Magnitude and quality of tumor-infiltrating T-cell response upon poxvirus-based active immunotherapy alone and in combination with CTLA-4 immune checkpoint inhibition.

Foy, Susan P.; Mandl, Stefanie; Cruz, Tracy dela; Cote, Joseph; Gordon, Evan; Trent, Erica; Franzusoff, Alexis J.; Rountree, Ryan B.

doi:10.1200/jco.2014.32.15_suppl.3013

Cited by 4 publications

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“…Although limitations in cell number prevented us from performing functional assays on the TILs, we believe that the phenotypic similarities of these highly activated (CD44+ and ICOS+) CD8 T cells add suggestive evidence that these cells have similar functional capabilities as the cells described in Figures 1 , 2 and 3 . Cytotoxic activity of TIL has been demonstrated by us in a different tumor model using a similar poxvirus-based immunotherapy product [ 29 ]. It is of note that the heterologous PROSTVAC prime-boost regimen increases the ratio of PSA-targeted to vaccinia-targeted CTL responses more than 100 fold compared to a homologous dosing regimen.…”

Section: Discussionmentioning

confidence: 99%

Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

Mandl¹,

Rountree²,

Cruz³

et al. 2014

j. immunotherapy cancer

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BackgroundPROSTVAC®, 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.MethodsPROSTVAC-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.ResultsThe 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.ConclusionsPROSTVAC 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-014-0034-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

Mandl¹,

Rountree²,

Cruz³

et al. 2014

j. immunotherapy cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although limitations in cell number prevented us from performing functional assays on the TILs, we believe that the phenotypic similarities of these highly activated (CD44+ and ICOS+) CD8 T cells add suggestive evidence that these cells have similar functional capabilities as the cells described in Figures 1, 2 and 3. Cytotoxic activity of TIL has been demonstrated by us in a different tumor model using a similar poxvirusbased immunotherapy product [29]. It is of note that the heterologous PROSTVAC prime-boost regimen increases the ratio of PSA-targeted to vaccinia-targeted CTL responses more than 100 fold compared to a homologous dosing regimen.…”

Section: Discussionmentioning

confidence: 95%

Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

Mandl¹,

Rountree²,

Cruz³

et al. 2014

Journal for ImmunoTherapy of Cancer

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Background: PROSTVAC W , 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.

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“…Poxvirus-based active immunotherapy results in significant antitumor immunity characterized by robust CD8 T cell infiltration of the tumor [ 3 , 5 , 37 , 38 ]. The studies in this report show that this is also accompanied by significant upregulation of PD-L1 expression in the tumor microenvironment, a known adaptive resistance mechanism that occurs in response to IFNγ produced by tumor-infiltrating T cells [ 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…Because PD-L1 upregulation is a mechanism of tumoral adaptive resistance, the observed PD-L1 upregulation in the tumor microenvironment following poxvirus-based active immunotherapy treatment is interpreted as the evasion response to activated cytotoxic CD8 T cells producing IFNγ in high amounts [ 5 , 37 , 39 ]. These data corroborate evidence from preclinical studies demonstrating that tumors do not upregulate PD-L1 expression in mice lacking T cells or in IFNγ-knockout mice [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Poxvirus-Based Active Immunotherapy with PD-1 and LAG-3 Dual Immune Checkpoint Inhibition Overcomes Compensatory Immune Regulation, Yielding Complete Tumor Regression in Mice

et al. 2016

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Poxvirus-based active immunotherapies mediate anti-tumor efficacy by triggering broad and durable Th1 dominated T cell responses against the tumor. While monotherapy significantly delays tumor growth, it often does not lead to complete tumor regression. It was hypothesized that the induced robust infiltration of IFNγ-producing T cells into the tumor could provoke an adaptive immune evasive response by the tumor through the upregulation of PD-L1 expression. In therapeutic CT26-HER-2 tumor models, MVA-BN-HER2 poxvirus immunotherapy resulted in significant tumor growth delay accompanied by a robust, tumor-infiltrating T cell response that was characterized by low to mid-levels of PD-1 expression on T cells. As hypothesized, this response was countered by significantly increased PD-L1 expression on the tumor and, unexpectedly, also on infiltrating T cells. Synergistic benefit of anti-tumor therapy was observed when MVA-BN-HER2 immunotherapy was combined with PD-1 immune checkpoint blockade. Interestingly, PD-1 blockade stimulated a second immune checkpoint molecule, LAG-3, to be expressed on T cells. Combining MVA-BN-HER2 immunotherapy with dual PD-1 plus LAG-3 blockade resulted in comprehensive tumor regression in all mice treated with the triple combination therapy. Subsequent rejection of tumors lacking the HER-2 antigen by treatment-responsive mice without further therapy six months after the original challenge demonstrated long lasting memory and suggested that effective T cell immunity to novel, non-targeted tumor antigens (antigen spread) had occurred. These data support the clinical investigation of this triple therapy regimen, especially in cancer patients harboring PD-L1neg/low tumors unlikely to benefit from immune checkpoint blockade alone.

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Magnitude and quality of tumor-infiltrating T-cell response upon poxvirus-based active immunotherapy alone and in combination with CTLA-4 immune checkpoint inhibition.

Cited by 4 publications

References 0 publications

Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

Poxvirus-Based Active Immunotherapy with PD-1 and LAG-3 Dual Immune Checkpoint Inhibition Overcomes Compensatory Immune Regulation, Yielding Complete Tumor Regression in Mice

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