 used to prevent myelosuppression. Therefore, the maturation and growth of hematopoietic cells (19-21). GM- use of cytokines will permit the use of higher doses of radioantibody for greater tumor therapy with less myelotoxicity than in the absence of CSF has been used effectively to induce recovery from radial ion cytokine treatments. and chemotherapy-induced hematopoietic suppression (22-24). In this report, we evaluate the effectiveness of using either IL- 1 or GM-CSF to ablate RAIT-induced myelosuppression. Introduction Radioantibody-mediated tumor regression has been reported for numerous tumor xenograft models (1-4). Clinical trials with Materials and Methods RAIT' have also been initiated by several investigators (5, 6). Antibody Purification and Radioiodination. Goat anti-CEA antibody Radionuclides coupled to antibodies are more advantageous was prepared by affinity chromatography using a CEA immunoadsor- than drug and toxin conjugates because radioantibodies need bent, as described elsewhere (25). Purity was assessed by immunoelec- not be internalized in order to mediate cell killing, nor must trophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis they bind to every tumor cell to be therapeutically efficacious. of reduced and unreduced samples, and size exclusion high pressure a- and ÃŸ-emitters can kill at distances of 50 or more cell liquid chromatography on Micropak TSK-3000 SW (7.5 x 300 mm; diameters (7). It is this property, however, that also constitutes Varian, Walnut Creek, CA). lodination with '"I (Du Pont-New England Nuclear, North Billerica, the greatest potential limitation to RAIT, namely toxicity to MA) was performed by the chloramine-T method (26) to a specific adjacent normal tissues. Mitotically active precursor cells in activity of 12-15 mCi/mg. Free radioiodinc was removed by passing hematopoietic tissues are depleted by low levels of radiation. the labeled material over a PD-10 column (Pharmacia). All radioanti The supply of mature cells to the peripheral circulation is then body preparations were characterized by molecular sieve chromatogra diminished and resistance to pathogens decreases within weeks phy over an S-200 column (1.6 x 60 cm; Pharmacia) and for immuno- after irradiation (8). We have observed a 50-85% reduction in reactivity by passage through a CEA immunoadsorbent. There was less pWBC lasting 5-9 weeks following a single dose of 1-3 mCi of than 5% aggregated antibody and less than 3% free iodine in all u'I-labeled intact antibody in the Syrian hamster.4 Dosimetrie radioantibodies. Immunoreactivity of the labeled material was in the evaluation in one reported animal study indicated that a thera range of 60-75%. peutically effective dose of '"I-antibody yielded a radiation Animal Model. Ten- to 14-week-old female Syrian hamsters were dose of 16.3 and 32.3 Gy to marrow and spleen, respectively implanted with GW-39 tumors, a serially propagated CEA-producing (9). Mild to severe leukopenia has also been reported in clinical human colonie xenograft (27, 28), in both cheek pouches. Transplants were performed with 20% suspensions (w/v) in 0.5 ml phosphate- trials by Ettinger et al. (10) and Larson et al. 11). buffered saline (0.01 M phosphate-0.15 M NaCI-0.02% NaN3, pH 7.2). One approach to reduce host myelotoxicity involves the use For biodistribution analysis of radioantibody, the animals were given of immunomodulators which have been reported to confer i.p. injections of 100 MCiof '"I-labeled goat anti-CEA and 25 MCiof radioprotection. Thirty years ago, lipopolysaccharide, a micro- 125I-labelednormal goat IgG. At specified time intervals, the animals bial component, was shown to enhance hematopoietic and were sacrificed and radioactivity in the blood, tumor, and organs (liver, immune functions (12, 13). More recently, IL-1, a lipopolysac- spleen, kidney, lung, and muscle) was determined with a gamma scin charide-stimulated product, conferred radioprotection to hu- tillation counter. All data were corrected for physical decay and back- scatter of '"1 into the '"I channel. For therapy studies, tumor growth 1Presented at the "Second Conference on Radioimmunodetection and Ra dioimmunotherapy of Cancer." September 8-10, 1988. Princeton. NJ. Supported rate was determined by measuring the size of each tumor on day 0 in part by NIH Grant CA39841. when the radioantibody was administered and at weekly intervals there ! To whom requests for reprints should be addressed, at the Center for after. The hamsters were anesthetized with sodium pentobarbital (6.5 Molecular Medicine and Immunology. 1 Bruce Street, Newark, NJ 07103. mg/100 g of animal) and the cheek pouches were everted to permit J The abbreviations used are: RAIT, radioimmunotherapy; CEA, carcinoem- caliper measurements in 3 dimensions. Tumor volume in cm3 was bryonic antigen; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-1, interleukin 1; pWBC, peripheral WBC. calculated as the product of length x width x thickness. The average 4 R. D. Blumenthal. R. M. Sharkey, R. Kashi, and D. M. Goldenberg, unpub change in tumor size of 10-12 tumors was recorded. lished results. 1988. Cytokines. Recombinant human IL-1 (lot 1-87) was a gift from Dr. 1003s

P. Lomedico of Hoffmann-LaRoche Inc., Nutley, NJ. The preparation 8000 had a specific activity of 3 x 10" units/mg. The protein was purified from Escherichia coli, consisted of the carboxyl-terminal 154 amino acids of the 271 amino acids found in the human IL-1 precursor, and was essentially free from endotoxin (29). A lyophilized preparation of murine GM-CSF (lot 620-029) was made available by Immunex, Se attle, WA. The powder was diluted to the desired concentration with phosphate-buffered saline (pH 7.4) and used the same day. WBC Measurements and HistolÃ³gica) Evaluations. Anesthetized hamsters were bled by cardiac puncture and samples were collected into heparinized syringes. RBC were lysed as described previously (18). WBC were quantitated with an Ortho Spectrum III laser flow cytometer equipped with a micropressor which records total number of cells and sorts cells by their size and internal complexity into granulocyte and agranulocyte populations. pWBC values of groups of treated animals are reported either as a percentage of the untreated group or as the absolute number of cells/Vl of blood. Slides were prepared from each blood sample and stained with Wright's dye, and individual leukocyte populations were identified and quantitated.

Results Recombinant human interleukin administered as a single i.p. O Untreated injection augments the number of total pWBC in a dose- â€¢¿2mCi I-131-Ab dependent manner (Fig. 1). This stimulation ranges from 1.6- to 4.0-fold as doses of IL-1 are escalated from 25,000 to 100,000 units of lymphocyte-activating factor activity. A 1.0-mCi dose of ml radioantibody results in a 50-55% decline in pWBC within 7 days. A 24-h pretreatment with 25,000 units of IL-1 reduced this pWBC loss to 35%. Higher doses of IL-1 (50,000- 100,000 units) elevated WBC 2.0-2.5-fold above the levels observed in untreated animals. Partial protection was achieved (80% of untreated levels) with 100,000 units of IL-1 adminis tered 24 h before a 2.0-mCi dose of '" I-antibody, which itself resulted in a 75-80% loss in WBC. In addition, administration of IL-1 7 days after radioantibody treatments yielded a partial 20 40 60 recovery (25% increase) from myelosuppression (18). Further Days Post Injection of Radioantibody studies are under way to determine the optimal number of Fig. 2. Total pWBC. granulocytes. and agranulocytes were monitored by flow treatments and the optimal schedule of administration of IL-1 cytometry over a 7-week period in groups of 10 animals that were untreated or for both protection and rescue from radioantibody-induced treated with 2 mCi of '"I-antibody (Ab). Results are recorded as the absolute number of cells/mm3 in whole blood [mean Â±SD (bars)]. hematopoietic injury. Analysis of the subpopulations of WBC affected by radioan tibody therapy is shown in Fig. 2. Fourteen days after a 2.0- mCi dose of '"I-antibody, the circulating granulocytes were 65%. The animals recover from this loss within 6 weeks after reduced by 80-85% and the agranulocytes were reduced by 60- the initial 2-mCi dose of radioantibody (4-5 weeks for a 1.0- mCi dose of the same antibody; data not shown). This extended Peripheral WBCs 7 Days Post 1 mCi 1-131-Ab time for recovery from myelosuppression would therefore pre vent administration of a second treatment of radioantibody for 500 up to 6 weeks. Furthermore, it becomes essential that the CD Untreated method chosen to increase pWBC levels, either before or after 400 â€¢¿l1mCi 1-131 -Ab radioantibody therapy, be stimulatory to both granulocytes and o v agranulocytes. 300- Examination of the enhancement of subpopulations of WBC with II-1 or with GM-CSF is shown in Fig. 3. A 24-h pretreat 200- ment with either IL-1 or GM-CSF provides a 2.6-fold or 2.1- oCO fold stimulation of granulocytes, respectively, and both resulted m 100- in a 1.8-fold stimulation of agranulocytes after 24 h. Since both cytokines were effective at stimulating both populations of leukocytes, the choice of cytokine for future use will depend on 0 2.5 5.0 10.0 which cytokine is tolerated better on repeated dosing. In addi rH-IL-1 (Units x 104) tion, we are currently evaluating the stimulatory effective of Fig. 1. Matched aged hamsters were assigned lo one of the following groups: both cytokines administered simultaneously. (a) untreated: (b) those treated with one of three doses of IL-1 alone; (c) those We next assessed the biodistribution of radioantibody as the treated with 1 mCi of '"I-antibody (Ah) alone: and (

pWBCs 24 hours after Cytokine Administration known. The total rad dose of tumors was 1381 rads/mCi from untreated animals and 1189 rads/mCi from IL-1-treated ani iz-10-Ã®o- mals, a 16% decline. However, this reduction may not have any-

TotalpWBCsâ€¢â€¢ biological significance, since the therapeutic efficacy of radioan tibody is not compromised by IL-1 treatment (Fig. 4). GranulocytesCH 8-Xto 'I5*1Agranulocytes /1/ V| Discussion E6-E.g TÃ©l Myelosuppression is a major side effect associated with pa 11 tients undergoing either radiotherapy or chemotherapy (30). 4-502-Q7771 This effect has also been reported in clinical trials with radioan tÃ•[*l X tibody therapy (10, 11). Hematopoietic toxicity can put patients 1â€¢â€¢¿ at risk to life-threatening infections, due to reduced pWBC. An ! â€¢¿â€¢¿ X N : X agent or method capable of preventing hematopoietic injury or XUntreatedIs/1

Table 1 Biodistribution of "I-goal anti-CEA in untreated or IL-1-treated animals % injected dose/g h1.81 h2.38 h1.18 Untreated100.000 Â±0.47Â°0.58 Â±0.310.24 Â±0.780.08 Â±0.110.54 Â±0.050.26 Â±0.020.1 Â±0.100.74 Â±0.050.28 2Â±0.060.11 Â±0.120.93 Â±0.090.50 Â±0.030.1 Â±0.422.29 Â±0.061.21 7Â±0.030.41 Â±0.621.16 Â±0.161.94 Â±0.091.41

units IL-1TissueGW-39LiverSpleenKidneyLungsBloodGW-39LiverSpleenKidneyLungsBloodN147777724131313131324Â±0.400.48 Â±0.740.1 Â±0.940.08 Â±0.110.50 7Â±0.050.1 Â±0.030.08 Â±0.090.63 7Â±0.050.23 Â±0.030.10 Â±0.140.82 Â±0.070.33 Â±0.040.15 Â±0.181.96 Â±0.110.73 Â±0.050.33 Â±0.36N158888836181818IS1896 Â±0.24N16888882615151515IS168 Â±0.13 ' Mean Â±SD. 1005s

(16, 39). In addition, radioprotection may also be the result of noembryonic antigen. Cancer Res., 47: 5672-5677, 1987. the ability of IL-1 to induce the production of acute-phase Order, S. E. Analysis, results and future prospective of the therapeutic use of radiolabeled antibody in cancer therapy. In: R. W. Baldwin and V. S. Byers reaction proteins which have free radical-scavenging capabilities (eds.). Monoclonal Antibodies for Cancer Detection and Therapy, pp. 303- (17). IL-1 is also able to stimulate the production of other 316. New York: Academic Press. 1985. Carrasquillo. J. A., Krohn, K. A., Beumier. P.. McGaffin, R. W., Brown, J. colony-stimulating factors (40). It is for this reason that we are P., HellstrÃ¶m,K. E., HellstrÃ¶m,I., and Larson, S. M. Diagnosis and therapy currently exploring the myeloprotective and recovery possibili for solid tumors with radiolabeled antibody and immune fragments. Cancer ties of combining IL-1 with other growth factors (e.g., GM- Treat. 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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1990 American Association for Cancer Research. Use of Hematopoietic Growth Factors to Control Myelosuppression Caused by Radioimmunotherapy

R. D. Blumenthal, R. M. Sharkey, L. M. Quinn, et al.

Cancer Res 1990;50:1003s-1007s.

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