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 receptor1

When OX40 is bound to its ligand, OX40L, which is typically expressed on activated antigen-presenting cells,2 an immune response may be augmented through several mechanisms that could include:

OX40 agonists* are being clinically evaluated as monotherapy and combination therapy for the potential treatment of cancer5,6

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 is a transcription factor that plays a critical role in regulating intracellular signaling pathways, including immune suppressive signaling mechanisms driven by immune cells infiltrating the tumor microenvironment. Reduction of STAT3 signaling in hematopoietic cells has been shown to enhance antitumor immunity1,2

AZD9150* is an investigational generation 2.5 antisense oligonucleotide that blocks STAT3 expression in a variety of cell types,3 including those of the tumor microenvironment. It is currently being evaluated for safety and efficacy in human clinical trials4

STAT3 Reduction pt.1 STAT3 Reduction pt.2 *AZD9150: Partnered with IONIS Pharmaceuticals, Inc.

Figure adapted from Yu H, et al. Nat Rev Immunol. 2007;7:41-51.

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 cells and lymphocytes, including T cells. This is known to suppress many aspects of antitumor immunity, including T-cell effector function1

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 systems2

AZD4635 is currently being evaluated as a monotherapy, and in combination with durvalumab (anti–PD-L1), for safety and efficacy in human clinical trials2

A2AR antagonism may help overcome adenosine-mediated immunosuppression in a number of solid tumor model systems A2AR antagonism Figure adapted from: Bendell JC, et al. ASCO 2016. Abstract TPS3096.

CD73


CD73 Inhibition

CD73 or ecto-5’-nucleotidase is a cell surface enzyme expressed on tumor cells, endothelial cells, lymphoid cells, and myeloid cells, including antigen-presenting cells.1 It catalyzes the conversion of extracellular adenosine monophosphate (AMP) to the nucleoside adenosine1,2

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.1,3-5 This is known to suppress many aspects of antitumor immunity4,5

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 trials6

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 antigen1

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 tumors1,2

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 regulatory T cells through Fc-mediated effector functions. This molecule is currently being evaluated for safety and efficacy in human clinical trials3

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.1,2 Its natural ligand, HLA-E, is highly expressed on many solid and hematologic tumors.3,4 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 killing5,6

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

This molecule is being evaluated in human clinical trials as a potential treatment for solid tumors and hematologic malignancies7

NKG2A Inhibition pt.1 NKG2A Inhibition pt.2 *Monalizumab is partnered with Innate Pharma through a co-development and co-commercialization agreement.

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 cells1

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 tumor2

Preclinical studies suggest that MEDI9197 may induce a prolonged localized and systemic cell mediated, antitumor immune response in solid tumors, without systemic cytokine-storm like effects, after intratumor delivery

This molecule is currently being evaluated as a monotherapy for safety and efficacy in human clinical trials3

TLR7 and TLR8 Agonism

Figure adapted from: Gupta S, et al. ASCO 2016. Abstract TPS3095.

*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 marrow1,2

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 CD8+ T-cell trafficking and activation, dampening NK cell activity, and promoting regulatory T-cell expansion.2,3 CXCR2 plays a key role in different disease models4-7

AZD5069 is an investigational selective CXCR2 antagonist that inhibits the migration of CXCR2+ MDSCs to the tumor microenvironment and may enhance immune-mediated tumor killing. It is currently being evaluated for safety and efficacy in human clinical trials8

CXCR2 antagonism pt.1 CXCR2 antagonism pt.2

VACCINE


Therapeutic Vaccine for HPV-16/18+ Cancers

Approximately 60% of all HPV-associated cancers are attributable to HPV-16 or HPV-18. Viral E6 and E7 proteins regulate p53 and Rb tumor suppressors, respectively1

MEDI0457 (INO-3112) is an investigational plasmid DNA vaccine consisting of three plasmids expressing HPV-16 and HPV-18 E6 and E7 proteins along with interleukin-12 as an adjuvant. It’s administered via intramuscular injection followed by electroporation and has been shown to generate a robust immune response in subjects with HPV-driven high grade cervical dysplasia as well as in HPV-associated head and neck squamous cell carcinoma2,3

MEDI0457 is currently being evaluated in combination with durvalumab for safety and efficacy in human clinical trials4

Therapeutic Vaccine for Cancers

Some compounds illustrated from AZ/MedImmune may refer to selected pipeline products still under investigation and development. AZ/MedImmune pipeline products are investigational products and as such, are not approved by the US Food & Drug Administration (FDA), the European Medicines Agency (EMA), or any other regulatory agency for the uses under investigation. Information regarding these investigational products should under no circumstances be regarded as a recommendation for their use or of their safety or efficacy.

References

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1. CDC. How Many Cancers Are Linked with HPV Each Year? https://www.cdc.gov/cancer/hpv/statistics/cases.htm. Accessed December 12, 2017. 2. Trimble CL, Morrow MP, Kraynyak KA, et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet. 2015;386(10008):2078-2088. 3. Aggarwal C, Cohen RB, Morrow MP, Kraynyak K, Bauml J, Weinstein GS. Immunogenicity results using human papillomavirus (HPV) specific DNA vaccine, INO-3112 (HPV16/HPV18 plasmids + IL-12) in HPV+ head and neck squamous cell carcinoma (HNSCCa). J Clin Oncol. 2017;35(15):suppl 6073. doi: 10.1200/JCO.2017.35.15_suppl.6073. 4. Clinical trials appendix year-to-date and Q3 2017 results update. https://www.astrazeneca.com/content/dam/az/PDF/2017/Q3/Year-to-date_and_Q3_2017_Results_Clinical_Trial_Appendix.pdf. Accessed December 12, 2017.

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