Other Pathways

Other Promising Immuno-Oncology Pathways

OX40

OX40 Agonism

The OX40 receptor is transiently expressed on activated T cells and serves as a late co-stimulatory receptor.1,2

When OX40 is bound to its ligand, OX40L, which is typically expressed on activated antigen-presenting cells,3 an immune response may be augmented through several mechanisms that could include:

Activation of OX40 can also be achieved through the use of agonistic OX40-directed antibodies.6 Such treatment has the potential to enhance T-cell stimulation and promote potential tumor killing by the immune system.4 Agonistic OX40-directed antibodies can work as monotherapy or in combination with other immunotherapies to augment antitumor immune responses.1

MEDI0562 is a humanized mAb OX40 agonist, currently in clinical development to determine its antitumor effect where it may enhance T-cell stimulation and promote the immune system to kill tumors.6,7

OX40 agonism MOA pt.1 OX40 agonism MOA pt.2 OX40 agonists developed in partnership with AgonOx, LLC.

Figure adapted from Medimmune Oncology Pipeline: MEDI6469, targeting OX40. ©2013 MedImmune, LLC. 11326A. AstraZeneca; 264701, May 2013.

TAKE A DEEPER LOOKat activating the OX40/OX40L axis

STAT3

STAT3 Reduction

STAT3 (signal transducer and activator of transcription 3) is a transcription factor that plays a critical role in normal cell proliferation, differentiation, and apoptosis (programmed cell death). Constitutive activation of STAT3 has been identified in many types of tumors.8-10

AZD9150* is an investigational generation 2.5 antisense oligonucleotide that prevents STAT3 expression, thereby blocking tumor-intrinsic and tumor-extrinsic STAT3-mediated signaling. It is currently being evaluated for safety and efficacy in human clinical trials.7,11

STAT3 inhibition
*AZD9150: Partnered with IONIS Pharmaceuticals, Inc.Figure adapted from Siveen KS, et al. BBA. 2014;1845:136-154.

A2AR

A2AR Antagonism

Elevated extracellular levels of adenosine in the microenvironment of many solid tumors, driven by overexpression of CD73 (an ectoenzyme that catalyzes the conversion of AMP to adenosine) and by tissue breakdown and hypoxia, can exert potent immunosuppressive effects by binding of adenosine to the adenosine 2A receptor (A2AR) on antigen-presenting cell and lymphocytes, including T cells. This is known to suppress many aspects of anti-tumor immunity, including T-cell effector function.12

AZD4635 is an investigational small molecule A2AR antagonist that selectively binds to A2AR. A2AR antagonists help to overcome adenosine-mediated immunosuppression in a number of solid tumor model systems.7,12

AZD4635 is currently being evaluated as a monotherapy, and in combination with durvalumab, for safety and efficacy in human clinical trials.7

A2AR antagonism help overcome adenosine-mediated immunosuppression in a number of solid tumor model systems A2AR antagonism

CD73

CD73 Inhibition

CD73 or ecto-5’-nucleotidase is a cell surface enzyme expressed on endothelial cells, lymphoid cells, and myeloid cells, including antigen-presenting cells. It catalyzes the conversion of extracellular adenosine monophosphate (AMP) to the nucleoside adenosine.13,14

Overexpression of CD73 and elevated extracellular levels of adenosine in the microenvironments of many solid tumors are known to exert potent immunosuppressive effects by binding of adenosine to adenosine receptors on antigen-presenting cells and lymphocytes including T cells. This is known to suppress many aspects of antitumor immunity.13,15-17

MEDI9447 is an investigational human IgG1λ monoclonal antibody that selectively binds to and inhibits the ectonucleotidase activity of CD73. Results from preclinical studies suggest that MEDI9447 may help to overcome adenosine-mediated immunosuppression in a number of solid tumor model systems. The molecule is currently being evaluated for safety and efficacy in human clinical trials.7,18

CD73 Inhibition pt.1 CD73 Inhibition pt.2

GITR

GITR Agonism

GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) is a surface receptor expressed on regulatory T cells (Tregs) and on activated effector T cells. Interaction of GITR and its ligand (GITR-L) enhances the proliferation and activation of T cells in response to antigen.19,20

Activation of GITR by agonistic anti-GITR antibodies stimulates effector T-cell expansion and cytokine production, which has been reported to induce antitumor immune responses and regression of tumors.19,20

MEDI1873 is an investigational human GITR-L fusion protein that binds to GITR and drives T-cell activation signals. In addition to stimulating T-cell expansion and cytokine production, the molecule has the potential to deplete Tregs through Fc-mediated effector functions.21 This molecule is currently being evaluated for safety and efficacy in human clinical trials.7

GITR Agonism pt.1 GITR Agonism pt.2

NKG2A

NKG2A Inhibition

NKG2A is an immune checkpoint inhibitor receptor that is primarily expressed on tumor infiltrating innate immune effector NK cells, as well as on some CD8+ T cells.22-24 Its natural ligand, HLA-E, is highly expressed on many solid and hematologic tumors.25 Binding of tumor-associated HLA-E to NKG2A inhibits NK cell and CD8 T-cell activation and ablates NK cell and CD8 T-cell-mediated antitumor killing.26

Monalizumab* (IPH2201) is a first-in-class, investigational anti-NKG2A antibody that binds to NKG2A on NK cells and some CD8+ T cells, and helps block the inhibitory interactions between tumor-associated HLA-E and the NKG2A receptor. This, in turn, may enhance innate immune antitumor responses.23

This molecule is being evaluated in human clinical trials as a potential treatment for solid tumors and hematologic malignancies.7,23

NKG2A Inhibition pt.1 NKG2A Inhibition pt.2 *Monalizumab is partnered with Innate Pharma through a co-development and co-commercialization agreement. The initial plan includes combination trial with durvalumab (MEDI4736) in solid tumors.23

TLR7/8

TLR7/8 Agonism

Stimulation of toll-like receptor (TLR) 7 and TLR8 on dendritic cells induces a local tumor immune response characterized by secretion of Th1 proinflammatory cytokines and chemokines and activation of NK cells and tumor-specific CD8 cytotoxic T cells.27

MEDI9197 (formerly 3M-052*) is an investigational imidazoquinoline-like TLR7/8 agonist designed with a lipid tail that, when injected, helps retain the molecule within the tumor.28,29

Preclinical studies suggest that MEDI9197 may induce a prolonged localized and systemic cell mediated, anti-tumor immune response in solid tumors, without systemic cytokine-storm like effects, after intra-tumor delivery.7,29

This molecule is currently being evaluated as a monotherapy for safety and efficacy in human clinical trials.7

TLR7 and TLR8 Agonism

*Licensed from 3M Corporation.

CXCR2

CXCR2 Antagonism

CXCR2 is a chemokine receptor that binds its chemokine ligands CXCL1 and CXCL8 and is found on myeloid-derived suppressor cells (MDSCs)—a class of immature myeloid cells that originate in the bone marrow.30,31

During tumorigenesis, CXCR2+ MDSCs migrate via the vasculature in response to increased ligand production by the tumor and localize in tumor microenvironments. There, they contribute to immune evasion by secreting cytokines that modify the tumor microenvironment, reducing T-cell trafficking and activation, and dampening NK cell activity and promoting regulatory T-cell (Treg) expansion.31,32

AZD5069 is an investigational selective CXCR2 antagonist that inhibits the migration of CXCR2+ MDSCs to tumor microenvironments and may enhance immune-mediated tumor killing. It is currently being evaluated for safety and efficacy in human clinical trials.7,32

CXCR2 antagonism pt.1 CXCR2 antagonism pt.2

Safety and efficacy of the agent under investigation have not been established. Investigational agents are not approved by the US or any other regulatory agency for the uses under investigation.

The information provided here includes details of products that are still in development and is for personal information purposes only. AstraZeneca does not, under any circumstances, promote its products for off-label, unapproved uses.

References

1. Gao J, Bernatchez C, Sharma P et al. Advances in the development of cancer immunotherapies. Trends Immunol. 2013:34(2):90-98. 2. Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol. 2005;23:23-68. 3. Jensen SM, Maston LD, Gough MJ et al. Signaling through OX40 enhances antitumor immunity. Semin Oncol. 2010;3(5)7:524-532. 4. Voo KS, Bover L, Harline ML et al. Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function. J Immunol. 2013;191(6):3641-3650. 5. Vu MD, Xiao X, Gao W et al. OX40 costimulation turns off Foxp3+ Tregs. Blood. 2007;110(10):2501-2510. 6. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. 7. AstraZeneca. Clinical trials appendix Q1 2017 results update. https://www.astrazeneca.com/content/dam/az/PDF/2017/QR1/Q1_2017_Results_Clinical_Trial_Appendix.pdf. Accessed June 26, 2017. 8. Bar-Natan M, Nelson EA, Xiang M et al. STAT signaling in the pathogenesis and treatment of myeloid malignancies. JAKSTAT. 2012;(2)1:55-64. 9. Qi QR, Yang ZM. Regulation and function of signal transducer and activator of transcription 3. World J Biol Chem. 2014;5(2):231-239. 10. Walker SR, Frank DA. Screening approaches to generating STAT Inhibitors: Allowing the hits to identify the targets. JAKSTAT. 2012;1(4):292-299. 11. Odate S, Veschi V, Yan S, Lam N, Woessner R, Thiele CJ. Inhibition of STAT3 with the generation 2.5 antisense oligonucleotide, AZD9150, decreases neuroblastoma tumorigenicity and increases chemosensitivity. Clin Cancer Res. 2017;23(7):1771-1784. 12. Leone RD, Lo YC, Powell JD. A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biol J. 2015;13:265-272. 13. Zhang B. CD73 promotes tumor growth and metastasis. Oncoimmunology. 2012;1(1):67-70. 14. Jin D, Fan J, Wang L et al. CD73 on tumor cells impairs anti-tumor T cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res. 2010;70(6):2245-2255. 15. Ohta A, Gorelik E, Prasad S et al. A2A adenosine receptors protects tumors from antitumor T cells. PNAS. 2006;103(35):13132-13137. 16. Hoskin DW, Mader JS, Furlong SJ et al. Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells. Int J Oncol. 2008;32(3):527-535. 17. Young A, Mittal D, Stagg J et al. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 2014;4(8):879-888. 18. NCI Drug Dictionary: anti-CD73 monoclonal antibody MEDI9447. National Cancer Institute Web site. https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=775839. Accessed August 22, 2017. 19. Schaer DA, Murphy JT, Wolchok JD. Modulation of GITR for cancer immunotherapy. Curr Opin Immunol. 2012;24(2):217-224. 20. Schaer DA, Budhu S, Liu C et al. GITR pathway activation abrogates tumor immune suppression through loss of regulatory T-cell lineage. Cancer Immunol Res. 2013;1(5):320-331. 21. NCI Drug Dictionary: GITR agonist MEDI1873. National Cancer Institute Web site. https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=776837. Accessed August 22, 2017. 22. Platonova S, Chertils-Vicini J, Damotte D et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res. 2011;7:5412-5422. 23. AstraZeneca and Innate Pharma announce global co-development and commercialisation collaboration for IPH2201 in immuno-oncology. AstraZeneca Web site. https://www.astrazeneca.com/media-centre/press-releases/2015/astrazeneca-innate-pharma-global-collaboration-immuno-oncology-24042015.html#. Published April 24, 2015. Accessed August 22, 2017. 24. Sheu BC, Chiou SH, Lin HH et al. Up-regulation of inhibitory natural killer receptors on CD94/N KG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8+ T lymphocytes in human cervical carcinoma. Cancer Res. 2005;1:2921-2929. 25. Talebian Yazdi M, van Riet S, van Schadewijk A et al. The positive prognostic effect of stromal CD8+ tumor-infiltrating T cells is restrained by the expression of HLA-E in non-small cell lung carcinoma. Oncotarget. 2015;7(3):3477-3488. 26. Pace E, Di Sano C, Ferraro M et al. Altered CD94/N KG2A and perforin expression reduce the cytotoxic activity in malignant pleural effusions. Eur J Cancer. 2011;47:296-304. 27. Gorden K, Gorski K, Gibson S et al. Synthetic TLR agonists reveal functional difference between human TLR7 and TLR8. J Immunol. 2005;174:1259-1268. 28. Mullins SR, Vogel K, Vasilakos J et al. Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment and holds potential for combination with immune checkpoint inhibitors [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 4697. 29. Fakhari A, Nugent S, Elvecrog J et al. Thermosensitive gel-based formulation for intratumoral delivery of toll-like receptor 7/8 dual agonist, MEDI9197. J Pharm Sci. 2017;106(8):2037-2045. 30. Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Ann Rev Immunol. 2014;32:659-702. 31. Highfill SL, CuiY, Giles AJ et al. Disruption of CXCR2-mediated MDSC tumor Trafficking enhances anti-PD1 efficacy. Sci Transl Med. 2014;6:1-13. 32. Martz L. CXCR2 antibodies for antitumor immunity. Targets & Mechanisms. Science-Business Exchange. Published online June 19, 2014. 2014;7(24). doi:10.1038/scibx.2014.693.

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