Antigen-presenting cells (APCs) play a critical role in initiating the cancer-immunity cycle1
As tumor cells are killed, neoantigens from the tumor are taken up by APCs, leading to immunogenic cell death1
Antigens are presented to T cells, thereby initiating the cancer-immunity cycle and, ultimately, activation and expansion of the antitumor immune response1
Tumors may escape immune response by inhibiting maturation of APCs and priming of T cells1
The toll-like receptor (TLR) 7/8 pathway activates APCs that prime T cells and recruit immune cells within the tumor microenvironment2,4
Activation of the TLR 7/8 signaling pathway [1] promotes the maturation of APCs, [2] which both:
Enhance recruitment and proper activation of immune cells [3]
Drive tumor antigen presentation and resulting activation (priming) of T cells [4]
TLR 7/8 agonists could improve antitumor immune response when combined with other immunotherapies2,4
Nektar is exploring sustained and targeted TLR 7/8 signaling in combination with other immunotherapies5
References: 1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10. 2. Adams S. Toll-like receptor agonists in cancer therapy. Immunotherapy. 2009;1(6):949-964. 3. Rabeony H, Pohin M, Vasseur P, et al. IMQ-induced skin inflammation in mice is dependent on IL-1R1 and MyD88 signaling but independent of the NLRP3 inflammasome. Eur J Immunol. 2015;45:2847-2857. doi:10.1002/eji.201445215. 4. Singh M, Khong H, Dai Z, et al. Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J Immunol. 2014;193:1-10. doi:10.4049/jimmunol.1401160. 5. Kivimäe S, Pena R, Hennessy M, et al. Systemic anti-tumor immunity and immune memory formation by a novel TLR7/8 targeting agent NKTR-262 combined with CD122-biased immunostimulatory cytokine NKTR-214. Presented at: Society for Immunotherapy of Cancer annual meeting. November 7-11, 2018; Washington, D.C., USA.
ENGAGING IMMUNE RESPONSE THROUGH THE IL-15 PATHWAY
Both innate and adaptive immunity are needed for sustained immune response
Natural killer (NK) cells mediate an innate immune response whereas cytotoxic T cells mediate the adaptive immune response. Both are independently correlated with positive patient outcomes1-3
Once the adaptive immune response has been generated, a small number of T cells will be maintained as memory T cells to enable long-term immunity3
Pre-clinical and clinical studies have shown that memory T cells are also necessary for optimal immunological control of certain tumors3
Activation of the IL-15 pathway engages both adaptive and innate antitumor immunity
IL-15 signaling [1] induces both the proliferation and activation [2] of both NK cells and of cytotoxic T cells to1,3,4
Enhance NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cells [4]6
Boost cytotoxic T-cell mediated killing of tumor cells [4]1
Promote the maintenance of memory T cells [3] that can cause tumor cell death [4]1,3,4
IL-15 agonists show potential in combination with other oncology therapeutics1
Nektar is investigating sustained and controlled engagement of the IL-15 pathway6
References: 1. Robinson TO, Schluns KS. The potential and promise of IL-15 in immuno-oncogenic therapies. Immunol Lett. 2017;190:159-168. 2. Messaoudene M, Frazao A, Gavlovsky PJ, Toubert A, Dulphy N, Caignard A. Patient's natural killer cells in the era of targeted therapies: role for tumor killers. Front Immunol. 2017;8:683. doi:10.3389/fimmu.2017.00683. 3. Osborne LC, Abraham N. Regulation of memory T cells by yc cytokines. Cytokine. 2010;50(2):105-113. 4. Kennedy MK, Glaccum M, Brown SN, et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med. 2000;191(5):771-780. 5. Stonier SW and Schluns KS. Trans-presentation: a novel mechanism regulating IL-15 delivery and responses. Immunol Lett. 2010;127(2):85-92. doi:10.1016/j.imlet.2009.09.009. 6. Data on File. Nektar Therapeutics.
THE ROLE OF THE IL-2 PATHWAY IN IMMUNE RESPONSE
Higher levels of cytotoxic T cells and natural killer (NK) cells raise tumor cell killing potential in the tumor microenvironment1,2
In patients with cancer, the immunosuppressive tumor microenvironment may inhibit the activation and proliferation of both cytotoxic T cells and NK cells1,2
Higher densities of cytotoxic T cells and NK cells have been positively correlated with greater tumor cell killing3-5
The IL-2 pathway can both stimulate and regulate immune responses
The IL-2 pathway is a key immune regulatory pathway that helps govern immune activation of cytotoxic T cells and NK cells or immune suppression via regulatory T cells (Tregs)6
The IL-2 receptor complex exists in either a dimeric or a trimeric form [1], each generating unique biological outcomes upon activation6
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IMMUNE SYSTEM REGULATION:
IL-2 cytokine binding of the trimeric complex [alpha (CD25) + beta (CD122) + gamma (CD132)] on Tregs[2] causes their activation and proliferation, and thereby immune regulation [4]7-10
IMMUNE SYSTEM STIMULATION:
IL-2 cytokine binding of the dimeric complex [beta (CD122) + gamma (CD132)] on cytotoxic T cells and NK cells [2] induces their proliferation and activation leading to immune activation [3]7
Preferential dimeric activation of the IL-2 receptor is a target for further research7
Preferential activation of the dimeric (CD122 + CD132) IL-2 receptor complex may increase the numbers of cytotoxic T cells and NK cells over Tregs in the tumor microenvironment 6,7
Nektar is investigating preferential binding of the dimeric IL-2 receptor for sustained and controlled activation and expansion of cytotoxic T cells and NK cells over immunosuppressive Tregs7,11
References: 1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10. 2. Messaoudene M, Frazao A, Gavlovsky PJ, et al. Patient's natural killer cells in the era of targeted therapies: role for tumor killers. Front Immunol. 2017;8:683. doi:10.3389/fimmu.2017.00683. 3. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568-583. 4. Halle S, Keyser KA, Stahl FR, et al. In vivo killing capacity of cytotoxic t cells is limited and involves dynamic interactions and t cell cooperativity. Immunity. 2016;44(2):233-245. 5. Cursons J, Souza-Fonseca-Guimaraes F, Foroutan M. et al. A gene signature predicting natural killer cell infiltration and improved survival in melanoma patients. Cancer Immunology Research. 2019;7(7):1162-1174. 6. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nature Rev Immunol. 2012;12(3):180-190. 7. Charych D, Khalili S, Dixit V, et al. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLoS One. 2017;12(7):e0179431. doi:10.1371/journal.pone.0179431. eCollection 2017. 8. Ye C, Brand D, Zheng SG. Targeting IL-2: an unexpected effect in treating immunological diseases. Signal Transduct Target Ther. 2018;3:1-10. 9. Johnson K, Choi Y, Wu Z, et al. Soluble IL-2 receptor beta and gamma subunits: ligand binding and cooperativity. Eur Cytokine Netw. 1994;5:23-34. 10. Liparoto SF, Myszka DG, Wu Z, et al. Analysis of the role of the interleukin-2 receptor gamma chain in ligand binding. Biochemistry. 2002;41:2543-2551. 11. Bentebibel SE, Hurwitz ME, Bernatchez C, et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019;9:1-11.
