-
[show abstract]
[hide abstract]
ABSTRACT: Cancer cell expression of the B7-H1 glycoprotein has been implicated as a potent inhibitor of T cell-mediated antitumoral immunity. We recently reported that B7-H1 is aberrantly expressed in renal cell carcinoma (RCC) and suggested that blockade of B7-H1, as demonstrated in several murine cancer models, represents a promising therapeutic target in RCC. Herein, we update our results with tumor-associated B7-H1 and discuss future clinical applications. Between 2000 and 2002, 196 patients underwent nephrectomy for clear-cell RCC and had fresh-frozen tissue available for review. Immunohistochemical analysis was performed on tumor cryosections, and outcome was obtained from the Mayo Clinic Nephrectomy Registry (Rochester, MN). At last follow-up 38 of the 196 patients died of RCC. The median duration of follow-up for patients still alive was 2.7 years. Among the 196 RCC specimens, 130 (66.3%) demonstrated aberrant tumor-associated B7-H1 expression. Patients with tumor-associated B7-H1 expression were significantly more likely to die of RCC compared with patients whose specimens did not have aberrant tumor-associated B7-H1 expression (risk ratio, 3.34; 95% confidence interval [CI], 1.30 - 8.55; P = 0.012). This risk persisted in multivariate analysis even after adjusting for the Mayo Clinic SSIGN (stage, size, grade, and necrosis) score (risk ratio, 3.52; 95% CI, 1.35-9.15; P = 0.010). Tumor-associated B7-H1 expression is significantly associated with poor prognosis among patients with clear-cell RCC. Manipulation of B7-H1 with therapeutic intent remains a realistic and viable therapeutic option.
Urology 12/2005; 66(5 Suppl):10-4. · 2.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Perinephric and renal sinus fat invasion are classified as pT3a renal cell carcinoma (RCC) according to the 2002 American Joint Committee on Cancer. We investigated the prognostic significance of each of these pathological features using a cohort of pT3a patients.
Between 1970 and 2002, 205 patients without direct adrenal invasion underwent nephrectomy for pT3a clear cell RCC. The associations of fat invasion with death from RCC were evaluated using Cox proportional hazards regression models.
Of the 162 patients with perinephric fat invasion and 43 patients with renal sinus fat invasion 95 (59%) and 31 (72%), respectively, died of RCC. Patients with renal sinus fat invasion were 63% more likely to die of RCC compared with those with perinephric fat invasion (RR 1.63, 95% CI 1.09-2.46, p=0.018). In addition, the risk of death persisted in multivariate analysis after adjusting for regional lymph nodes and distant metastases (RR 1.91, 95% CI 1.26-2.89, p=0.002) and after adjusting for the Mayo Clinic SSIGN (stage, size, grade and necrosis) score (RR 1.90, 95% CI 1.25-2.88, p=0.003).
Our results indicate that clear cell tumors invading the renal sinus fat are more aggressive than tumors with perinephric fat involvement. We believe both of these features should be individually assessed during routine pathological examination. External validation is needed before suggesting a change to the TNM staging system.
The Journal of Urology 11/2005; 174(4 Pt 1):1218-21. · 3.75 Impact Factor
-
R Houston Thompson,
Michael D Gillett,
John C Cheville,
Christine M Lohse,
Haidong Dong,
W Scott Webster,
Lieping Chen,
Horst Zincke,
Michael L Blute,
Bradley C Leibovich, Eugene D Kwon
[show abstract]
[hide abstract]
ABSTRACT: Cancer cell expression of costimulatory molecule B7-H1 has been implicated as a potent inhibitor of T-cell-mediated antitumoral immunity. The authors recently reported that B7-H1 is aberrantly expressed in primary renal cell carcinoma (RCC). Blockade of B7-H1, as demonstrated in several murine cancer models, now represents a promising therapeutic target in RCC. However, the potential expression of B7-H1 in metastatic RCC has not been investigated. In the current study, the authors updated their primary RCC results with additional follow-up and investigated the potential role of B7-H1 in metastatic RCC.
Between 2000 and 2004, 196 patients underwent nephrectomy and 26 patients had resection of RCC metastases for clear cell RCC. Immunohistochemical analysis was performed on tumor cryosections using a B7-H1 monoclonal antibody (clone 5H1). A urologic pathologist quantified the percentage of B7-H1-positive tumor cells and lymphocytes.
Variable levels of B7-H1 were expressed on primary RCC tumor cells (n = 130 [66.3%]) and primary tumor-infiltrating lymphocytes (n = 115 [58.7%]). Patients with high expression of B7-H1 on primary tumor cells and/or lymphocytes were significantly more likely to die of RCC compared with patients with low B7-H1 expression (risk ratio [RR] = 4.17; 95% confidence interval [95% CI], 1.97-8.84; P < 0.001) and this risk persisted in multivariate analysis after adjusting for the Mayo Clinic stage, size, grade, and necrosis score (RR = 2.63; 96% CI, 1.23-5.64; P = 0.013). Of the 26 metastatic specimens, cancer cell and lymphocyte B7-H1 expression were demonstrated in 17 (65.4%) and 18 (69.2%) specimens, respectively. In total, 14 (54.3%) metastatic specimens had high aggregate B7-H1 levels compared with 44.4% in primary RCC specimens.
Patients with RCC with high B7-H1 expression were significantly more likely to die even after multivariate analysis. The authors also demonstrated that a high percentage of RCC metastases similarly harbored B7-H1. The authors surmised that B7-H1 blockade may augment current immunotherapy, including patients treated for metastases after cytoreductive nephrectomy.
Cancer 11/2005; 104(10):2084-91. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Prognostic markers for renal cell carcinoma (RCC), such as patient symptoms, tumor stage, tumor size, and tumor grade, are useful for determining appropriate follow-up and selecting patients for adjuvant therapy. Histologic coagulative tumor necrosis, also reported to be a prognostic marker for RCC, has not previously been extensively described or investigated. Hence, the objective of the current study was to characterize tumor necrosis as a prognostic feature of RCC.
The authors of the current study identified 3009 patients treated surgically for RCC between 1970 and 2002 from the Mayo Clinic Nephrectomy Registry (Rochester, MN). Associations of tumor necrosis with clinical, laboratory, and pathologic features were examined with chi-square, Fisher exact test, and Wilcoxon rank-sum tests. Cancer-specific survival was estimated with the Kaplan-Meier method, and associations with outcome were assessed with Cox proportional hazard models.
Tumor necrosis was present in 690 of 2445 (28%) clear cell, 196 of 421 (47%) papillary, and 28 of 143 (20%) chromophobe RCCs. The risk ratio for death from RCC in patients with necrotic compared with non-necrotic tumors was 5.27 (95% confidence interval [CI]: 4.56-6.09; P < 0.001) for clear cell, 4.20 (CI: 1.65-10.68; P < 0.001) for chromophobe, and 1.49 (CI: 0.81-2.74; P = 0.199) for papillary RCC. The survival difference for clear cell RCC persisted even after multivariate adjustment for tumor stage, size, and grade (risk ratio 1.90; P < 0.001).
Histologic coagulative tumor necrosis is an independent predictor of outcome for clear cell and chromophobe RCC, and it should be routinely reported and used in clinical assessment.
Cancer 09/2005; 104(3):511-20. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The significance of adrenal invasion and tumor thrombus in renal cell carcinoma (RCC) has been debated recently. The authors evaluated the associations of direct adrenal invasion, perinephric fat invasion, and tumor thrombus level with outcome to determine whether reclassification would improve the prognostic accuracy of the current primary tumor classification.
The authors studied 697 patients treated with nephrectomy for pT3 and pT4 RCC between 1970 and 2000. Associations with outcome were evaluated using Cox proportional hazards regression and prognostic accuracy was measured using the c index.
Among patients with pT3 RCC, direct adrenal invasion was significantly associated with death from RCC (risk ratio, 2.11; P = 0.004). No significant difference in survival was found between patients with pT4 RCC and pT3 tumors with direct adrenal invasion (P = 0.490). Among patients with pT3b RCC, those with level I-III tumor thrombus were significantly more likely to die of RCC compared with patients harboring level 0 tumor thrombus (risk ratio, 1.62; P < 0.001). In addition, patients with fat invasion were more likely to die of RCC compared with pT3 patients without fat invasion (risk ratio, 1.87; P < 0.001). Therefore, patients with pT3 RCC were reclassified into 4 prognostic groups, and this reclassification significantly improved prediction of death from RCC compared with the current classification (c indices of 0.61 vs. 0.55, respectively).
Direct adrenal invasion from RCC should be reclassified as pT4. In addition, the proposed reclassification for patients with pT3 RCC improved prognostic accuracy.
Cancer 08/2005; 104(1):53-60. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We compared histological subtype, pathological features and outcome of patients with solid renal masses who were 18 to 40 years old vs patients who were 60 to 70 years old.
We conducted a retrospective review of the Mayo Clinic Nephrectomy Registry from 1970 to 2000, and identified 124 patients 18 to 40 years old and 1,067 patients 60 to 70 years old available for analysis.
There was no significant difference in the incidence of benign solid renal masses between patients 18 to 40 years old and those 60 to 70 years old (13.7% vs 10.2%). Among patients with renal cell carcinoma (RCC), younger patients were more likely to have chromophobe RCC (13.1% vs 3.6%) and less likely to have clear cell RCC (70.1% vs 81.5%) than older patients. Among patients with clear cell RCC, younger patients were more likely to have stage pT2b or lower tumors (82.7% vs 69.9%) and a higher incidence of cystic clear cell RCC (10.7% vs 2.2%) than older patients. Younger patients had an improved cancer specific survival compared with older patients but this difference was not statistically significant (risk ratio 0.71, p =0.127).
We found that patients 18 to 40 years old were more likely to have chromophobe and less likely to have clear cell RCC compared with patients 60 to 70 years old. We did not identify a higher incidence of papillary RCC in younger patients. Patients with clear cell RCC 18 to 40 years old had a higher incidence of low stage and cystic tumors compared with patients 60 to 70 years old, features which have been shown to have a favorable prognosis. These factors likely contributed to improved cancer specific survival for younger patients.
The Journal of Urology 07/2005; 173(6):1893-6. · 3.75 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The 2002 American Joint Committee on Cancer primary tumor classification for renal cell carcinoma (RCC) defines a tumor as pT3a if it invades the perinephric or renal sinus fat or directly invades the ipsilateral adrenal gland. In the current study we evaluated the association of direct ipsilateral adrenal invasion with outcome to determine if reclassification of these tumors as pT4 would improve the accuracy of the current tumor classification.
We studied 424 patients who underwent nephrectomy and adrenalectomy for unilateral, sporadic, pT3 or pT4 RCC between 1970 and 2000 at the Mayo Clinic. Cancer specific survival was estimated using the Kaplan-Meier method.
Cancer specific survival for the 22 patients with pT3a or pT3b tumors that directly invaded the ipsilateral adrenal gland was significantly worse compared with that of patients with pT3a (p <0.001) or pT3b (p = 0.011) disease that did not invade the adrenal gland. There was no significant difference in the 5-year cancer specific survival between the patients with pT3a or pT3b tumors that directly invaded the ipsilateral adrenal gland and patients with pT4 tumors (cancer specific survival rates of 20% and 14%, respectively, p = 0.490).
Although rare, RCC with direct ipsilateral adrenal invasion behaves more aggressively than tumors involving perinephric or renal sinus fat. We believe that RCC tumors with direct adrenal invasion should be classified as pT4.
The Journal of Urology 04/2005; 173(3):918-21. · 3.75 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The 2002 primary tumor classification for renal cell carcinoma (RCC) does not distinguish between patients with tumor thrombus involving the renal vein only and those with inferior vena cava tumor thrombus below the diaphragm. We evaluated the association of tumor thrombus level and fat invasion with outcome to determine if further subclassification would improve the prognostic accuracy of the current classification.
We studied 675 patients treated with radical nephrectomy or nephron sparing surgery for pT3a (206, 30.5%), pT3b (422, 62.5%), pT3c (19, 2.8%) or pT4 (28, 4.2%) RCC at the Mayo Clinic between 1970 and 2000. Associations with outcome were evaluated using Cox proportional hazards regression.
There were 531 deaths from RCC at a median of 1.5 years following nephrectomy. Patients with pT3b RCC and level I, II or III tumor thrombus were significantly more likely to die of RCC compared to patients with pT3b RCC and level 0 tumor thrombus (risk ratio 1.62, p <0.001). Patients with peripheral perinephric or renal sinus fat invasion were also more likely to die of RCC compared to patients without fat invasion (risk ratio 1.87, p <0.001). Therefore, patients with pT3 RCC were reclassified into 4 groups as thrombus level 0 without fat invasion, fat invasion only, thrombus level 0 with fat invasion or thrombus level I, II or III without fat invasion, and thrombus level I, II or III with fat invasion or thrombus level IV. This reclassification significantly improved prediction of death from RCC compared with the current classification (c indexes of 0.61 versus 0.55, respectively).
Further subclassification of the primary tumor classification for patients with pT3 RCC improved prognostic accuracy.
The Journal of Urology 04/2005; 173(3):716-9. · 3.75 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The 2002 tumor classification for renal cell carcinoma (RCC) classifies pT2 tumors as more than 7 cm in greatest dimension, limited to the kidney. In this study we determined whether a size cutoff point exists within pT2 tumors and whether such subclassification would further improve the accuracy of the current tumor classification.
We studied 544 patients with unilateral, sporadic pT2 RCC treated with radical nephrectomy or nephron sparing surgery between 1970 and 2000. The association of tumor size with death from RCC was examined using martingale residuals from a Cox proportional hazards regression model to determine the optimal size cutoff point.
There were 204 deaths from RCC a median of 3.8 years following nephrectomy. Univariately tumor size was significantly associated with death from RCC (risk ratio 1.08, 95% CI 1.04 to 1.13, p <0.001). A scatterplot of tumor size vs expected risk of death per patient suggested that a cutoff point between 9 and 10 cm was appropriate. When adjusted for regional lymph node involvement and distant metastases, the 10 cm cutoff point performed better than the 9 cm point (risk ratio 1.42, 95% CI 1.07 to 1.90, p = 0.017 vs 1.22, 95% 0.86 to 1.72, p = 0.268). Therefore, we propose using a 10 cm cutoff point to subclassify patients into pT2a and pT2b.
Our data suggest that the prognostic accuracy of the 2002 pT2 tumor classification can be further improved by subclassifying patients with tumors greater than 7 and less than 10 cm into a pT2a category, and those with tumors 10 cm or greater into a pT2b category.
The Journal of Urology 02/2005; 173(2):380-4. · 3.75 Impact Factor
-
Anja C Roden,
Michael T Moser,
Samuel D Tri,
Maria Mercader,
Susan M Kuntz,
Haidong Dong,
Arthur A Hurwitz,
David J McKean,
Esteban Celis,
Bradley C Leibovich,
James P Allison, Eugene D Kwon
[show abstract]
[hide abstract]
ABSTRACT: Androgen has been implicated as a negative regulator of host immune function and a factor contributing to the gender dimorphism of autoimmunity. Conversely, androgen deprivation has been suggested to potentiate male host immunity. Studies have shown that removal of androgen in postpubertal male mice produces an increase in size and cellularity of primary and peripheral lymphoid organs, and enhances a variety of immune responses. Yet, few details are known about the effect of androgen removal on T cell-mediated immunity. In this study, we demonstrate two pronounced and independent alterations in T cell immunity that occur in response to androgen deprivation, provided by castration, in postpubertal male mice. First, we show that levels of T cells in peripheral lymphoid tissues of mice are increased by androgen deprivation. Second, T cells from these mice transiently proliferate more vigorously to TCR- and CD28-mediated costimulation as well as to Ag-specific activation. In addition, androgen deprivation accelerates normalization of host T and B cell levels following chemotherapy-induced lymphocyte depletion. Such alterations induced by androgen deprivation may have implications for enhancing immune responses to immunotherapy and for accelerating the recovery of the immune system following chemotherapy.
The Journal of Immunology 12/2004; 173(10):6098-108. · 5.79 Impact Factor
-
R Houston Thompson,
Michael D Gillett,
John C Cheville,
Christine M Lohse,
Haidong Dong,
W Scott Webster,
Kent G Krejci,
John R Lobo,
Shomik Sengupta,
Lieping Chen,
Horst Zincke,
Michael L Blute,
Scott E Strome,
Bradley C Leibovich, Eugene D Kwon
[show abstract]
[hide abstract]
ABSTRACT: Expression of B7-H1, a costimulating glycoprotein in the B7 family, is normally restricted to macrophage-lineage cells, providing a potential costimulatory signal source for regulation of T cell activation. In contrast, aberrant expression of B7-H1 by tumor cells has been implicated in impairment of T cell function and survival, resulting in defective host antitumoral immunity. The relationship between tumor-associated B7-H1 and clinical cancer progression is unknown. Herein, we report B7-H1 expression by both renal cell carcinoma (RCC) tumors of the kidney and RCC tumor-infiltrating lymphocytes. In addition, our analysis of 196 clinical specimens reveals that patients harboring high intratumoral expression levels of B7-H1, contributed by tumor cells alone, lymphocytes alone, or tumor and/or lymphocytes combined, exhibit aggressive tumors and are at markedly increased risk of death from RCC. In fact, patients with high tumor and/or lymphocyte B7-H1 levels are 4.5 times more likely to die from their cancer than patients exhibiting low levels of B7-H1 expression (risk ratio 4.53; 95% confidence interval 1.94-10.56; P < 0.001.) Thus, our study suggests a previously undescribed mechanism whereby RCC may impair host immunity to foster tumor progression. B7-H1 may prove useful as a prognostic variable for RCC patients both pre- and posttreatment. In addition, B7-H1 may represent a promising target to facilitate more favorable responses in patients who require immunotherapy for treatment of advanced RCC.
Proceedings of the National Academy of Sciences 12/2004; 101(49):17174-9. · 9.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: For decades urologists have successfully used immunotherapy in the battle against cancer. Interleukin-2 in renal cell carcinoma and bacillus Calmette-Guerin in bladder cancer are standard primary and/or adjunctive therapies for these diseases. Recent advances in our understanding of mechanisms governing immune system activation have fostered a myriad of novel immunotherapeutic approaches that show great promise in vivo but have had limited success in human trials to date. This review highlights current immunotherapy strategies that may prove to be successful treatments for urological cancers.
We performed a MEDLINE literature search for articles relating to immunotherapy in bladder, prostate and renal cell carcinoma in animals and humans. We included the most promising developments in this review.
In addition to combining existing therapies to improve their efficacy, novel approaches that attempt to exploit the immune system ability to identify, target and eradicate malignancies are now being developed. These therapies include the use of antitumoral monoclonal and bi-specific antibodies, manipulation of T-lymphocyte costimulatory molecules and the administration of newly discovered cytokines as well as the development of antitumor vaccines.
To date the full potential of immunotherapy for the treatment of urological malignancies has not been recognized. As our knowledge of the immune system expands, so too may our ability to manipulate it to affect tumor regression. This review describes the most recent and most promising developments in immunotherapy for urological malignancies.
The Journal of Urology 03/2004; 171(2 Pt 1):870-6. · 3.75 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The objective of the current study was to develop an algorithm to predict progression to metastases after radical nephrectomy for patients with clinically localized renal cell carcinoma (RCC) to allow stratification of patients for potential adjuvant therapy trials.
The authors identified 1671 sporadic patients with clinically localized, unilateral clear cell RCC who underwent radical nephrectomy between 1970 and 2000. The clinical features examined included age, gender, smoking history, recent onset hypertension, performance status, and presenting symptoms. The pathologic features examined included surgical margins, tumor stage, regional lymph node status, tumor size, nuclear grade, histologic tumor necrosis, sarcomatoid component, cystic architecture, and multifocality. Metastases free survival was estimated using the Kaplan-Meier method. A multivariate Cox proportional hazards regression model was fit to determine associations between the clinical and pathologic features and distant metastases.
The median follow-up was 5.4 years (range, 0-31 years). Metastases occurred in 479 patients at a median of 1.3 years (range, 0-25 years) after nephrectomy. The estimated metastases free survival rates were 86.9% at 1 year, 77.8% at 3 years, 74.1% at 5 years, 70.8% at 7 years, and 67.1% at 10 years. Multivariate analysis showed that the following features were associated with progression to metastases: tumor stage, regional lymph node status, tumor size, nuclear grade, and histologic tumor necrosis (P < 0.001 for all).
In patients with clear cell RCC, tumor stage, regional lymph node status, tumor size, nuclear grade, and histologic tumor necrosis showed statistically significant associations with progression to metastatic RCC. The authors present a scoring algorithm based on these features that can be used to predict disease progression after patients undergo radical nephrectomy for clinically localized clear cell RCC. Cancer 2003;97:1663-71.
Cancer 04/2003; 97(7):1663-71. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The absence of curative therapies for advanced or recurrent forms of prostate cancer has prompted a vigorous search for novel treatment strategies. Immunotherapy encompasses one particularly promising systemic approach to the treatment of prostate cancer. Immune-based strategies for treating prostate cancer have recently been facilitated by the identification of a number of prostate tissue/tumour antigens that can be targeted, either by antibody or T cells, to promote prostate tumour cell injury or death. These same prostate antigens can also be used for the construction of vaccines to induce prostate-specific T cell-mediated immunity. Greater insight into specific mechanisms that govern antigen-specific T cell activation has brought with it a number of innovative methods to induce and enhance T cell-mediated responses against prostate tumours. For instance, autologous dendritic cells loaded with prostate antigens have proved useful to induce prostate-specific T cell activation. Similarly, in vivo manipulations of T cell costimulatory pathway receptors can greatly facilitate tumour-specific T cell activation and potentiate T cell-mediated responses against a number of malignancies, including prostate cancer. For example, blocking T cell cytotoxic lymphocyte-associated antigen 4 (CTLA-4) receptor binding to its ligand prevents the down-regulation of T cell responses and can even potentiate T cell antitumoural immunity in mouse models of prostate cancer. Androgen ablation (AA) may induce prostate tumour/tissue-specific T cell mediated inflammation and, as such, a phase II trial is currently in progress to ascertain whether CTLA-4 blockade can enhance AA-induced treatment responses in patients with advanced prostate cancer. Nevertheless, further basic and clinical investigation is still required to establish immunotherapy as a true prostate cancer treatment option.
BioDrugs 02/2003; 17(2):131-8. · 3.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The identification of potentially useful immune-based treatments for prostate cancer has been severely constrained by the
scarcity of relevant animal research models for this disease. Moreover, some of the most critical mechanisms involved in complete
and proper antitumoral T cell activation have only recently been identified for experimental manipulation, namely, components
involved in the costimulatory pathway for T cell activation. Thus, we have established a novel syngeneic murine prostate cancer
model that permits us to examine two distinct manipulations intended to elicit an antiprostate cancer response through enhanced
T cell costimulation: (i) provision of direct costimulation by prostate cancer cells transduced to express the B7.1 ligand and (ii) in vivo antibody-mediated blockade of the T cell CTLA-4, which prevents T cell down-regulation. In the present study we found that
a tumorigenic prostate cancer cell line, TRAMPC1 (pTC1), derived from transgenic mice, is rejected by syngeneic C57BL/6 mice,
but not athymic mice, after this cell line is transduced to express the costimulatory ligand B7.1. Also, we demonstrated that
in vivo antibody-mediated blockade of CTLA-4 enhances antiprostate cancer immune responses. The response raised by anti-CTLA-4 administration
ranges from marked reductions in wild-type pTC1 growth to complete rejection of these cells. Collectively, these experiments
suggest that appropriate manipulation of T cell costimulatory and inhibitory signals may provide a fundamental and highly
adaptable basis for prostate cancer immunotherapy. Additionally, the syngeneic murine model that we introduce provides a comprehensive
system for further testing of immune-based treatments for prostate cancer.
Proceedings of the National Academy of Sciences 07/1997; 94(15):8099-8103. · 9.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Costimulatory pathway ligands and receptors can deliver either positive or negative signals to help determine the ultimate fate of activated T lymphocytes. Cytotoxic T lymphocyte antigen-4 (CTLA-4) represents one of the most extensively studied receptors in the costimulatory pathway and has recently been shown to function as a potent inhibitor of T cell-mediated immunity. T-cell expression of CTLA-4 indirectly facilitates tumor progression by restraining host antitumoral immunity. In contrast, administration of a monoclonal antibody to block CTLA-4 function can alleviate restraints on T-cell activity to promote immune-mediated tumor regression. We review the preclinical and clinical experience with CTLA-4 blockade as a promising immunotherapeutic approach to treat patients with advanced prostate cancer.
Urologic Oncology 24(5):442-7. · 3.22 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Advances in our understanding of T cell costimulatory molecules have provided a vast array of novel approaches to tumor immunotherapy. In the past year, combinatorial immunotherapy based on earlier studies of CTLA-4 blockade, the identification of novel B7-family members, the modulation of CD40 to reverse tolerance to tumor-associated antigens and the use of OX40 to enhance antitumor responses of CD4+ T cells have all contributed to the development of more-powerful immunomodulatory cancer therapies.
Current Opinion in Immunology.
