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IMMUNOTHERAPY OF BLADDER CANCER
0022-5347/99/1625-158UO THEJOURNALOF UROLOGY Copyright 0 1999 by AMERICANUROLOCICAL. ASSOCIATION, INC.
Vol. 162,1581, November 1999 Printed in U S A
This Month in Investigative Urology IMMUNOTHERAPY OF BLADDER CANCER An estimated 54,200 new cases of bladder cancer will be diagnosed in this country in 1999 and this neoplasm will account for 12,100 cancer-related deaths. Over 90% ofbladder malignancies are transitional cell carcinomas, which are typified by the field cancerization concept. The latter implies a predisposition to multifocality and recurrence rates of 50%-75%. In contrast to this long-recognized trend toward polychronotropism, recent molecular studies strongly support the uniclonal origin of most bladder cancers. Geographically distinct bladder tumors appear to manifest identical genomic abnormalities, including identical point mutations in the p53 gene. Over 75% of bladder cancers arise superficial to the tunica muscularis propria (Ta, Tis, Tla-c). Within this group, Tis and T1 lesions exhibit progression to muscle-invasive disease with a frequency exceeding 25% in most series. Molecular phenotypes which predispose t o disease progression include DNA aneuploidy, high S-phase activity, l l p deletions, increased expression of epidermal growth factor receptor and its ligans (EGF and TGF-a), preferential expression of the thymidine phosphorylase angiogenic pathway and loss of heterozygosity at 17p (the locus for the p53 tumor suppressor gene). Normal or wild type p53 is a strategic cell-cycle regulator, which modulates the traverse through the GUS interface. The p53 tumor suppressor protein also responds to cellular stress by signaling apoptotic machinery to induce programmed cell death through a pathway that is mechanistically linked to caspase activation. Over-expression of mutated p53 constitutes a significant independent predictor of disease recurrence and overall survival. The use of intravesical BCG has profoundly influenced the management of recurrent superficial bladder cancer. Patients treated with TURBT plus BCG exhibit a 10-year progression-free rate of 62% and a 10-year disease-specific survival rate of approximately 75%. Most tumors recur or progress within the first 5 years. Although the detection of p53 over-expression does not appear t o predict response to BCG therapy, post-BCG p53 over-expression represents a powerful independent marker of disease progression. In this subset of patients, the use of alternative intravesical agents (mitomycin-C,valrubricin, a-interferon) and photodynamic therapy infrequently achieve durable complete responses. For that reason, cystectomy remains the preferential salvage therapy. Obviously, the identification of less drastic, but durably effective treatments constitutes an important scientific and clinical goal. The article by Peralta and associates in this month’s section of Investigative Urology, “Immunotherapy of Bladder Cancer Targeting p53”, is aimed at determining whether the growth of human bladder cancer xenograRs (heterotopic and orthotopic tumors) established in SCID mice could be favorably modulated by the systemic administration of cytotoxic T cells (CTL) which were designed to recognize over-expressed p53. Their approach was based on two important precepts. First, tumor cells which over-express mutant p53 continue to process and present to the immune system mainly wild-type epitopes. Second, these epitopes probably give rise to tumor associated antigens for recognition by CTL through the same proteolytic pathways used for the processing and presentation of self-proteins in association with class 1MHC molecules. In keeping with these principles, Peralta and associates generated murine CTL which were specific for human p53. This was accomplished following the immunization of HLA A2.1 transgenic mice with the immunodominant human p53 nonamer peptide, which spanned amino acid residues 149-157. In vitro studies which employed relevant human cancer cell lines and p53 specific CTL demonstrated that expression of both A2.1 and p53 phenotypes were necessary for immune recognition. For their in vivo studies, the investigators utilized the p53 over-expressing HLA A2.1 human bladder cancer cell line 582 to establish subcutaneous (heterotopic) or intravesicular (orthotopic) tumors in SCID mice. The mice received tail vein injections of 5 x lo7 p53-specific CTL, control CTL, or phosphate buffered saline 48 hours post-heterotopic injection and 7 days post-orthotopic injection. Strikingly favorable tumor responses were noted in both groups following the injection of p53 specific CTL, but the observations generated in mice with intravesicular tumors did not achieve statistical significance. These preliminary observations suggest the potential utility of targeting treatment-refractory transitional cell carcinomas which exhibit p53 over-expression by using novel immunotherapeutic approaches. The investigators suggest that it may be possible to selectively target p53 over-expressing human tumors, while circumventing the problem of immune tolerance, by specific T cell receptor (TCR) from murine to human T cells. They suggest that these the transfer of a high affinity p53,,,-,,, TCR-modified human CTL might prove useful following intravesicular or systemic administration. The ultimate utility and safety of such novel therapies must rate more rigorous evaluation. Nonetheless, this approach is a viable and potentially exciting translational research opportunity which may prove valuable in the management of superficial and advanced-stage urothelial cancer.
James Kozlowski, M.D. Department of Urology Northwestern University Chicago, Illinois
1581
Vol. 162,1581, November 1999 Printed in U S A
This Month in Investigative Urology IMMUNOTHERAPY OF BLADDER CANCER An estimated 54,200 new cases of bladder cancer will be diagnosed in this country in 1999 and this neoplasm will account for 12,100 cancer-related deaths. Over 90% ofbladder malignancies are transitional cell carcinomas, which are typified by the field cancerization concept. The latter implies a predisposition to multifocality and recurrence rates of 50%-75%. In contrast to this long-recognized trend toward polychronotropism, recent molecular studies strongly support the uniclonal origin of most bladder cancers. Geographically distinct bladder tumors appear to manifest identical genomic abnormalities, including identical point mutations in the p53 gene. Over 75% of bladder cancers arise superficial to the tunica muscularis propria (Ta, Tis, Tla-c). Within this group, Tis and T1 lesions exhibit progression to muscle-invasive disease with a frequency exceeding 25% in most series. Molecular phenotypes which predispose t o disease progression include DNA aneuploidy, high S-phase activity, l l p deletions, increased expression of epidermal growth factor receptor and its ligans (EGF and TGF-a), preferential expression of the thymidine phosphorylase angiogenic pathway and loss of heterozygosity at 17p (the locus for the p53 tumor suppressor gene). Normal or wild type p53 is a strategic cell-cycle regulator, which modulates the traverse through the GUS interface. The p53 tumor suppressor protein also responds to cellular stress by signaling apoptotic machinery to induce programmed cell death through a pathway that is mechanistically linked to caspase activation. Over-expression of mutated p53 constitutes a significant independent predictor of disease recurrence and overall survival. The use of intravesical BCG has profoundly influenced the management of recurrent superficial bladder cancer. Patients treated with TURBT plus BCG exhibit a 10-year progression-free rate of 62% and a 10-year disease-specific survival rate of approximately 75%. Most tumors recur or progress within the first 5 years. Although the detection of p53 over-expression does not appear t o predict response to BCG therapy, post-BCG p53 over-expression represents a powerful independent marker of disease progression. In this subset of patients, the use of alternative intravesical agents (mitomycin-C,valrubricin, a-interferon) and photodynamic therapy infrequently achieve durable complete responses. For that reason, cystectomy remains the preferential salvage therapy. Obviously, the identification of less drastic, but durably effective treatments constitutes an important scientific and clinical goal. The article by Peralta and associates in this month’s section of Investigative Urology, “Immunotherapy of Bladder Cancer Targeting p53”, is aimed at determining whether the growth of human bladder cancer xenograRs (heterotopic and orthotopic tumors) established in SCID mice could be favorably modulated by the systemic administration of cytotoxic T cells (CTL) which were designed to recognize over-expressed p53. Their approach was based on two important precepts. First, tumor cells which over-express mutant p53 continue to process and present to the immune system mainly wild-type epitopes. Second, these epitopes probably give rise to tumor associated antigens for recognition by CTL through the same proteolytic pathways used for the processing and presentation of self-proteins in association with class 1MHC molecules. In keeping with these principles, Peralta and associates generated murine CTL which were specific for human p53. This was accomplished following the immunization of HLA A2.1 transgenic mice with the immunodominant human p53 nonamer peptide, which spanned amino acid residues 149-157. In vitro studies which employed relevant human cancer cell lines and p53 specific CTL demonstrated that expression of both A2.1 and p53 phenotypes were necessary for immune recognition. For their in vivo studies, the investigators utilized the p53 over-expressing HLA A2.1 human bladder cancer cell line 582 to establish subcutaneous (heterotopic) or intravesicular (orthotopic) tumors in SCID mice. The mice received tail vein injections of 5 x lo7 p53-specific CTL, control CTL, or phosphate buffered saline 48 hours post-heterotopic injection and 7 days post-orthotopic injection. Strikingly favorable tumor responses were noted in both groups following the injection of p53 specific CTL, but the observations generated in mice with intravesicular tumors did not achieve statistical significance. These preliminary observations suggest the potential utility of targeting treatment-refractory transitional cell carcinomas which exhibit p53 over-expression by using novel immunotherapeutic approaches. The investigators suggest that it may be possible to selectively target p53 over-expressing human tumors, while circumventing the problem of immune tolerance, by specific T cell receptor (TCR) from murine to human T cells. They suggest that these the transfer of a high affinity p53,,,-,,, TCR-modified human CTL might prove useful following intravesicular or systemic administration. The ultimate utility and safety of such novel therapies must rate more rigorous evaluation. Nonetheless, this approach is a viable and potentially exciting translational research opportunity which may prove valuable in the management of superficial and advanced-stage urothelial cancer.
James Kozlowski, M.D. Department of Urology Northwestern University Chicago, Illinois
1581