Skip Navigation LinksHome > April 2007 - Volume 2 - Issue 4 > Cytokine Gene Therapy for Malignant Pleural Mesothelioma
Journal of Thoracic Oncology:
doi: 10.1097/01.JTO.0000263706.23579.35
Pathway of the Month

Cytokine Gene Therapy for Malignant Pleural Mesothelioma

Vachani, Anil MD; Sterman, Daniel H. MD; Albelda, Steven M. MD

Free Access
Article Outline
Collapse Box

Author Information

Thoracic Oncology Research Laboratory, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania.

Disclosure: The authors declare no conflict of interest.

Address for correspondence: Anil Vachani, MD, Pulmonary, Allergy, and Critical Care Division, 1016A Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104. E-mail: avachani@mail.med.upenn.edu

The treatment of advanced pleural malignancies, such as malignant pleural mesothelioma (MPM), remains generally ineffective despite the use of surgery, external beam radiation therapy, and chemotherapy individually or in combination.1,2 Given the current lack of effective therapies, new treatment approaches for MPM are clearly needed, including the novel approach of intrapleural genetic immunotherapy. MPM is a particularly attractive target for gene transfer studies because of the paucity of effective therapies and the relative accessibility of the tumors in the pleural space for delivery of experimental therapies. Because MPM rarely metastasizes early to distant sites, treatment of the primary tumor can lead to significant palliative benefits and may potentially prolong survival.

Cancer gene therapy is defined as the transfer of genetic material, including full-length genes, complementary DNA, RNA, or oligonucleotides, into cancer or host cells for the ultimate purpose of killing an autologous tumor. The basis for cytokine gene therapy in MPM lies not only in the direct antiproliferative effects on mesothelioma cells but also in the ability of certain cytokines to activate systemic, intrapleural, and intratumoral immune effector cells. Although mesothelioma is well known to inhibit host cellular and humoral anti-tumor immune responses, animal and clinical data support the use of immunotherapeutic approaches.3,4 Prolonged local cytokine expression can activate tumor-associated dendritic cells to phagacytose tumor antigens (after the induction of tumor cell apoptosis) and to express these antigens on major histocompatibility complex heterodimers in conjunction with costimulatory molecules. These activated dendritic cells can then migrate to regional lymph nodes, where they stimulate the proliferation of CD4 and CD8 lymphocytes, inducing anti-tumoral cytotoxicity at distant tumor sites. Several published phase I and phase II clinical trials have documented mesothelioma tumor responses to intrapleural infusion of interleukin-2 (IL-2), interferon (IFN)-α, and IFN-γ.5–10

Back to Top | Article Outline

Interferons

IFNs (especially type I IFNs like IFN-α and -β) are known to inhibit tumor cell growth and stimulate the immune system.11 IFNs have immunoregulatory effects on antibody production, natural killer (NK) and T-cell activation, macrophage function, delayed-type hypersensitivity, and major histocompatibility complex antigen expression, as well as anti-proliferative effects and anti-angiogenic properties.12–16 The results of human clinical trials of IFNs in the treatment of various solid tumors have yielded disappointing results. This is, in part, related to the short plasma half-life of IFNs after systemic, local, or subcutaneous injection with a resulting lack of sustained tissue levels.17 Doses of systemic IFNs necessary to achieve intratumoral levels equivalent to those found in vitro to induce cytostatic and anti-proliferative effects are associated with significant, and likely intolerable, toxicity.18 The rationale behind the use of gene transfer approaches to cytokine therapy is that local, continuous delivery and production of IFNs in and around tumors would compensate for the short half-life of IFNs, inhibit tumor growth and metastasis, and minimize systemic side effects.

IFN-β gene transfer in animal models of various malignancies (both xenografts and autologous tumors) has demonstrated impressive anti-tumor effects (Figure 1).19–22 Preclinical studies in MPM have demonstrated that: 1) an adenoviral vector encoding mouse IFN-β (Ad.IFN-β) had dramatic therapeutic efficacy in syngeneic animal models of MPM;23–25 2) intraperitoneal and intratumoral injections of Ad.IFN-β showed significant activity both in the injected tumor and in distant tumors;23–25 and 3) in these models, this effect was immunologic, in large part because of the generation of cytotoxic T-lymphocytes directed against as yet undetermined tumor antigens and activation of natural killer cells. These experiments served as the basis for the initiation of a phase I clinical trial.

Figure 1
Figure 1
Image Tools

We hypothesized that the intracavitary administration of Ad.IFN-β through an indwelling pleural catheter would be an effective local and systemic treatment for advanced thoracic malignancies, such as MPM. After confirming vector safety in extensive rodent experiments, we initiated a single-center dose-escalation phase I clinical trial assessing the safety of single-dose intrapleural infusion of Ad.IFN-β in patients with MPM (and patients with metastatic pleural effusions).26 Secondary goals of the phase I clinical trial included evaluation of induced anti-vector and anti-tumor immune responses, viral shedding, and any discernible clinical responses. Given the ability to sample the pleural space with the indwelling catheter, we could also monitor intrapleural gene expression and immunologic responses. The results of this trial demonstrated that intrapleural Ad.INF-β was well tolerated, generated anti-tumor immune response in almost all of the patients, and resulted in encouraging anti-tumor activity (unpublished data).26

Back to Top | Article Outline

Future Directions

Although we may be able to generate anti-tumor responses with intrapleural Ad.IFN-β, we believe that, in bulky tumors, this will not likely be sufficient to effect a significant clinical response because of a low effector cell to target cell (tumor) ratio, strong immunosuppressive effects (mediated by factors such as prostaglandin E2, transforming growth factor β, or interleukin-10) within the tumor microenvironment, and restrictions of leukocyte trafficking. It is our hypothesis that the generation of anti-tumor reactive T-cells by administration of Ad.IFN-β will not be optimally effective unless other approaches are used to block immunologic checkpoints and enhance trafficking into tumors. Studies performed by our group have shown the utility of multiple vector dose administration, tumor debulking,27 adjuvant COX-2 inhibitors,28 and immunomodulatory chemotherapy (with drugs such as gemcitabine) when combined with Ad.IFN-β gene transfer. A second phase I study of repeated-dose intrapleural Ad.INF-β is currently ongoing at our institution, and the combination of Ad.IFN-β with surgery, chemotherapy, and/or COX-2 inhibitors will be incorporated into future phase II trials.

Back to Top | Article Outline

REFERENCES

1. Baldini EH, Recht A, Strauss GM, et al. Patterns of failure after trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 1997;63:334–338.

2. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636–2644.

3. Bielefeldt-Ohmann H, Fitzpatrick DR, Marzo AL, et al. Potential for interferon-alpha-based therapy in mesothelioma: assessment in a murine model. J Interferon Cytokine Res 1995;15:213–223.

4. Fitzpatrick DR, Manning LS, Musk AW, et al. Potential for cytokine therapy of malignant mesothelioma. Cancer Treat Rev 1995;21:273–288.

5. Astoul P, Picat-Joossen D, Viallat JR, et al. Intrapleural administration of interleukin-2 for the treatment of patients with malignant pleural mesothelioma: a Phase II study. Cancer 1998;83:2099–2104.

6. Boutin C, Viallat JR, Van Zandwijk N, et al. Activity of intrapleural recombinant gamma-interferon in malignant mesothelioma. Cancer 1991;67:2033–2037.

7. Boutin C, Nussbaum E, Monnet I, et al. Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer 1994;74:2460–2467.

8. Goey SH, Eggermont AM, Punt CJ, et al. Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I–II study. Br J Cancer 1995;72:1283–1288.

9. Robinson BW, Bowman R, Manning LS, et al. Interleukin-2 and lymphokine-activated killer cells in malignant mesothelioma. Eur Respir Rev 1993;3:220–222.

10. Christmas TI, Manning LS, Garlepp MJ, et al. Effect of interferon-alpha 2a on malignant mesothelioma. J Interferon Res 1993;13:9–12.

11. Lengyel P. Biochemistry of interferons and their actions. Annu Rev Biochem 1982;51:251–282.

12. Biron CA. Role of early cytokines, including alpha and beta interferons (IFN-alpha/beta), in innate and adaptive immune responses to viral infections. Semin Immunol 1998;10:383–390.

13. Qin XQ, Runkel L, Deck C, et al. Interferon-beta induces S phase accumulation selectively in human transformed cells. J Interferon Cytokine Res 1997;17:355–367.

14. Pfeffer LM, Dinarello CA, Herberman RB, et al. Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons. Cancer Res 1998;58:2489–2499.

15. Sen GC, Lengyel P. The interferon system: a bird’s eye view of its biochemistry. J Biol Chem 1992;267:5017–5020.

16. Brem H, Gresser I, Grosfeld J, et al. The combination of antiangiogenic agents to inhibit primary tumor growth and metastasis. J Pediatr Surg 1993;28:1253–1257.

17. Sturzebecher S, Maibauer R, Heuner A, et al. Pharmacodynamic comparison of single doses of IFN-beta1a and IFN-beta1b in healthy volunteers. J Interferon Cytokine Res 1999;19:1257–1264.

18. Ravandi F, Estrov Z, Kurzrock R, et al. A phase I study of recombinant interferon-beta in patients with advanced malignant disease. Clin Cancer Res 1999;5:3990–3998.

19. Yagi K, Hayashi Y, Ishida N, et al. Interferon-beta endogenously produced by intratumoral injection of cationic liposome-encapsulated gene: cytocidal effect on glioma transplanted into nude mouse brain. Biochem Mol Biol Int 1994;32:167–171.

20. Natsume A, Tsujimura K, Mizuno M, et al. IFN-beta gene therapy induces systemic antitumor immunity against malignant glioma. J Neurooncol 2000;47:117–124.

21. Natsume A, Mizuno M, Ryuke Y, et al. Antitumor effect and cellular immunity activation by murine interferon-beta gene transfer against intracerebral glioma in mouse. Gene Ther 1999;6:1626–1633.

22. Lu W, Fidler IJ, Dong Z. Eradication of primary murine fibrosarcomas and induction of systemic immunity by adenovirus-mediated interferon beta gene therapy. Cancer Res 1999;59:5202–5208.

23. Odaka M, Sterman DH, Wiewrodt R, et al. Eradication of intraperitoneal and distant tumor by adenovirus-mediated interferon-beta gene therapy is attributable to induction of systemic immunity. Cancer Res 2001;61:6201–6212.

24. Odaka M, Wiewrodt R, DeLong P, et al. Analysis of the immunologic response generated by Ad.IFN-beta during successful intraperitoneal tumor gene therapy. Mol Ther 2002;6:210–218.

25. Wilderman MJ, Kim S, Gillespie CT, et al. Blockade of TNF-alpha decreases both inflammation and efficacy of intrapulmonary Ad.IFNbeta immunotherapy in an orthotopic model of bronchogenic lung cancer. Mol Ther 2006;13:910–917.

26. Sterman DH, Gillespie CT, Carroll RG, et al. Interferon beta adenoviral gene therapy in a patient with ovarian cancer. Nat Clin Pract Oncol 2006;3:633–639.

27. Kruklitis RJ, Singhal S, Delong P, et al. Immuno-gene therapy with interferon-beta before surgical debulking delays recurrence and improves survival in a murine model of malignant mesothelioma. J Thorac Cardiovasc Surg 2004;127:123–130.

28. DeLong P, Tanaka T, Kruklitis R, et al. Use of cyclooxygenase-2 inhibition to enhance the efficacy of immunotherapy. Cancer Res 2003;63:7845–7852.

Cited By:

This article has been cited 4 time(s).

European Respiratory Journal
Local effector failure in mesothelioma is not mediated by CD4(+) CD25(+) T-regulator cells
Jackaman, C; Cornwall, S; Lew, AM; Zhan, Y; Robinson, BWS; Nelson, DJ
European Respiratory Journal, 34(1): 162-175.
10.1183/09031936.00101008
CrossRef
Current Treatment Options in Oncology
Peritoneal Mesothelioma
Hesdorffer, ME; Chabot, J; DeRosa, C; Taub, R
Current Treatment Options in Oncology, 9(): 180-190.
10.1007/s11864-008-0072-2
CrossRef
Cancer Research
Endothelial Cell Protein C Receptor Opposes Mesothelioma Growth Driven by Tissue Factor
Keshava, S; Sahoo, S; Tucker, TA; Idell, S; Rao, LVM; Pendurthi, UR
Cancer Research, 73(): 3963-3973.
10.1158/0008-5472.CAN-12-1690
CrossRef
Clinics in Chest Medicine
Malignant Pleural Mesothelioma Update on Treatment Options with a Focus on Novel Therapies
Haas, AR; Sterman, DH
Clinics in Chest Medicine, 34(1): 99-+.
10.1016/j.ccm.2012.12.005
CrossRef
Back to Top | Article Outline

© 2007International Association for the Study of Lung Cancer

Login

Article Tools

Images

Share

Other Ways to Connect

Twitter
twitter.com/JTOonline

 



Visit JTO.org on your smartphone. Scan this code (QR reader app required) with your phone and be taken directly to the site.

 For additional oncology content, visit LWW Oncology Journals on Facebook.