The loss of expression of the cyclin-dependent kinase

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1 D2000 Nature America, Inc /00/$15.00/+0 Gene therapy of established mesothelioma xenografts with recombinant p16 INK4a adenovirus Sandra P.Frizelle, 1 Jeffrey B.Rubins, 1,2 Joan X.Zhou, 1 David T.Curiel, 3 and Robert A.Kratzke 1,4 1 The Department of Medicine and Research Service, Minneapolis Veterans Affairs Medical Center, University of Minnesota Medical School, Minneapolis, Minnesota 55417; 2 Pulmonary and Critical Care Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55417; 3 Gene Therapy Program, University of Alabama, Birmingham, Alabama 35294;and 4 Sections of Hematology/Oncology/Transplant, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota The absence of expression of the p16 INK4a gene product is observed in virtually all mesothelioma tumors and cell lines, whereas wild-type prb expression is maintained. We have examined the potential therapeutic role of re-expressing the p16 INK4a gene product in mice with established human mesothelioma xenografts. Experiments using Adp16 treatments in mesothelioma xenografts demonstrated prolonged survival and potential cure following treatment with p16 INK4a -based gene therapy. These results demonstrate that p16 INK4a gene transfer may play a therapeutic role in the treatment of mesothelioma. Cancer Gene Therapy (2000) 7, 1421±1425 Key words: p16 INK4a ; mesothelioma; tumor suppressor; gene therapy; cell cycle. The loss of expression of the cyclin-dependent kinase (Cdk) inhibitor, p16 INK4a, occurs in the overwhelming majority of mesothelioma cell lines and tumors examined. 1 As seen in a variety of other tumors, the molecular phenotype of absence of p16 INK4a expression is associated with retention of wild- type expression of the critical cell cycle regulator prb. Re-expression of p16 INK4a in mesothelioma cells and xenografts is associated with cell cycle arrest, cell growth inhibition, and apoptosis. 2 Mesothelioma presents clinically with tumors involving the parietal or visceral pleura or, less commonly, the parietal peritoneum. 3 Because of the anatomical location of these cancers within a body cavity, these tumors have presented attractive targets for intracavitary gene therapy. Currently, gene therapy approaches using direct instillation of viral vectors into the pleural cavity in mesothelioma are being carried out. 4 The present study was designed to treat, prolong survival, and cure mice with established mesothelioma xenografts with p16 INK4a -based gene therapy, and compare these therapies directly to no treatment or treatment with gene therapy expressing only a control protein, - galactosidase. Received March 8, 2000;accepted July 8, Address correspondence and reprint requests to Dr. Robert A. Kratzke, Section of Hematology/ Oncology 111E, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN address: MATERIALS AND METHODS Cell lines and cell culture The cell lines used in this study were derived, characterized, and propagated as previously published. 4±7 Mesothelioma cell lines were obtained in collaboration with Dr. Frederick Kaye ( National Cancer Institute). All the studies used cells propagated in RPMI 1640 media supplemented with 10% fetal bovine serum. Four mesothelioma cell lines that had previously been shown to be sensitive to Adp16 transduction in vitro were tested in the murine model. 2 The mesothelioma cell lines H513, H2373, H2461, and H2595 grow as adherent cultures in standard tissue culture dishes. All mesothelioma cell lines we previously examined have shown cell growth inhibition when transduced with the Adp16 vector. 2 Like all mesothelioma cell lines that have been examined, these four cell lines retain wild-type expression of prb while demonstrating no expression of the p16 INK4a gene product, thus possessing a molecular phenotype that should be sensitive to p16 INK4a -mediated cell cycle inhibition. 2 Adenoviral vectors Construction, propagation, and titering of the Adp16 and Adlacz viral vectors are described elsewhere. 8 Viral stocks (both p16 INK4a ± and -galactosidase±expressing vectors) were propagated in 293 cells from a single plaque and were subsequently tested for gene product expression by immunoblotting as described. 2 Viral stocks were then titered and frozen in glycerol aliquots for use in the study. Prior to freezing, stocks were tested on the control cell lines ( cell : pp 1421±

2 1422 FRIZELLE, RUBINS, ZHOU, ET AL: P 16 INK4a THERAPY IN MESOTHELIOMA lines to be treated in experiments described) to ensure that they remained replication- deficient. The Adp16 construct expresses a functional p16 INK4a that is translated from a start codon eight codons past the consensus start codon as first reported. 9 The resulting protein is slightly smaller than the endogenous p16 INK4a protein, yet remains fully functional in its capacity to inhibit Cdk4- mediated phosphorylation and to suppress cell growth. 2,7,8,10,11 The Adp16 vector was generated at the Gene Therapy Program, University of Alabama, Birmingham. 8 Intraperitoneal tumors In experiments in which established tumors were treated, athymic nude mice (Balb/C) (Harlan, Indianapolis, IN) were inoculated with mesothelioma cells 1, 2, or 4 weeks prior to beginning treatment with the viral vectors. Although the animals developed widespread diffuse intraperitoneal disease, mice with established mesothelioma xenografts that died usually developed progressive obstructive jaundice as previously described from common bile duct involvement with tumor. 12 Adenoviral injections Adenoviral injections were carried out in a volume of 100 L of sterile phosphate- buffered saline injected directly into the intraperitoneal cavity. Injections consisted of pfu/injection for both vectors. 12 The titer used in these injections was the minimum previously demonstrated to result in gene product expression in murine mesothelioma intraperitoneal xenografts. 13 Injections began after a fixed period for the development of intraperitoneal tumors, which varied depending upon the growth rate of the tumors derived from the various cell lines ( Fig 1). Once treatments started, injections were delivered three times a week for the remainder of the animal's life. Animals that appeared premorbid from their disease were euthanized. For cell line H2373, one experiment began after 2 weeks of tumor growth, and the second after 4 weeks. However, in experiments involving the more rapidly growing cell line H513, one experiment began after 1 week of tumor growth, and the second after 2 weeks. Attempts to grow H513 tumors for 4 weeks resulted in the death of the animals before the end of the 4 weeks of tumor growth from progressive disease prior to beginning the treatments. Injections of the mesothelioma cell line, H2461, began after 4 weeks of In all of the experiments, four groups of five mice were tested. This number, although small, would provide sufficient power to demonstrate a 5- fold increase in survival (P=.05). One group consisted of untreated mice that were sacrificed at the time that treatment began in order to assure the development of widespread intraperitoneal disease, a second group received no treatment, a third group received Adlacz, and the final group received Adp16 (Fig 1). Statistical analysis Survival curves were calculated by the Kaplan- Meier method and compared using the log rank test, with a P value of <.05 considered significant. Calculations were performed using SPSS 1 for Windows (release 6.1, Chicago, IL). RESULTS Three of four cell lines that had previously demonstrated sensitivity to in vitro transduction of the p16 INK4a gene 2 were found to be capable of forming intraperitoneal tumors and were subsequently tested in our murine xenograft model. A fourth cell line, H2595, which had been tested in previous in vitro studies, failed to form tumors after injection into mice in our model system and thus could not be used in these studies. Figure 1. Schema for treatment of established human mesothelioma xenografts in mice. Groups of 20 mice received intraperitoneal injection of H513, H2373 cells, or H2461 cells. After 1, 2, or 4 weeks, treatments with viral vectors would begin. Mice injected with H513cells began treatments after 1 or 2 weeks. Mice injected with H2373 cells began treatments after 2 or 4 weeks. Mice injected with H2461 began treatment after 4 weeks. In all experiments, one group of mice (n=5) was sacrificed at the start of treatment to ensure and assess establishment of disease. The remaining mice received either Adp16 (n=5), Adlacz ( n=5), or no treatment (n=5).

3 FRIZELLE, RUBINS, ZHOU, ET AL: P 16 INK4a THERAPY IN MESOTHELIOMA 1423 Figure 2. Survival of mice with established H2373 mesothelioma xenografts treated with Adp16 beginning treatments after 2 weeks of Tumors that arose following intraperitoneal injection of cells of the H2373 cell line were allowed to grow for either 2 ( Fig 2) or 4 weeks ( Fig 3) following implantation. Following the 2- or 4- week period of tumor establishment and growth, mice were started on treatment with either Adp16, Adlacz, or no treatment. There were five mice in each of the three arms of the study. A fourth group of mice was sacrificed at the time of the beginning of therapy (2 or 4 weeks after implantation) to assure establishment of intraperitoneal disease. In all cases when this control group was sacrificed at the time of commencing treatment, there was diffuse disease throughout the peritoneal cavity of the mice. In the two arms of the studies that received adenoviral treatment ( Adp16 or Adlacz), viral therapies were intraperitoneally delivered at a dosage of 10 9 pfu every Monday, Wednesday, or Friday (Fig 1). In both of these experiments, there were mice alive exclusively in the Adp16 treatment group at the time when all of the mice in the other two arms were dead (Figs 2 and 3). In the experimental cohort that began treatment following 2 weeks of tumor growth (Fig 2), Kaplan- Meier survival analysis demonstrated a strong statistical significance in improved survival in the Adp16- treated group as compared to the untreated or Adlacz- treated Figure 4. Survival of mice with established H513mesothelioma xenografts treated with Adp16 beginning treatments after 1 week of mice (P=.0309). The treatment group that started treatment after 4 weeks of tumor growth appeared to have superior survival in the Adp16- treated group as well ( Fig 3), although it did not reach statistical significance. At the time that all of the mice in the untreated or Adlacz-treated groups were dead of progressive disease ( as identified at necropsy), two mice remained alive in the Adp16-treated group. One of these was a long-term survivor and following sacrifice was found to be free of disease and likely cured. Mice that received the H513 cell line had a more aggressive disease course ( consistent with the more robust in vitro growth of this cell line) and thus were treated beginning only 1 and 2 weeks following tumor establishment (Fig 1). Mice that had treatment, which began 1 week after tumor establishment, had an apparent trend toward superior survival in the Adp16-treated group (P=.0725) (Fig 4), although eventually all mice died of progressive disease. All of these treatment groups possessed subcutaneous ( extraperitoneal) tumors that grew at the cell injection site. These extraperitoneal tumors grew and progressed equally in all arms of the study, suggesting the absence of any detectable antitumor effect outside of the peritoneum from intraperitoneally administered Adp16 Figure 3. Survival of mice with established H2373 mesothelioma xenografts treated with Adp16 beginning treatments after 4 weeks of Figure 5. Survival of mice with established H513mesothelioma xenografts treated with Adp16 beginning treatments after 2 weeks of

4 1424 FRIZELLE, RUBINS, ZHOU, ET AL: P 16 INK4a THERAPY IN MESOTHELIOMA Figure 6. Survival of mice with established H2461 mesothelioma xenografts treated with Adp16 beginning treatments after 4 weeks of therapy. In mice with tumor xenografts from H513 cells that were allowed to grow for 2 weeks prior to beginning treatment, there was a less pronounced trend toward superior survival (P=.1311) (Fig 5). However, as in the previous experiments, the mice surviving the longest were from the Adp16- treated group. Mice receiving a third cell line, H2461, in addition to developing extensive intraperitoneal disease, developed sanguinous ( bloody) peritoneal effusions. This was different from the previous two cell lines tested. Following 4 weeks of tumor growth after implantation, the mice were treated as in the previous experiments. This time, however, there was no difference in survival between any of the treatment or control groups (P=.9528) (Fig 6). In summary, a total of 75 mice with well-established and diffusely spread intraperitoneal mesothelioma xenografts were treated with Adp16 therapy (n=25), Adlacz (n=25), or no treatment (n=25). Three different cell lines were used and several different time points for beginning treatment were tested. In general, Adp16 treatment was associated with a longer survival in all but the H2461 cell line. When the five experiments were analyzed as an aggregate (Fig 7), Adp16 therapy was associated with a highly significant prolongation (P=.0050) in survival when compared to the other two modalities ( Fig 7). There was no significant difference in survival in any of the trials between the no treatment and Adlacz treatment groups. The one mesothelioma cell line in which there was no therapeutic effect was the H2461 cell line, which produced sanguinous effusions in all mice injected with this cell line (including the group receiving no treatment). Excluding this cell line from the aggregate analysis demonstrated an even stronger significance ( P=.0010) toward the beneficial effects of Adp16 therapy. locally administered gene-based therapies. 4 Loss of p16 INK4a gene product expression is perhaps the most common molecular abnormality in these tumors. In this study, we have identified that re- expression of exogenous p16 INK4a by adenoviral-based vectors appears to be effective in the murine model for prolonging life and possibly curing this disease in some cases. As our protocol was designed to study intraperitoneal tumors in the absence of whole body scanning, we cannot adequately address whether Adp16 therapy results only in slower tumor progression or in tumor regression followed by progression. It is a compelling evidence of tumor regression; however, it should be noted that the few long-surviving mice were all in the Adp16- treated groups, including mice with no detectable disease. Our previous studies demonstrated that re- expression of p16 INK4a results in apoptosis of mesothelioma cells, which would be consistent with a model of tumor regression. 2 In any event, it is obvious that as currently designed, the effectiveness of this therapy appears modest in its potential to cure these mesothelioma xenografts. In comparison, the effects seen in the current study appear less dramatic than those previously described for mesothelioma xenografts using virally transduced HSVtk followed by ganciclovir. 15 One of the major drawbacks with the technology we have used is the need for high levels of vector administration. The doses we gave, 10 9 pfu three times per week, were largely limited by the amount of vector that we could conveniently produce and deliver. It is likely that higher doses of vector would result in increasingly greater therapeutic effect consistent with the previously demonstrated in vitro dose response data. 2 One of the cell lines tested, H2461, was totally resistant in the murine model to Adp16 therapy. This cell line has been shown to be sensitive to in vitro transduction of Adp16. 2 This highlights another potential deficiency in adenoviralbased therapy. Although these therapies can be effectively delivered in humans and are currently in clinical trials, 4 these vectors are quickly inactivated in blood. It is possible that sanguinous ( bloody) effusions may prove refractory to this type of therapy. Many of the pleural effusions that are observed in mesothelioma are found to be sanguinous. 3 DISCUSSION Mesothelioma is a largely incurable cancer of the pleural or peritoneal linings of the body cavities. 3,14 It progresses locally with metastases occurring in only the latest stages of disease. As such, it makes an attractive theoretical target for Figure 7. Combined survival curves of all treatment groups with established mesothelioma xenografts.

5 FRIZELLE, RUBINS, ZHOU, ET AL: P 16 INK4a THERAPY IN MESOTHELIOMA 1425 Although loss of p16 INK4a expression occurs commonly in mesothelioma, its re- expression in these cells would not be expected to cause anything more than cell cycle arrest. One hypothesis for why these cells may be sensitive to p16 INK4a expression may be related to the relative absence of p53 mutations seen in mesothelioma. 6,16 The exogenous coexpression of wild-type p53 and p16 INK4a has been noted to cause death in a variety of transformed cells. 17 In view of the extremely common, perhaps universal, mesothelioma phenotype of loss of p16 INK4a protein with retention of wildtype p53 and prb, 1 re-expression of an exogenous p16 INK4a may be expected to lead to cell death. Consideration also needs to be given to the reported presence of SV40 sequences in mesotheliomas. 16 This remains an intriguing observation that suggests a significant role for SV40 large T antigen in the dysregulation of the cell cycle regulatory machinery in mesothelioma. Given the capacity for SV40 large T antigen to bind both p53 and prb, 18 it is difficult to know what effect the presence of SV40 large T antigen may have following exogenous re-expression of p16 INK4a. Nonetheless, following re- expression of exogenous p16 INK4a, p16 INK4a -mediated G 1 phase Cdk inhibition, followed by prb hypophosphorylation and cell cycle arrest, is intact in mesothelioma cell lines and apparently unaffected by the presence of any functional SV40 large T antigen. 2,7 Adp16 therapy for mesothelioma holds promise for prolonging life and offering a potential cure for mesothelioma. Nonetheless, more efficient methods of transduction appear necessary for truly effective gene-based therapies for this disease. It is almost certain that most mesothelioma cells will prove to be susceptible to cell cycle arrest by exogenous re-expression of p16 INK4a. 2 Whether this common molecular phenotype can be further exploited for the clinical benefit of patients afflicted with this largely incurable disease likely awaits the use of either very high titer of currently available vectors, more efficient vectors, or perhaps novel nonviralmediated methods of p16 INK4a re-expression. ACKNOWLEDGMENTS The authors thank Alexander Shar, Ryan Dick, and Jacob Liston for their assistance with animal care. This study was supported by grants from the Minnesota Medical Foundation ( R.A.K), the Research Service of the Department of Veterans Affairs ( R.A.K), and the National Institutes of Health (D.T.C.) (R01 CA72532; R01 CA74242). REFERENCES 1. Xu HJ, Hu SX, Hashimoto T, Takahashi R, Benedict WF. The retinoblastoma susceptibility gene product: a characteristic pattern in normal cells and abnormal expression in malignant cells. Oncogene. 1989;4:807 ± Frizelle SP, Grim J, Zhou J, et al. Re-expression of p16 INK4a in mesothelioma cells results in cell cycle arrest, cell death, tumor suppression and tumor regression. Oncogene. 1998;16:3087 ± Borow M, Conston A, Livornese L, Schalet N. Mesothelioma following exposure to asbestos: a review of 72 cases. Chest. 1973;64:641 ± Treat J, Kaiser LR, Sterman DH, et al. Treatment of advanced mesothelioma with the recombinant adenovirus H5.010RSVTK: a phase 1 trial (BB-IND 6274). Hum Gene Ther. 1996;7:2047 ± Pass HI, Stevens EJ, Oie H, et al. Characteristics of nine newly derived mesothelioma cell lines. Ann Thorac Surg. 1995;59: 835± Pass HI, Mew, DJ. In vitro and in vivo studies of mesothelioma. J Cell Biochem Suppl. 1996;24:142 ± Kratzke R, Otterson, GA, Lincoln, CE, et al. Immunohistochemical analysis of the p16 INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma. J Natl Cancer Inst. 1995;87:1870 ± Grim J, D'Amico A, Frizelle S, Zhou J, Kratzke RA, Curiel DT. Adenovirus- mediated delivery of p16 to p16- deficient human bladder cancer cells confers chemoresistance to cisplatin and paclitaxel. Clin Cancer Res. 1997;3:2415 ± Nihei T, Takahashi S, Sagae S, Sato N, Kikuchi K. Protein interaction of retinoblastoma gene product prb110 with M( r) 73,000 heat shock cognate protein. Cancer Res. 1993;53: 1702± Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell cycle control causing specific inhibition of cyclin D/ CDK4. Nature. 1993;366:704 ± Parry D, Peters G. Temperature-sensitive mutants of p16 CDKN2 associated with familial melanoma. Mol Cell Biol. 1996;16: 3844± Weintraub SJ, Prater CA, Dean DC. Retinoblastoma protein switches the E2F site from positive to negative element. Nature. 1992;358:259 ± Smythe WR, Kaiser, LR, Hwang, HC, et al. Successful adenovirus- mediated gene transfer in an in vivo animal model of human malignant mesothelioma. Ann Thorac Surg. 1994;57: 1395± Antman KH, Pass, HI, Recht A. Benign and malignant mesothelioma. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principle and Practices of Oncology. 3rd ed. Philadelphia: JB Lippincott; 1989:1399 ± Smythe WR, Hwang HC, Amin KM, et al. Use of recombinant adenovirus to transfer the herpes simplex virus thymidine kinase ( HSVtk) gene to thoracic neoplasms: an effective in vitro drug sensitization system. Cancer Res. 1994;54:2055 ± Carbone M, Rizzo P, Grimley PM, et al. Simian virus-40 large T antigen binds p53 in human mesotheliomas. Nat Med. 1997;3:908 ± Sandig V, Brand K, Herwig S, Lukas J, Bartek J, Strauss M. INK4 / CDKN2 Adenovirally transferred p16 and p53 genes cooperate to induce apoptotic tumor cell death. Nat Med. 1997;3:313 ± DeCaprio JA, Ludlow JW, Figge J, et al. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell. 1988;54:275 ± 283.

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