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PDT combined with Intravesical BCG instillation would form an autovaccine for bladder cancer?
Medical Hypotheses 73 (2009) 559–560
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
PDT combined with Intravesical BCG instillation would form an autovaccine for bladder cancer? HuiXuan Pan a,1, Xiaopeng Ma b,*,1, JunZhang Chen c, Hong Jiang c a
Department of Medicine, Clinical Medical College of Yangtze University, Jingzhou 434000, China Department of Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China c Department of Nephrology, First Affiliated Hospital, Clinical Medical College of Yangtze University, Jingzhou 434000, China b
a r t i c l e
i n f o
Article history: Received 9 May 2009 Accepted 12 May 2009
s u m m a r y Bladder cancer is the second most common urologic malignancy after prostate cancer. Intravesical BCG as a treatment of superficial bladder cancer (SBC) has been used by urologists for over 30 years. Recently, photodynamic therapy (PDT), which uses a red laser and a photosensitive drug to destroy cancer cells, has been showed encouraging results in SBC treatment. However, BCG and PDT are applied to treatment of SBC alone. Currently, cancer vaccines are made in vitro. Several studies confirmed that tumour cells treated in vitro by PDT can be used for generating potent cancer vaccines, which were more effective than other modes of creating whole tumor vaccines, i.e., UV or ionizing irradiation [Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 2002;62:1604–8]. Moreover, BCG is a pleiotropic immune stimulator oriented to cellular immunity. We thought that: after PDT destroyed targeted tumor cells on a large scale, Intravesical BCG could elicit and amplify the immune responses, which would directly form an in situ autovaccine in vivo against the primary tumor and metastases at distant sites. In this paper, we propose that the combination of Intravesical BCG and PDT would be a promising new modality for bladder cancer. Ó 2009 Elsevier Ltd. All rights reserved.
Treatment of Intravesical BCG Bacillus Calmette-Guérin (BCG) as a nonspecific immune stimulant, is currently the most effective intravesical agent for the treatment and prophylaxis of superficial bladder cancer [2]. BCG is a pleiotropic immune stimulator oriented to cellular immunity, the possible mechanisms include: inducing a local Type II immunologic response; activation of immunocytes; stimulating cytokine production, and so on [2], Otherwise, changes were also seen in peripheral blood, such as the enhancement of immunoproliferative response to BCG antigen and production of specific antibody [3]. Treatment of Intravesical PDT Photodynamic therapy (PDT) of cancer is based on preferential uptake and/or retention of a photosensitive drug (photosensitizer) in tissues and subsequent activation of photosensitizer by the specific wavelengths of light. More and more studies are in agreement that patients with diffuse superficial bladder carcinoma could benefit from Intravesical PDT [4,5]. The mechanisms of PDT include di-
* Corresponding author. Address: Department of Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China. Tel.: +86 27 83663818; fax: +86 27 83662851. E-mail address: [email protected] (X. Ma). 1 These authors contributed equally to this study. 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.05.037
rect cytotoxicity mediated by singlet oxygen and free radicals; vascular endothelial damage with thrombosis and hypoxia; and intense local inflammation associated with immune response [2]. Although PDT can achieve controlled local tumor cell destruction, total tumor eradication may not be accomplished because of the incomplete local tumor killing or the presence of tumor metastases [6]. Moreover, PDT is a local rather than systemic treatment. Patients with extensive flat papillary lesions did not appear to respond well to PDT [4]. Effect of combination therapy of PDT and Immunoadjuvant When PDT combined with intratumoral injection of BCG or other Immunoadjuvants, which was called, ‘‘Photo immunotherapy” or ‘‘Laser immunotherapy”, the effects of PDT can be amplified and make it a promising therapeutic interventions for the treatment of cancers [7,8]. Immunoadjuvants, such as: mycobacterium cell-wall extract (MCWE) including BCG, glycated chitosan gel (GCG), schizophyllan had shown to significantly increase the survival of tumor-bearing animals, when they were combined with Photofrin Photofrin and other photosensitizers1. Combination Therapy was considered superior to either therapy alone in treatment of murine mammary tumor [7–10]. The minimization of total tumor burden, both primary and metastatic, were observed after this treatment [9]. Korbelik and Cecic [10] demonstrated that BCG was a highly effective adjuvant to PDT, both pre- and post-PDT
560
H. Pan et al. / Medical Hypotheses 73 (2009) 559–560
treatments with BCG were effective in reducing the incidence of tumor recurrence in a mammary tumor model. Mechanisms of combination therapy of PDT and Immunoadjuvant Immunoadjuvant was administrated to the tumor center. After PDT destroyed targeted tumor cells on a large scale, the localized acute inflammatory reaction elicited by BCG could amplify and sustain the immune responses triggered by PDT [7,11]. Chen found that it had triggered a specific humoral immune response in the tumor-bearing rats [7]. Furthermore, recent studies demonstrate that tumour cells treated in vitro by PDT can be used for generating potent cancer vaccines [1]. Interestingly, PDT-generated vaccines are more effective than other modes of creating whole tumor vaccines, i.e., UV or ionizing irradiation [1]. The combination Immunoadjuvant with cellular antigens released from disrupted tumor cells would form an in situ autovaccine eliciting an immune reaction against the primary tumor and metastases at distant sites [7,9]. Comparison between ‘‘PDT + BCG’’ and ‘‘PDT + MMC’’ The field of combination of PDT with chemotherapy for the treatment of cancer is continuously expanding .A phase-1 study demonstrated that mitomycin C (MMC) followed by ALA-PDT was a safe and well-tolerated procedure in recurrent superficial bladder carcinoma [12]. It was the combination of different cytotoxic effects, cytotoxicity of mitomycin C and that of sonosensitizers (activated by light in PDT), from this point of view, it similar with intravesical combined chemotherapy. By cistoscope, the drugs act directly on cancer cells in bladder, but it may not kill cancer cells at distant site which they cannot be reached at. Apart from the intravesical cytotoxicity of this modality, the combination of immune response of BCG and cytotoxicity of PDT, would elicit systemic immunity against residual cancer. ‘‘BCG + PDT” seems to be theoretically superior to ‘‘MMC + PDT” in the prophylaxis of SBC recurrence. Viewpiont Recently, PDT has been regarded as a second-line treatment for patients with tumor recurrence after BCG failure [13]. If the interval between BCG and PDT were shorten enough to make them combined each other, the effect of two modalities may be amplified. It may be reasonable to make early use of PDT when it could be combined with BCG to prevent the recurrence of malignant lesions and ensure their permanent eradication, rather than use it until waiting to found the relapses or witness the failure of BCG. By cistoscope, intravesical instillation of BCG just similar with intratumoral injection of BCG, would be facilitatedly combinated
with PDT. We propose that the combination of direct cytotoxicity of PDT and immune response induced by BCG, may be form an in situ autovaccine and trigger a specific immune response to SBC, therefore, the combination therapy for the treatment of SBC would be more effective than current Intravesical BCG or PDT alone. Since Intravesical BCG has been adopted in clinical SBC therapy, and PDT has been recommended for diffuse superficial bladder carcinoma or refractory carcinoma in situ of the bladder. There seems to be no obstacle to carry out the Clinical Trial of this combination therapy and put it into application. The field of combination of PDT with Immunotherapy for the treatment of diseases is continuously expanding. We believe that present and future clinical trials for ‘‘BCG + PDT” should commence soon. Acknowledgements We thank Dr. Zhifang Yang, Wenzhuang Shen for critical review of the manuscript. References [1] Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 2002;62:1604–8. [2] Schenkman E, Lamm DL. Superficial bladder cancer therapy. Sci World J 2004;4(Suppl. 1):387–99. [3] Schmidt AC, Bouic PJ, Heyns CF, DeKock ML. Peripheral blood lymphocyte response in patients with superficial transitional cell carcinoma of the bladder treated with intravesical bacillus Calmette-Guerin – a useful marker of response? Br J Urol 1993;71:179–82. [4] Manyak MJ, Ogan K. Photodynamic therapy for refractory superficial bladder cancer: long-term clinical outcomes of single treatment using intravesical diffusion medium. J Endourol 2003;17(8):633–9. [5] Shackley DC, Briggs C, Gilhooley A, Whitehurst C, O’Flynn KJ, Betts CD, Moore JV, Clarke NW. Photodynamic therapy for superficial bladder cancer under local anaesthetic. BJU Int 2002;89(7):665–70. [6] Korbelik M, Cecic I. Enhancement of tumour response to photodynamic therapy by adjuvant mycobacterium cell-wall treatment. J Photochem Photobiol B 1998;44:151–8. [7] Chen WR, Huang Z, Korbelik M, Nordquist RE, Liu H. Photoimmunotherapy for cancer treatment. J Environ Pathol Toxicol Oncol 2006;25:281–91. [8] Chen WR, Carubelli R, Liu H, Nordquist RE. Laser immunotherapy: a novel treatment modality for metastatic tumors. Mol Biotechnol 2003;25:37–44. [9] Chen WR, Adams RL, Carubelli R, Nordquist RE. Laser-photosensitizer assisted immunotherapy: a novel modality for cancer treatment. Cancer Lett 1997;115(1):25–30. [10] Korbelik M, Sun J, Posakony JJ. Interaction between photodynamic therapy and BCG immunotherapy responsible for the reduced recurrence of treated mouse tumors. Photochem Photobiol 2001;73(4):403–9. [11] Krosl G, Korbelik M. Potentiation of photodynamic therapy by immunotherapy: the effect of schizophyllan (SPG). Cancer Lett 1994;84:43–9. [12] Skyrme RJ, French AJ, Datta SN, Allman R, Mason MD, Matthews PN. A phase-1 study of sequential mitomycin C and 5-aminolaevulinic acid-mediated photodynamic therapy in recurrent superficial bladder carcinoma. BJU Int 2005;95(9):1206–10. [13] Berger AP, Steiner H, Stenzl A, Akkad T, Bartsch G, Holtl L, et al. Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer: a single-center study. Urology 2003; 61(2):338–41.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
PDT combined with Intravesical BCG instillation would form an autovaccine for bladder cancer? HuiXuan Pan a,1, Xiaopeng Ma b,*,1, JunZhang Chen c, Hong Jiang c a
Department of Medicine, Clinical Medical College of Yangtze University, Jingzhou 434000, China Department of Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China c Department of Nephrology, First Affiliated Hospital, Clinical Medical College of Yangtze University, Jingzhou 434000, China b
a r t i c l e
i n f o
Article history: Received 9 May 2009 Accepted 12 May 2009
s u m m a r y Bladder cancer is the second most common urologic malignancy after prostate cancer. Intravesical BCG as a treatment of superficial bladder cancer (SBC) has been used by urologists for over 30 years. Recently, photodynamic therapy (PDT), which uses a red laser and a photosensitive drug to destroy cancer cells, has been showed encouraging results in SBC treatment. However, BCG and PDT are applied to treatment of SBC alone. Currently, cancer vaccines are made in vitro. Several studies confirmed that tumour cells treated in vitro by PDT can be used for generating potent cancer vaccines, which were more effective than other modes of creating whole tumor vaccines, i.e., UV or ionizing irradiation [Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 2002;62:1604–8]. Moreover, BCG is a pleiotropic immune stimulator oriented to cellular immunity. We thought that: after PDT destroyed targeted tumor cells on a large scale, Intravesical BCG could elicit and amplify the immune responses, which would directly form an in situ autovaccine in vivo against the primary tumor and metastases at distant sites. In this paper, we propose that the combination of Intravesical BCG and PDT would be a promising new modality for bladder cancer. Ó 2009 Elsevier Ltd. All rights reserved.
Treatment of Intravesical BCG Bacillus Calmette-Guérin (BCG) as a nonspecific immune stimulant, is currently the most effective intravesical agent for the treatment and prophylaxis of superficial bladder cancer [2]. BCG is a pleiotropic immune stimulator oriented to cellular immunity, the possible mechanisms include: inducing a local Type II immunologic response; activation of immunocytes; stimulating cytokine production, and so on [2], Otherwise, changes were also seen in peripheral blood, such as the enhancement of immunoproliferative response to BCG antigen and production of specific antibody [3]. Treatment of Intravesical PDT Photodynamic therapy (PDT) of cancer is based on preferential uptake and/or retention of a photosensitive drug (photosensitizer) in tissues and subsequent activation of photosensitizer by the specific wavelengths of light. More and more studies are in agreement that patients with diffuse superficial bladder carcinoma could benefit from Intravesical PDT [4,5]. The mechanisms of PDT include di-
* Corresponding author. Address: Department of Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China. Tel.: +86 27 83663818; fax: +86 27 83662851. E-mail address: [email protected] (X. Ma). 1 These authors contributed equally to this study. 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.05.037
rect cytotoxicity mediated by singlet oxygen and free radicals; vascular endothelial damage with thrombosis and hypoxia; and intense local inflammation associated with immune response [2]. Although PDT can achieve controlled local tumor cell destruction, total tumor eradication may not be accomplished because of the incomplete local tumor killing or the presence of tumor metastases [6]. Moreover, PDT is a local rather than systemic treatment. Patients with extensive flat papillary lesions did not appear to respond well to PDT [4]. Effect of combination therapy of PDT and Immunoadjuvant When PDT combined with intratumoral injection of BCG or other Immunoadjuvants, which was called, ‘‘Photo immunotherapy” or ‘‘Laser immunotherapy”, the effects of PDT can be amplified and make it a promising therapeutic interventions for the treatment of cancers [7,8]. Immunoadjuvants, such as: mycobacterium cell-wall extract (MCWE) including BCG, glycated chitosan gel (GCG), schizophyllan had shown to significantly increase the survival of tumor-bearing animals, when they were combined with Photofrin Photofrin and other photosensitizers1. Combination Therapy was considered superior to either therapy alone in treatment of murine mammary tumor [7–10]. The minimization of total tumor burden, both primary and metastatic, were observed after this treatment [9]. Korbelik and Cecic [10] demonstrated that BCG was a highly effective adjuvant to PDT, both pre- and post-PDT
560
H. Pan et al. / Medical Hypotheses 73 (2009) 559–560
treatments with BCG were effective in reducing the incidence of tumor recurrence in a mammary tumor model. Mechanisms of combination therapy of PDT and Immunoadjuvant Immunoadjuvant was administrated to the tumor center. After PDT destroyed targeted tumor cells on a large scale, the localized acute inflammatory reaction elicited by BCG could amplify and sustain the immune responses triggered by PDT [7,11]. Chen found that it had triggered a specific humoral immune response in the tumor-bearing rats [7]. Furthermore, recent studies demonstrate that tumour cells treated in vitro by PDT can be used for generating potent cancer vaccines [1]. Interestingly, PDT-generated vaccines are more effective than other modes of creating whole tumor vaccines, i.e., UV or ionizing irradiation [1]. The combination Immunoadjuvant with cellular antigens released from disrupted tumor cells would form an in situ autovaccine eliciting an immune reaction against the primary tumor and metastases at distant sites [7,9]. Comparison between ‘‘PDT + BCG’’ and ‘‘PDT + MMC’’ The field of combination of PDT with chemotherapy for the treatment of cancer is continuously expanding .A phase-1 study demonstrated that mitomycin C (MMC) followed by ALA-PDT was a safe and well-tolerated procedure in recurrent superficial bladder carcinoma [12]. It was the combination of different cytotoxic effects, cytotoxicity of mitomycin C and that of sonosensitizers (activated by light in PDT), from this point of view, it similar with intravesical combined chemotherapy. By cistoscope, the drugs act directly on cancer cells in bladder, but it may not kill cancer cells at distant site which they cannot be reached at. Apart from the intravesical cytotoxicity of this modality, the combination of immune response of BCG and cytotoxicity of PDT, would elicit systemic immunity against residual cancer. ‘‘BCG + PDT” seems to be theoretically superior to ‘‘MMC + PDT” in the prophylaxis of SBC recurrence. Viewpiont Recently, PDT has been regarded as a second-line treatment for patients with tumor recurrence after BCG failure [13]. If the interval between BCG and PDT were shorten enough to make them combined each other, the effect of two modalities may be amplified. It may be reasonable to make early use of PDT when it could be combined with BCG to prevent the recurrence of malignant lesions and ensure their permanent eradication, rather than use it until waiting to found the relapses or witness the failure of BCG. By cistoscope, intravesical instillation of BCG just similar with intratumoral injection of BCG, would be facilitatedly combinated
with PDT. We propose that the combination of direct cytotoxicity of PDT and immune response induced by BCG, may be form an in situ autovaccine and trigger a specific immune response to SBC, therefore, the combination therapy for the treatment of SBC would be more effective than current Intravesical BCG or PDT alone. Since Intravesical BCG has been adopted in clinical SBC therapy, and PDT has been recommended for diffuse superficial bladder carcinoma or refractory carcinoma in situ of the bladder. There seems to be no obstacle to carry out the Clinical Trial of this combination therapy and put it into application. The field of combination of PDT with Immunotherapy for the treatment of diseases is continuously expanding. We believe that present and future clinical trials for ‘‘BCG + PDT” should commence soon. Acknowledgements We thank Dr. Zhifang Yang, Wenzhuang Shen for critical review of the manuscript. References [1] Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 2002;62:1604–8. [2] Schenkman E, Lamm DL. Superficial bladder cancer therapy. Sci World J 2004;4(Suppl. 1):387–99. [3] Schmidt AC, Bouic PJ, Heyns CF, DeKock ML. Peripheral blood lymphocyte response in patients with superficial transitional cell carcinoma of the bladder treated with intravesical bacillus Calmette-Guerin – a useful marker of response? Br J Urol 1993;71:179–82. [4] Manyak MJ, Ogan K. Photodynamic therapy for refractory superficial bladder cancer: long-term clinical outcomes of single treatment using intravesical diffusion medium. J Endourol 2003;17(8):633–9. [5] Shackley DC, Briggs C, Gilhooley A, Whitehurst C, O’Flynn KJ, Betts CD, Moore JV, Clarke NW. Photodynamic therapy for superficial bladder cancer under local anaesthetic. BJU Int 2002;89(7):665–70. [6] Korbelik M, Cecic I. Enhancement of tumour response to photodynamic therapy by adjuvant mycobacterium cell-wall treatment. J Photochem Photobiol B 1998;44:151–8. [7] Chen WR, Huang Z, Korbelik M, Nordquist RE, Liu H. Photoimmunotherapy for cancer treatment. J Environ Pathol Toxicol Oncol 2006;25:281–91. [8] Chen WR, Carubelli R, Liu H, Nordquist RE. Laser immunotherapy: a novel treatment modality for metastatic tumors. Mol Biotechnol 2003;25:37–44. [9] Chen WR, Adams RL, Carubelli R, Nordquist RE. Laser-photosensitizer assisted immunotherapy: a novel modality for cancer treatment. Cancer Lett 1997;115(1):25–30. [10] Korbelik M, Sun J, Posakony JJ. Interaction between photodynamic therapy and BCG immunotherapy responsible for the reduced recurrence of treated mouse tumors. Photochem Photobiol 2001;73(4):403–9. [11] Krosl G, Korbelik M. Potentiation of photodynamic therapy by immunotherapy: the effect of schizophyllan (SPG). Cancer Lett 1994;84:43–9. [12] Skyrme RJ, French AJ, Datta SN, Allman R, Mason MD, Matthews PN. A phase-1 study of sequential mitomycin C and 5-aminolaevulinic acid-mediated photodynamic therapy in recurrent superficial bladder carcinoma. BJU Int 2005;95(9):1206–10. [13] Berger AP, Steiner H, Stenzl A, Akkad T, Bartsch G, Holtl L, et al. Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer: a single-center study. Urology 2003; 61(2):338–41.