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Intraprostatic distribution and long-term follow-up after AdV-tk immunotherapy as neoadjuvant to surgery in patients with prostate cancer.

Rojas-Martínez A, Manzanera AG, Sukin SW, Esteban-María J, González-Guerrero JF, Gomez-Guerra L, Garza-Guajardo R, Flores-Gutiérrez JP, Elizondo Riojas G, Delgado-Enciso I, Ortiz-López R, Aguilar LK, Butler EB, Barrera-Saldaña HA, Aguilar-Cordova E - Cancer Gene Ther. (2013)

Bottom Line: Patients were monitored for tumor progression and acute and long-term safety.There were no significant adverse events deemed related to the treatment and no late toxicities after median follow-up of 11.3 years.AdV-tk demonstrated no significant acute or late toxicities.

View Article: PubMed Central - PubMed

Affiliation: 1] Facultad de Medicina, Universidad Autónoma de Nuevo León (UANL), Monterrey, Mexico [2] Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autónoma de Nuevo León (UANL), Monterrey, Mexico [3] Department of Biochemistry, Universidad Autónoma de Nuevo León (UANL), Monterrey, Mexico.

ABSTRACT
A phase I-II study to evaluate gene-mediated cytotoxic immunotherapy in newly diagnosed prostate cancer before radical prostatectomy was conducted in Monterrey, Mexico. First, to investigate delivery of adenovirus to the prostate, fluorescently labeled vector was injected into fresh prostatectomy specimens and distribution was visually analyzed. The optimal volume and site instillation was then used for transrectal ultrasound guided intraprostatic injection in 10 patients with adenocarcinoma scheduled for radical prostatectomy. Each received two apical and two basal 0.5 ml injections of AdV-tk for a total of 1 × 10(11) vp followed by 14 days of prodrug. Nine patients continued to tumor resection: six high risk, one intermediate and two low risk. In vivo vector distribution was analyzed from the resected tissue of four patients. Patients were monitored for tumor progression and acute and long-term safety. For vector delivery, two apical and two basal injections of 0.5 ml led to optimal organ-wide distribution ex vivo and in vivo. Cytotoxicity was evidenced by transient rise in PSA and tumor histology. There were no significant adverse events deemed related to the treatment and no late toxicities after median follow-up of 11.3 years. All six high-risk patients had positive surgical margins and one had seminal vesicle involvement. Despite slow PSA rise post surgery in three of these patients, none developed metastases. The intermediate- and low-risk patients had complete resections and none have progressed. In conclusion, in vivo transrectal ultrasound guided instillation of an adenoviral vector into four sites in the prostate was practical as an outpatient procedure, well tolerated and led to distribution throughout the intraprostatic tumor mass. AdV-tk demonstrated no significant acute or late toxicities. Trends in PSA and disease progression conveyed the possibility of a sustained immune response against residual disease.

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Immune cytolytic cell infiltration in treated tumor compared to untreated control tumorResected prostate tumors were processed and immunohistochemical analysis performed with antibody to human TIA-1 followed by immunoperoxidase staining using avidin-biotin complex. A and B, 10X; C and D, 20X and E and F, 40X.
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Figure 3: Immune cytolytic cell infiltration in treated tumor compared to untreated control tumorResected prostate tumors were processed and immunohistochemical analysis performed with antibody to human TIA-1 followed by immunoperoxidase staining using avidin-biotin complex. A and B, 10X; C and D, 20X and E and F, 40X.

Mentions: Nine prostate specimens were analyzed for necrosis, apoptosis and inflammatory response was (Table 2). Characterization of inflammatory infiltrate revealed a predominance of T cells compared to B cells (ratio 4:1) in neoplastic areas with a CD4:CD8 ratio of 1:4. CD4 cells were predominantly found in the stroma. TIA-1 (T-cell intracytoplasmic antigen) is a granule-associated RNA binding protein expressed in cells with cytolytic potential, including activated CD8+ T cells and NK cells 19. As shown in Figure 3, AdV-tk treated prostate tumors had an increased infiltration of TIA-1+ cells compared to untreated control.


Intraprostatic distribution and long-term follow-up after AdV-tk immunotherapy as neoadjuvant to surgery in patients with prostate cancer.

Rojas-Martínez A, Manzanera AG, Sukin SW, Esteban-María J, González-Guerrero JF, Gomez-Guerra L, Garza-Guajardo R, Flores-Gutiérrez JP, Elizondo Riojas G, Delgado-Enciso I, Ortiz-López R, Aguilar LK, Butler EB, Barrera-Saldaña HA, Aguilar-Cordova E - Cancer Gene Ther. (2013)

Immune cytolytic cell infiltration in treated tumor compared to untreated control tumorResected prostate tumors were processed and immunohistochemical analysis performed with antibody to human TIA-1 followed by immunoperoxidase staining using avidin-biotin complex. A and B, 10X; C and D, 20X and E and F, 40X.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3842423&req=5

Figure 3: Immune cytolytic cell infiltration in treated tumor compared to untreated control tumorResected prostate tumors were processed and immunohistochemical analysis performed with antibody to human TIA-1 followed by immunoperoxidase staining using avidin-biotin complex. A and B, 10X; C and D, 20X and E and F, 40X.
Mentions: Nine prostate specimens were analyzed for necrosis, apoptosis and inflammatory response was (Table 2). Characterization of inflammatory infiltrate revealed a predominance of T cells compared to B cells (ratio 4:1) in neoplastic areas with a CD4:CD8 ratio of 1:4. CD4 cells were predominantly found in the stroma. TIA-1 (T-cell intracytoplasmic antigen) is a granule-associated RNA binding protein expressed in cells with cytolytic potential, including activated CD8+ T cells and NK cells 19. As shown in Figure 3, AdV-tk treated prostate tumors had an increased infiltration of TIA-1+ cells compared to untreated control.

Bottom Line: Patients were monitored for tumor progression and acute and long-term safety.There were no significant adverse events deemed related to the treatment and no late toxicities after median follow-up of 11.3 years.AdV-tk demonstrated no significant acute or late toxicities.

View Article: PubMed Central - PubMed

Affiliation: 1] Facultad de Medicina, Universidad Autónoma de Nuevo León (UANL), Monterrey, Mexico [2] Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autónoma de Nuevo León (UANL), Monterrey, Mexico [3] Department of Biochemistry, Universidad Autónoma de Nuevo León (UANL), Monterrey, Mexico.

ABSTRACT
A phase I-II study to evaluate gene-mediated cytotoxic immunotherapy in newly diagnosed prostate cancer before radical prostatectomy was conducted in Monterrey, Mexico. First, to investigate delivery of adenovirus to the prostate, fluorescently labeled vector was injected into fresh prostatectomy specimens and distribution was visually analyzed. The optimal volume and site instillation was then used for transrectal ultrasound guided intraprostatic injection in 10 patients with adenocarcinoma scheduled for radical prostatectomy. Each received two apical and two basal 0.5 ml injections of AdV-tk for a total of 1 × 10(11) vp followed by 14 days of prodrug. Nine patients continued to tumor resection: six high risk, one intermediate and two low risk. In vivo vector distribution was analyzed from the resected tissue of four patients. Patients were monitored for tumor progression and acute and long-term safety. For vector delivery, two apical and two basal injections of 0.5 ml led to optimal organ-wide distribution ex vivo and in vivo. Cytotoxicity was evidenced by transient rise in PSA and tumor histology. There were no significant adverse events deemed related to the treatment and no late toxicities after median follow-up of 11.3 years. All six high-risk patients had positive surgical margins and one had seminal vesicle involvement. Despite slow PSA rise post surgery in three of these patients, none developed metastases. The intermediate- and low-risk patients had complete resections and none have progressed. In conclusion, in vivo transrectal ultrasound guided instillation of an adenoviral vector into four sites in the prostate was practical as an outpatient procedure, well tolerated and led to distribution throughout the intraprostatic tumor mass. AdV-tk demonstrated no significant acute or late toxicities. Trends in PSA and disease progression conveyed the possibility of a sustained immune response against residual disease.

Show MeSH
Related in: MedlinePlus