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Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy.

Mandl SJ, Rountree RB, Dela Cruz TB, Foy SP, Cote JJ, Gordon EJ, Trent E, Delcayre A, Franzusoff A - J Immunother Cancer (2014)

Bottom Line: The heterologous prime-boost regimen of the two PROSTVAC vectors significantly enhanced the magnitude and quality of activated PSA-specific CD4 and CD8 T cell responses compared to homologous, single vector regimens.In vivo CD4 and CD8 depletion revealed that both T cell subsets contributed to anti-tumor efficacy.The clinical validation is ongoing in the PROSPECT Phase 3 clinical study.

View Article: PubMed Central - PubMed

Affiliation: Bavarian Nordic, Inc, 2425 Garcia Ave, Mountain View, CA 94043 USA.

ABSTRACT

Background: PROSTVAC®, an active immunotherapy currently studied for the treatment of metastatic castration-resistant prostate cancer (mCRPC), consists of a heterologous prime-boost regimen with two different poxvirus-based vectors to provoke productive immune responses against prostate specific antigen (PSA) as the target tumor antigen. A Phase 2 study of PROSTVAC immunotherapy showed significantly improved median overall survival by 8.5 months and is currently being validated in a global Phase 3 study (PROSPECT; NCT01322490). Here, preclinical models were explored to investigate the mechanism of action and immune signatures of anti-tumor efficacy with PROSTVAC immunotherapy with the goal to identify potential immune correlates of clinical benefit.

Methods: PROSTVAC-induced immune responses and anti-tumor efficacy were studied in male BALB/c mice. Functionality of the induced T cell response was characterized by interferon-gamma (IFNγ) ELISPOT, cytotoxic degranulation, multi-cytokine intracellular staining, and in vivo T cell depletion. Tumor infiltrating lymphocytes (TILs) were evaluated phenotypically by flow cytometry.

Results: The heterologous prime-boost regimen of the two PROSTVAC vectors significantly enhanced the magnitude and quality of activated PSA-specific CD4 and CD8 T cell responses compared to homologous, single vector regimens. PROSTVAC-activated CD4 and CD8 T cells were highly functional as evidenced by expression of activation markers, production of multiple cytokines, and amplified cytotoxic T cell activity. Importantly, PROSTVAC immunotherapy resulted in significant anti-tumor efficacy in a transplantable prostate cancer mouse model. Antigen-spreading occurred in PROSTVAC-treated animals that rejected PSA-expressing tumors, as shown by subsequent rejection of PSA-negative tumors. In vivo CD4 and CD8 depletion revealed that both T cell subsets contributed to anti-tumor efficacy. Characterization of TILs demonstrated that PROSTVAC immunotherapy greatly increased the intra-tumoral ratio of activated effector to regulatory T cells.

Conclusions: PROSTVAC immunotherapy activates broad, highly functional T cell immunity to PSA and to endogenous tumor antigens via immune-mediated antigen spreading. These preclinical results further elucidate the mode of action of PROSTVAC immunotherapy and its potential causal relationship to extended overall survival as observed in the PROSTVAC Phase 2 study. The clinical validation is ongoing in the PROSPECT Phase 3 clinical study.

No MeSH data available.


Related in: MedlinePlus

PROSTVAC mediated anti-tumor efficacy and antigen spreading. (A & B) BALB/c mice (10-20/group) were challenged by i.d. injection of RM-11-PSA cells on day 1 and treated 3 times at weekly intervals as described in text. Graphs show data from 2 independently performed experiments. (C) Previously-challenged, tumor-free PROSTVAC V/F-treated mice (n = 6) and naïve BALB/c (n = 10) were injected i.d. with 2E5 RM11-WT cells. ****P < 0.0001.
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Fig4: PROSTVAC mediated anti-tumor efficacy and antigen spreading. (A & B) BALB/c mice (10-20/group) were challenged by i.d. injection of RM-11-PSA cells on day 1 and treated 3 times at weekly intervals as described in text. Graphs show data from 2 independently performed experiments. (C) Previously-challenged, tumor-free PROSTVAC V/F-treated mice (n = 6) and naïve BALB/c (n = 10) were injected i.d. with 2E5 RM11-WT cells. ****P < 0.0001.

Mentions: The anti-tumor activity of heterologous PROSTVAC-V/F immunotherapy was confirmed in a mouse prostate cancer model using transplanted RM-11-PSA cells. Mice were challenged with tumors and subsequently dosed with a regimen of heterologous wild-type (WT) parental virus vectors with no transgenes, with heterologous UV-inactivated PROSTVAC-V/F or heterologous PROSTVAC-V/F active immunotherapy (Figures 4A). The dosing regimen was accelerated to weekly administration due to the rapid growth kinetics of this tumor model. The anti-tumor response was dependent on dosing with active viral vectors, since no efficacy was observed with UV-inactivated viruses (Figure 4A). Although a visible trend in anti-tumor activity was noted within a 100 fold PROSTVAC-V/F dose range (Additional file 1: Figure SD5), the efficacy of PROSTVAC-V/F immunotherapy, compared to dosing with empty vectors (2E7/1E8 WT controls), was statistically equivalent over that 100 fold dose range. For all follow on studies, the highest dose of 2E7/1E8 VFF was used.Figure 4


Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy.

Mandl SJ, Rountree RB, Dela Cruz TB, Foy SP, Cote JJ, Gordon EJ, Trent E, Delcayre A, Franzusoff A - J Immunother Cancer (2014)

PROSTVAC mediated anti-tumor efficacy and antigen spreading. (A & B) BALB/c mice (10-20/group) were challenged by i.d. injection of RM-11-PSA cells on day 1 and treated 3 times at weekly intervals as described in text. Graphs show data from 2 independently performed experiments. (C) Previously-challenged, tumor-free PROSTVAC V/F-treated mice (n = 6) and naïve BALB/c (n = 10) were injected i.d. with 2E5 RM11-WT cells. ****P < 0.0001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4201731&req=5

Fig4: PROSTVAC mediated anti-tumor efficacy and antigen spreading. (A & B) BALB/c mice (10-20/group) were challenged by i.d. injection of RM-11-PSA cells on day 1 and treated 3 times at weekly intervals as described in text. Graphs show data from 2 independently performed experiments. (C) Previously-challenged, tumor-free PROSTVAC V/F-treated mice (n = 6) and naïve BALB/c (n = 10) were injected i.d. with 2E5 RM11-WT cells. ****P < 0.0001.
Mentions: The anti-tumor activity of heterologous PROSTVAC-V/F immunotherapy was confirmed in a mouse prostate cancer model using transplanted RM-11-PSA cells. Mice were challenged with tumors and subsequently dosed with a regimen of heterologous wild-type (WT) parental virus vectors with no transgenes, with heterologous UV-inactivated PROSTVAC-V/F or heterologous PROSTVAC-V/F active immunotherapy (Figures 4A). The dosing regimen was accelerated to weekly administration due to the rapid growth kinetics of this tumor model. The anti-tumor response was dependent on dosing with active viral vectors, since no efficacy was observed with UV-inactivated viruses (Figure 4A). Although a visible trend in anti-tumor activity was noted within a 100 fold PROSTVAC-V/F dose range (Additional file 1: Figure SD5), the efficacy of PROSTVAC-V/F immunotherapy, compared to dosing with empty vectors (2E7/1E8 WT controls), was statistically equivalent over that 100 fold dose range. For all follow on studies, the highest dose of 2E7/1E8 VFF was used.Figure 4

Bottom Line: The heterologous prime-boost regimen of the two PROSTVAC vectors significantly enhanced the magnitude and quality of activated PSA-specific CD4 and CD8 T cell responses compared to homologous, single vector regimens.In vivo CD4 and CD8 depletion revealed that both T cell subsets contributed to anti-tumor efficacy.The clinical validation is ongoing in the PROSPECT Phase 3 clinical study.

View Article: PubMed Central - PubMed

Affiliation: Bavarian Nordic, Inc, 2425 Garcia Ave, Mountain View, CA 94043 USA.

ABSTRACT

Background: PROSTVAC®, an active immunotherapy currently studied for the treatment of metastatic castration-resistant prostate cancer (mCRPC), consists of a heterologous prime-boost regimen with two different poxvirus-based vectors to provoke productive immune responses against prostate specific antigen (PSA) as the target tumor antigen. A Phase 2 study of PROSTVAC immunotherapy showed significantly improved median overall survival by 8.5 months and is currently being validated in a global Phase 3 study (PROSPECT; NCT01322490). Here, preclinical models were explored to investigate the mechanism of action and immune signatures of anti-tumor efficacy with PROSTVAC immunotherapy with the goal to identify potential immune correlates of clinical benefit.

Methods: PROSTVAC-induced immune responses and anti-tumor efficacy were studied in male BALB/c mice. Functionality of the induced T cell response was characterized by interferon-gamma (IFNγ) ELISPOT, cytotoxic degranulation, multi-cytokine intracellular staining, and in vivo T cell depletion. Tumor infiltrating lymphocytes (TILs) were evaluated phenotypically by flow cytometry.

Results: The heterologous prime-boost regimen of the two PROSTVAC vectors significantly enhanced the magnitude and quality of activated PSA-specific CD4 and CD8 T cell responses compared to homologous, single vector regimens. PROSTVAC-activated CD4 and CD8 T cells were highly functional as evidenced by expression of activation markers, production of multiple cytokines, and amplified cytotoxic T cell activity. Importantly, PROSTVAC immunotherapy resulted in significant anti-tumor efficacy in a transplantable prostate cancer mouse model. Antigen-spreading occurred in PROSTVAC-treated animals that rejected PSA-expressing tumors, as shown by subsequent rejection of PSA-negative tumors. In vivo CD4 and CD8 depletion revealed that both T cell subsets contributed to anti-tumor efficacy. Characterization of TILs demonstrated that PROSTVAC immunotherapy greatly increased the intra-tumoral ratio of activated effector to regulatory T cells.

Conclusions: PROSTVAC immunotherapy activates broad, highly functional T cell immunity to PSA and to endogenous tumor antigens via immune-mediated antigen spreading. These preclinical results further elucidate the mode of action of PROSTVAC immunotherapy and its potential causal relationship to extended overall survival as observed in the PROSTVAC Phase 2 study. The clinical validation is ongoing in the PROSPECT Phase 3 clinical study.

No MeSH data available.


Related in: MedlinePlus