What’s the IL-15?
Interleukin-15 is a cytokine that works similarly to IL-2, including the capacity to elicit antitumor responses. Innate and adaptive immunity depend heavily on IL-15. It was identified as a four-helix bundle cytokine and was reported as a T cell proliferation factor that shared the same component, IL-2 receptor β subunit, and γ chain, with IL-2. IL-15 is a pleiotropic cytokine. Numerous cell types express IL-15 constantly in a wide range of tissue, including macrophages, monocytes, dendritic cells (DCs), T cells, epithelial cells, fibroblasts, and so on. Even so, macrophages, monocytes, and DCs are the primary producers of IL-15. ^[1]
 
What’s the ability of IL-15?
IL-15 shares some functions with IL-2, such as

• Regulating the proliferation of activated T cells
• Generating the cytotoxic T cells
• stimulating and maintaining the development and survival of the NK cell ^[2]
• Activating the immunoglobulin production by B cells ^[3]

Additionally, IL-15 acquires a few roles that set it apart from IL-2.

• Suppressing CD8+ effector T cells undergo activation-induce cell death (AICD) ^[4]
• Involving NK cells differentiation by DCs ^[5]
• Modulating the maintenance of memory and naive CD8+ T cells

How does IL-15 be presented to the cells?
Based on the structure, three kinds of IL-15 receptors are expressed on the cell surface. Unlike IL-2Rα, IL-15Rα is a high-affinity binding protein, the other is IL-2/IL-15Rβ and γ chain complex. A full heterotrimeric high-affinity complex made up of IL-15Rα, IL-2/15Rβ, and γ transmits signals via IL-2/15Rβ and γ. According to research, the isolated IL-15R is a different receptor type with a high affinity for IL-15 despite having no capability to exert signal transduction. Lymphoid cells, myeloid cells, monocytes, fibroblasts, epithelium, liver, and other cells all express IL-15Rα. Upon cells activation, IL-15Rα keeps IL-15 on the cell surface through trans-presenting, which binds to IL-2/15Rβ-γ on neighboring effector NK and T cells by forming an immunological synapse ^[6], as a membrane-bound heterodimer complex.



How does IL-15 be used in clinical?
Based on recent pre-clinical research, IL-15 and IL-2 toxicities seem to differ, with IL-15 showing less vascular capillary leak than IL-2. These considerations imply that IL-15 might be a more effective cytokine for immunotherapy against cancer. In addition to being used alone in cancer immunotherapy, IL-15 and its derivatives have also been included in numerous cancer adoptive cell therapies, specifically in conjunction with chimeric antigen receptor (CAR) engineering. IL-15 and its receptor have been included in CAR engineering in numerous recent studies to incorporate IL-15 beyond ex vivo precultures.
 


♦ T cells
Depending on the developmental and activation stage, IL-15 has different impacts on the CD8+ and CD4+ T lymphocyte subsets. Multiple studies demonstrate the significance of IL-15 in memory CD8+ T cell survival, like drastically decreased numbers of memory CD8+ T lymphocytes in IL-15- and IL-15Rα-deficient mouse strains ^[7], upregulating the expression of additional anti-apoptotic molecules by IL-15 to support the survival of CD8+ T lymphocytes at all development stages ^[8] In the clinical studies, several research teams looked into the possibility of using IL-15 into CAR-T engineering because of its special capacity to sustain the homeostasis and proliferation of memory CD8+ T cells. The IL-15-boosted CAR T cells displayed 10-fold in vitro proliferation and 3- to 15-fold expansion in vivo upon antigen stimulation, along with decreased cell death and low PD-1 expression. ^[9] Similar to the previous study, a different CAR design was evaluated using membrane-bound IL-15 (mbIL-15) fusion protein, which combines IL-15 with IL-15R through a linker to replicate the specific physiological mechanism of IL-15 trans-presentation. ^[10] IL-15 has also been combined with other CARs to target other tumor types, such as IL13Ra-CAR. ^[11] Consistently positive results show enhanced in vivo persistence and potent anti-tumor activity of IL15-armored CAR T cells. The patient experienced a 5-month full response with strong growth and long persistence of CAR T cells despite the significant tumor load before mbIL-15 CAR T cell injection. The serum level of IL-15 was kept low and harmful effects were reversible. ^[11]

♦ NK cells
Natural killer (NK) cells are able to lyse tumor cells without the need for antigen priming. Thus, NK cells become a popular and promising platform with positive therapeutic qualities and a reduced risk of inducing severe cytokine-related toxicities, which can address several limitations of the current cell therapies.
However, the short lifespan of NK cells is one of the challenges of using them. Despite research indicating the existence of long-lived memory NK cells, the selection of memory NK cells for immunotherapy was restricted by the absence of accurate markers to characterize them. Therefore, an appealing approach for NK cell-based immunotherapy is the ectopically generated IL-15 on NK cells, which promotes NK cell proliferation and persistence. It has been determined that overexpressing IL-15 or the IL-15 receptor complex in different CAR NK cells results in significantly higher NK cell survival rates and greater anti-tumor activity. ^[12-14] In a recent study, the majority of 11 individuals with relapsed or refractory B-cell lymphoma or leukemia responded to CAR-NK cell therapy without experiencing significant harmful side effects, like CSR. ^[12]


 
Related Products:
→ Croyez GMP ® IL-15 (Interleukin-15), Human
→ Croyez GMP ® IL-2 (Interleukin-2), Human

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Ref.

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2. Waldmann TA, Tagaya Y. The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annu Rev Immunol. 1999;17:19-49.
3. Armitage RJ, Macduff BM, Eisenman J, Paxton R, Grabstein KH. IL-15 has a stimulatory activity for the induction of B cell proliferation and differentiation. J Immunol. 1995 Jan 15;154(2):483-90.
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9. Hoyos V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M, Vera J, Heslop HE, Rooney CM, Brenner MK, Dotti G. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia. 2010 Jun;24(6):1160-70.
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12. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, Nassif Kerbauy L, Overman B, Thall P, Kaplan M, Nandivada V, Kaur I, Nunez Cortes A, Cao K, Daher M, Hosing C, Cohen EN, Kebriaei P, Mehta R, Neelapu S, Nieto Y, Wang M, Wierda W, Keating M, Champlin R, Shpall EJ, Rezvani K. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020 Feb 6;382(6):545-553.
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14. Du Z, Ng YY, Zha S, Wang S. piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells. Mol Ther Methods Clin Dev. 2021 Nov 4;23:582-596.