Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes

Sockolosky, Jonathan T.; Trotta, Eleonora; Parisi, Giulia; Picton, Lora K.; Su, Leon; Le, Alan; Chhabra, Akanksha; Silveria, Stephanie L.; George, Benson M.; King, Indigo Chris; Tiffany, Matthew; Jude, Kevin; Sibener, Leah V.; Baker, David; Shizuru, Judith A.; Ribas, Antoni; Bluestone, Jeffrey A.; García, K. Christopher

doi:10.1126/science.aar3246

Cited by 263 publications

(220 citation statements)

References 35 publications

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“…For example, if the clinical phenotype is due to hypomorphic IL-2Rb deficiency, there may be alternative corrective rescue methods or potential treatment strategies. It is feasible to boost IL-2 IL-2R interaction by IL-2 anti-IL-2 antibody complexes (Boyman et al 2006), IL-2 superkine (Levin et al 2012), ortho-IL2 analogs (Sockolosky et al 2018), and IL-2 Fc fusion proteins (Vazquez-Lombardi et al 2017) as a potential means of hyper-stimulating residual surface IL-2Rb. Monoclonal anti-human IL-2 antibody MAB602 (mouse S4B6) in complex with IL-2 was found to selectively promote proliferation of effector T cells, while the antibody clone 5344 (mouse JES61) induced proliferation of Tregs (Boyman et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, the H9 IL-2 superkine was engineered to have enhanced binding to IL-2Rb independent of CD25 (Levin et al 2012). Another approach to hyper-stimulating the IL-2Rb mutant would be to develop an orthoIL-2 with specific binding to the mutant (Sockolosky et al 2018). IL-2-Fc fusion proteins could also potentially rescue the IL-2Rb mutant by inducing proliferation of CD25 deficient T cells without affecting Tregs (Vazquez-Lombardi et al 2017).…”

Section: Discussionmentioning

confidence: 99%

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Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance

Zhang

Gothe

Pennamen

et al. 2018

Preprint

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Interleukin-2, which conveys essential signals for effective immunity and immunological tolerance, operates through a heterotrimeric receptor comprised of a, b, and g chains. Genetic deficiency of the a or g chain causes debilitating disease. Here we identify human interleukin-2 receptor (IL-2R) b chain (CD122) gene defects as a cause of life-threatening dysregulation of immunity and peripheral tolerance. We report homozygous mutations in the human IL-2Rb gene from four consanguineous families, comprising either recessive missense mutations in five children or an early stop-gain mutation in two deceased fetuses and a premature neonate. All patients surviving to childhood presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, and dermatological abnormalities, as well as cytomegalovirus disease in most cases. Patient T lymphocytes lacked surface expression of IL-2Rb and were unable to normally respond to high-dose IL-2 stimulation. By contrast, patient natural killer (NK) cells retained partial IL-2Rb expression and cytotoxic function. IL-2Rb loss of function was recapitulated in a recombinant system, in which endoplasmic reticulum sequestration was revealed as the mechanism by which certain missense mutations cause disease. Hematopoietic stem cell transplant resulted in resolution of clinical symptoms in one patient. The hypomorphic nature of this disease highlights the significance of variable IL-2Rb expression in different lymphocyte subsets as a means of modulating immune function. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance

Zhang

Gothe

Pennamen

et al. 2018

Preprint

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“…It consists of a mutated IL-2Rβ, ortho-IL-2Rβ, which no longer binds native IL-2 but its mutant form, ortho-IL-2. The expression of ortho-IL-2Rβ on chimeric antigen receptor T cells confers selective proliferation following ortho-IL-2 administration, avoiding bystander activation of other IL-2R + cells like Tregs (Sockolosky et al, 2018).…”

Section: Immunosuppressive and Immunostimulatory Il-2 Therapiesmentioning

confidence: 99%

Effects of interleukin-2 in immunostimulation and immunosuppression

Pol

Caudana

Paillet

et al. 2019

Journal of Experimental Medicine

113

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Historically, interleukin-2 (IL-2) was first described as an immunostimulatory factor that supports the expansion of activated effector T cells. A layer of sophistication arose when regulatory CD4+ T lymphocytes (Tregs) were shown to require IL-2 for their development, homeostasis, and immunosuppressive functions. Fundamental distinctions in the nature and spatiotemporal expression patterns of IL-2 receptor subunits on naive/memory/effector T cells versus Tregs are now being exploited to manipulate the immunomodulatory effects of IL-2 for therapeutic purposes. Although high-dose IL-2 administration has yielded discrete clinical responses, low-dose IL-2 as well as innovative strategies based on IL-2 derivatives, including “muteins,” immunocomplexes, and immunocytokines, are being explored to therapeutically enhance or inhibit the immune response.

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“…A creative approach to avoid unwanted IL-2 toxicity uses an engineered IL-2 receptor that recognizes an IL-2 ortholog. Sockolosky et al 27 developed a receptor-ligand pair that functions similarly to natural IL-2 receptor β and IL-2 but does not bind endogenous IL-2. This modified receptor can be transduced into T cells, and the IL-2 ortholog can be administered to promote specific T-cell proliferation and antitumor efficacy comparable to wild-type IL-2 signaling.…”

Section: Enhancing Responsesmentioning

confidence: 99%

“…This modified receptor can be transduced into T cells, and the IL-2 ortholog can be administered to promote specific T-cell proliferation and antitumor efficacy comparable to wild-type IL-2 signaling. 27 An alternative approach to supplementing with exogenous cytokines is to encode cytokines directly into the CAR construct. Adachi et al 28 generated CARs targeting human CD20 or (FITC), a fluorescent molecular label, providing a more generalizable comparator.…”

Section: Enhancing Responsesmentioning

confidence: 99%

Advances in Chimeric Antigen Receptor T‐Cell Therapies for Solid Tumors

Baybutt

Flíckinger

Caparosa

et al. 2018

Clin Pharma and Therapeutics

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In 2017, the US Food and Drug Administration approved the first two novel cellular immunotherapies using synthetic, engineered receptors known as chimeric antigen receptors (CARs), tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), expressed by patient‐derived T cells for the treatment of hematological malignancies expressing the B‐cell surface antigen CD19 in both pediatric and adult patients. This approval marked a major milestone in the use of antigen‐directed “living drugs” for the treatment of relapsed or refractory blood cancers, and with these two approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be targeted. This state‐of‐the‐art review will focus on the challenges, advances, and novel approaches being used to implement CAR T‐cell immunotherapy for the treatment of solid tumors.

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Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes

Cited by 263 publications

References 35 publications

Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance

Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance

Effects of interleukin-2 in immunostimulation and immunosuppression

Advances in Chimeric Antigen Receptor T‐Cell Therapies for Solid Tumors

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