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  • 1
    Online Resource
    Online Resource
    The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity
    Springer Science and Business Media LLC ; 2023
    In:  Nature
    Details
    In: Nature, Springer Science and Business Media LLC
    Abstract: Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance 1,2 . The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity 3–6 . However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8 + T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-023-06575-7
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 2
    Online Resource
    Online Resource
    Abstract A41: Small molecule inhibition of PTPN2/1 inflames the tumour microenvironment and unleashes potent CD8+ T cell immunity
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Immunology Research Vol. 10, No. 12_Supplement ( 2022-12-01), p. A41-A41
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 10, No. 12_Supplement ( 2022-12-01), p. A41-A41
    Abstract: Immune checkpoint blockade is effective for a subset of patients across many cancers, but most patients are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatase PTPN2 is a central regulator of inflammation, and genetic deletion of PTPN2 on either tumour cells or host immune cells promotes anti-tumour immunity. However, inhibitors of PTPN2 with suitable pharmacokinetic properties for oral administration have not been described. Here, we present the characterization of ABBV-CLS-484 (A484), a potent active site inhibitor of PTPN2 and the closely related phosphatase PTPN1. A484 treatment in vitro amplifies the response to interferon gamma, and monotherapy A484 treatment generates robust anti-tumour immunity in several murine cancer models. Through in vivo studies and single cell transcriptional profiling of tumour-infiltrating lymphocytes (TIL) from A484-treated mice, we show that A484 inflames the tumour microenvironment and promotes CD8+ T cell function by enhancing cytokine signaling and decreasing T cell exhaustion and dysfunction. Our results demonstrate that oral administration of small molecule inhibitors of PTPN2/N1 can induce potent anti-tumour immunity in mouse models. PTPN2/N1 inhibitors offer a promising new strategy for cancer immunotherapy and are currently being evaluated clinically in patients with advanced solid tumours (NCT04777994). More broadly, our study shows that small molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to current antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge A484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics targeting this important class of enzymes. Citation Format: Hakimeh Ebrahimi-Nik, Arvin Iracheta-Vellve, Kira E. Olander, Thomas R.G. Davis, Sarah Y. Kim, Mitchell D. Yeary, James C. Patti, Tyler M. Balon, Omar Ismail Avila, Cun Lan Chuong, Meng-Ju Wu, Christina K. Baumgartner, Keith M. Hamel, Kathleen A. McGuire, Rebecca Mathew, Carey Backus, Ian C. Kohnle, Zhaoming Xiong, Elliot P. Farney, Jennifer M. Frost, Geoff T. Halvorsen, Matthew Rees, Andrew Boghossian, Melissa Ronan, Jennifer A. Roth, Todd R. Golub, Gabriel K. Griffin, Nabeel El-Bardeesy, Clay C. Beauregard, Philip R. Kym, Kathleen B. Yates, Robert T. Manguso. Small molecule inhibition of PTPN2/1 inflames the tumour microenvironment and unleashes potent CD8+ T cell immunity [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A41.
    Type of Medium: Online Resource
    ISSN: 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM22-A41
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 3
    Online Resource
    Online Resource
    Abstract 606: Targeting the immune checkpoint PTPN2 with ABBV-CLS-484 inflames the tumor microenvironment and unleashes potent CD8+ T cell immunity
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 606-606
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 606-606
    Abstract: Immune checkpoint blockade is effective for a subset of patients across many cancers, but most patients are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatase PTPN2 is a central regulator of inflammation, and genetic deletion of PTPN2 on either tumor cells or host immune cells promotes anti-tumor immunity. However, inhibitors of PTPN2 have not been described. Here, we present the validation of ABBV-CLS-484, a potent catalytic inhibitor of PTPN2 and the closely related phosphatase PTPN1. ABBV-CLS-484 treatment of tumor cells in vitro phenocopies the genetic deletion of PTPN2/N1, causing both amplified transcriptional responses to IFNg and reduced cell viability across human cancer cell lines. Monotherapy ABBV-CLS-484 treatment generates robust anti-tumor immunity in several murine cancer models with efficacy comparable to anti-PD-1 treatment. Through genetic studies, we show that while ABBV-CLS-484 can act on both tumor cells and the host immune system, IFN sensing and PTPN2/N1 expression on tumor cells are not always required for efficacy, suggesting that PTPN2/N1 inhibition on host immune cells may be sufficient for activity of the drug. Through scRNAseq profiling of TILs from both ABBV-CLS-484-treated and anti-PD-1-treated tumors, we show that ABBV-CLS-484 induces unique transcriptional changes to both myeloid and lymphoid populations in the tumor microenvironment which are dominated by enhanced IFN sensing and a shift from suppressive to pro-inflammatory phenotypes. ABBV-CLS-484 treatment enhances the activation and effector functions of CD8+ T cells while decreasing the expression of genes classically associated with T cell exhaustion and dysfunction such as Tox. The efficacy of ABBV-CLS-484 is critically dependent on CD8+ T cells and treatment with ABBV-CLS-484 results in greater levels of T cell infiltration into tumors and a more diverse repertoire of expanded T cell clones relative to anti-PD-1. Thus, the PTPN2/N1 inhibitor ABBV-CLS-484 is a highly effective immunotherapy with monotherapy efficacy across mouse tumor models. Small molecule inhibitors of PTPN2 offer a promising new strategy for cancer immunotherapy by targeting an IFN signaling checkpoint and are currently being evaluated clinically in patients with advanced solid tumors (NCT04777994). Citation Format: Arvin Iracheta-Vellve, Hakimeh Ebrahimi-Nik, Thomas R. Davis, Kira E. Olander, Sarah Y. Kim, Mitchell D. Yeary, James C. Patti, Ian C. Kohnle, Christina K. Baumgartner, Keith M. Hamel, Kathleen A. McGuire, Cun Lan Chuong, Zhaoming Xiong, Elliot P. Farney, Jennifer M. Frost, Matthew Rees, Andrew Boghossian, Melissa Ronan, Jennifer A. Roth, Todd R. Golub, Gabriel K. Griffin, Clay Beauregard, Philip R. Kym, Kathleen B. Yates, Robert T. Manguso. Targeting the immune checkpoint PTPN2 with ABBV-CLS-484 inflames the tumor microenvironment and unleashes potent CD8+ T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 606.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-606
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
    Online Resource
    Online Resource
    Abstract ND06: ABBV-CLS-484: An active site PTPN2/N1 inhibitor that augments the immune response and sensitizes tumors to immune-mediated killing
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. ND06-ND06
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. ND06-ND06
    Abstract: Background: Pharmacologic inhibition of PTPN2 and PTPN1 (PTPN2/N1) represents a novel therapeutic approach in immuno-oncology that augments innate and adaptive immune responses in addition to enhancing tumor cell sensitivity to immune-mediated killing. PTPN2/N1 emerged as top hits in an in vivo CRISPR screen to identify tumor-intrinsic targets that enhance sensitivity and overcome resistance to anti-PD-1 treatment. PTPN2/N1 are phosphatases that act as negative regulators in numerous pathways including immune activation. While phosphatases have long been of interest, they are challenging drug targets, and the active site had been considered undruggable. Results: Here we report the discovery of the highly selective, active site PTPN2/N1 small molecule inhibitor, ABBV-CLS-484. Highly optimized ligand-protein interactions have led to the design of sub-nanomolar PTPN2/N1 inhibitors, confirmed through x-ray crystallography. PTPN2/N1 inhibitors increase the activation and function of cytotoxic T cells as well as increase the pro-inflammatory properties of CD103+ dendritic cells and macrophages in vitro. However, they do not cause non-specific activation in the absence of stimulation; rather, they augment signaling in cells that are already activated. PTPN2/N1 inhibition also has effects directly on tumor cells, where it amplifies sensitivity to immune-mediated killing by enhancing the interferon response. ABBV-CLS-484 promotes anti-tumor immunity as monotherapy and in combination with anti-PD-1 leading to dramatic tumor regression, even in models resistant to anti-PD-1 treatment such as 4T1, or those with minimal inflammation such as EMT6. Single-cell RNAseq analyses of tumor-infiltrating immune cells confirmed activation of T cells and demonstrated switching of myeloid-derived suppressor cells towards a proinflammatory phenotype, thereby revealing a distinct mechanism of action of ABBV-CLS-484 compared with PD-1 blockade. Our results show that PTPN2/N1 inhibitors have complementary effects on the immune system and tumor microenvironment that act to promote effective tumor killing. Based on these robust preclinical data, phase I clinical trials of ABBV-CLS-484 alone and in combination with an anti-PD-1 agent have been initiated to establish the safety, tolerability, and efficacy in diverse solid tumor indications. Conclusions: We have discovered a first-in-class PTPN2/N1 inhibitor, which represents a promising novel immunotherapy that both enhances the immune response and increases tumor sensitivity to immune-mediated killing. ABBV-CLS-484 is currently being evaluated in phase I clinical trials in patients with advanced solid tumors, as a monotherapy or in combination with a PD-1 targeting agent (NCT04777994). Citation Format: Christina K. Baumgartner, Marcia N. Paddock, Jennifer M. Frost, Keith M. Hamel, Kathleen A. McGuire, Kyle Halliwill, Zhaoming Xiong, Liang Mu, Kelly Klinge, Prasanthi Geda, Jaqueline Aguado, Marinka Bulic, Elliot P. Farney, Kathleen B. Yates, Robert T. Manguso, Clay Beauregard, Philip R. Kym. ABBV-CLS-484: An active site PTPN2/N1 inhibitor that augments the immune response and sensitizes tumors to immune-mediated killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND06.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-ND06
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
    Online Resource
    Online Resource
    PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment
    BMJ ; 2022
    In:  Journal for ImmunoTherapy of Cancer Vol. 10, No. 3 ( 2022-03), p. e003402-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 10, No. 3 ( 2022-03), p. e003402-
    Abstract: Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood. Methods We use an in vivo expression screen of known cancer-associated somatic mutations in mouse syngeneic tumor models treated with checkpoint blockade to identify oncogenes that promote immune evasion. We then validated candidates from this screen in vivo and analyzed the tumor immune microenvironment of tumors expressing mutant protein to identify mechanisms of immune evasion. Results We found that expression of a catalytically active mutation in phospho-inositol 3 kinase (PI3K), PIK3CA c.3140A 〉 G (H1047R) confers a selective growth advantage to tumors treated with immunotherapy that is reversed by pharmacological PI3K inhibition. PIK3CA H1047R-expression in tumors decreased the number of CD8 + T cells but increased the number of inhibitory myeloid cells following immunotherapy. Inhibition of myeloid infiltration by pharmacological or genetic modulation of Ccl2 in PIK3CA H1047R tumors restored sensitivity to programmed cell death protein 1 (PD-1) checkpoint blockade. Conclusions PI3K activation enables tumor immune evasion by promoting an inhibitory myeloid microenvironment. Activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy. Our data suggest that some oncogenes promote tumorigenesis by enabling tumor cells to avoid clearance by the immune system. Identification of those mechanisms can advance rational combination strategies to increase the efficacy of immunotherapy.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-003402
    Language: English
    Publisher: BMJ
    Publication Date: 2022
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  • 6
    Online Resource
    Online Resource
    Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade
    Springer Science and Business Media LLC ; 2019
    In:  Nature Vol. 565, No. 7737 ( 2019-1), p. 43-48
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 565, No. 7737 ( 2019-1), p. 43-48
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-018-0768-9
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
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    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 7
    Online Resource
    Online Resource
    Maintenance of CD4 T cell fitness through regulation of Foxo1
    Springer Science and Business Media LLC ; 2018
    In:  Nature Immunology Vol. 19, No. 8 ( 2018-08), p. 838-848
    Details
    In: Nature Immunology, Springer Science and Business Media LLC, Vol. 19, No. 8 ( 2018-08), p. 838-848
    Type of Medium: Online Resource
    ISSN: 1529-2908 , 1529-2916
    URL: Article
    DOI: 10.1038/s41590-018-0157-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2026412-4
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  • 8
    Online Resource
    Online Resource
    Targeting TBK1 to overcome resistance to cancer immunotherapy
    Springer Science and Business Media LLC ; 2023
    In:  Nature Vol. 615, No. 7950 ( 2023-03-02), p. 158-167
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 615, No. 7950 ( 2023-03-02), p. 158-167
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-023-05704-6
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 9
    Online Resource
    Online Resource
    In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target
    Springer Science and Business Media LLC ; 2017
    In:  Nature Vol. 547, No. 7664 ( 2017-7), p. 413-418
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 547, No. 7664 ( 2017-7), p. 413-418
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature23270
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 10
    Online Resource
    Online Resource
    Abstract 1019: In vivo CRISPR screening identifies Ptpn2 as a target for cancer immunotherapy
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1019-1019
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1019-1019
    Abstract: Despite the dramatic clinical success of cancer immunotherapy with PD-1 checkpoint blockade, most patients don’t experience sustained clinical benefit, suggesting that additional therapeutic strategies are needed. Functional genomic screens in cancer cells to discover new therapeutic targets are usually carried out in vitro where interaction with the immune system is absent. Here we report a pooled, loss-of-function genetic screening approach using CRISPR/Cas9 genome editing that is conducted in vivo in mouse transplantable tumors treated with vaccination and PD-1 checkpoint blockade. We tested 2,400 genes expressed by melanoma cells for those that synergize with or cause resistance to checkpoint blockade, and recovered the known immune evasion molecules, PD-L1 and CD47. Loss of function of multiple genes required to sense interferon-y caused resistance to immunotherapy. Deletion of Ptpn2, a pleotropic protein tyrosine phosphatase improved response to immunotherapy. In vivo, Ptpn2 deficient tumors showed increased infiltration of activated CD8+T cells. In vitro, Ptpn2 loss by tumor cells increased antigen presentation to T cells. Biochemical, transcriptional and genetic epistasis experiments demonstrated that loss of function of Ptpn2 sensitizes tumors to immunotherapy by enhancing interferon-y-mediated effects on the tumor cell. Thus, augmenting interferon-y signaling in tumor cells could increase the efficacy of immunotherapy. More generally, in vivo genetic screens in tumor models can identify new immunotherapy targets and rationally prioritize combination therapies. Citation Format: Robert T. Manguso, Hans W. Pope, Margaret D. Zimmer, Flavian D. Brown, Kathleen B. Yates, Brian C. Miller, Natalie B. Collins, Kevin Bi, Martin W. Lafleur, Vikram R. Juneja, Sarah A. Weiss, David E. Fisher, David E. Root, Arlene H. Sharpe, John G. Doench, W Nicholas Haining. In vivo CRISPR screening identifies Ptpn2 as a target for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1019. doi:10.1158/1538-7445.AM2017-1019
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-1019
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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