A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy

Hsu, Eric J.; Cao, Xuezhi; Moon, Benjamin; Bae, Joonbeom; Sun, Zhichen; Liu, Zhida; Fu, Yang–Xin

doi:10.1038/s41467-021-22980-w

Cited by 79 publications

(50 citation statements)

References 55 publications

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“…Low dose IL2 has been successfully used to enhance T cell responses in treatment of renal cell carcinoma and metastatic melanoma 48, 49 however is subject to variable patient tolerance. More recent work to develop a masked IL2 cytokine that is proteolytically cleaved and activated by tumour-associated MMPs to promote CD8 cell expansion and overcome resistance to ICI has been demonstrated 50 . Similarly, a tumour targeting recombinant antibody linked to IL2 that localises to tumour cells has been shown to induce cytotoxic CD8 expansion and overcome resistance to ICI 51 .…”

Section: Discussionmentioning

confidence: 99%

IL-2 stromal signatures dissect immunotherapy response groups in non-small cell lung cancer (NSCLC)

Monkman

Kim

Mayer

et al. 2021

Preprint

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IntroductionImmunotherapies, such as immune checkpoint inhibitors (ICI) have shown durable benefit in a subset of non-small cell lung cancer (NSCLC) patients. The mechanisms for this are not fully understood, however the composition and activation status of the cellular milieu contained within the tumour microenvironment (TME) is becomingly increasingly recognised as a driving factor in treatment-refractory disease.MethodsHere, we employed multiplex IHC (mIHC), and digital spatial profiling (DSP) to capture the targeted immune proteome and transcriptome of tumour and TME compartments of pre-treatment samples from a 2nd line NSCLC ICI-treated cohort (n=41 patients; n=25 responders, n=16 non-responders).ResultsWe demonstrate by mIHC that the interaction of CD68+ macrophages with PD1+, FoxP3+ cells is significantly enriched in ICI refractory tumours (p=0.012). Our study revealed that patients sensitive to ICI therapy expressed higher levels of IL2 receptor alpha (CD25, p=0.028) within the tumour compartments, which corresponded with the increased expression of IL2 mRNA (p=0.001) within their stroma, indicative of key conditions for ICI efficacy prior to treatment. IL2 mRNA levels within the stroma positively correlated with the expression of pro-apoptotic markers cleaved caspase 9 (p=2e-5) and BAD (p=5.5e-4) and negatively correlated with levels of memory T cells (CD45RO) (p=7e-4). Immuno-inhibitory markers CTLA-4 (p=0.021) and IDO-1 (p=0.023) were also supressed in ICI-responsive patients. Of note, tumour CD44 (p=0.02) was depleted in the response group and corresponded inversely with significantly higher stromal expression of its ligand SPP1 (osteopontin, p=0.008). Analysis of differentially expressed transcripts indicated the potential inhibition of stromal interferon-gamma (IFNγ) activity, as well as estrogen-receptor and Wnt-1 signalling activity within the tumour cells of ICI responsive patients. Cox survival analysis indicated tumour CD44 expression was associated with poorer prognosis (HR=1.61, p=0.01), consistent with its depletion in ICI sensitive patients. Similarly, stromal CTLA-4 (HR=1.78, p=0.003) and MDSC/M2 macrophage marker ARG1 (HR=2.37, p=0.01) were associated with poorer outcome while levels of apoptotic marker BAD (HR=0.5, p=0.01) appeared protective. Interestingly, stromal mRNA for E-selectin (HR=652, p=0.001), CCL17 (HR=70, p=0.006) and MTOR (HR=1065, p=0.008) were highly associated with poorer outcome, indicating pro-tumourigenic features in the tumour microenvironment that may facilitate ICI resistance.ConclusionsThrough multi-modal approaches, we have dissected the characteristics of NSCLC and provide evidence for the role of IL2 and stromal activation by osteopontin in the efficacy of current generations of ICI therapy. The enrichment of SPP1 in the stroma of ICI sensitive patients in our data is a novel finding, indicative of stromal activation that may aid immune cell survival and activity despite no clear association with increased levels of immune infiltrate.

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Section: Discussionmentioning

confidence: 99%

IL-2 stromal signatures dissect immunotherapy response groups in non-small cell lung cancer (NSCLC)

Monkman

Kim

Mayer

et al. 2021

Preprint

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“…IL-2–based fusion proteins are another IL-2 therapy strategy with a multitude of current preclinical and clinical trials ( 15 , 16 ). Fusion of IL-2 to a fragment crystallizable (Fc) region has proven to be beneficial due to increased half-life, complement activation, and induction of antibody-dependent cellular cytotoxicity (ADCC) toward Treg cells ( 17 – 19 ). Furthermore, fusion of IL-2 to antigen-specific antibodies (termed an immunocytokine) allows for targeted delivery of IL-2 to cells and tissues expressing a protein of interest.…”

Section: Manipulation Of T Cell Phenotype By Il-2 Therapymentioning

confidence: 99%

A forced marriage of IL-2 and PD-1 antibody nurtures tumor-infiltrating T cells

Holcomb¹,

Zou²

2022

Journal of Clinical Investigation

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IL-2 is a pleiotropic cytokine. In this issue of the JCI , Ren et al. report on the development of a low-affinity IL-2 paired with anti–PD-1 (PD-1–laIL-2) that reactivates intratumoral CD8 + T cells, but not CD4 + Treg cells. PD-1–laIL-2 treatment synergized with anti–PD-L1 therapy to overcome tumor resistance to immune checkpoint blockade (ICB) in tumor-bearing mice. Rejection of rechallenged tumors following PD-1–laIL-2 therapy demonstrated the establishment of a potent T cell memory response. Furthermore, PD-1–laIL-2 therapy manifested no obvious toxicity. These findings suggest the potential of PD-1–laIL-2 therapy in treating patients with cancer.

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“…A construct termed “pro-IL2” contains superkine IL-2 (sumIL-2) [ 43 ] fused with the extracellular domain of the IL-2R β and a WT Fc domain. The IL-2R β portion is attached via a cleavable linker, allowing IL-2 activity to be restricted until cleavage occurs in the tumor microenvironment [ 44 ]. Preclinical analysis demonstrated that pro-IL2 had comparable anti-tumor efficacy to sumIL2-Fc with a superior toxicity profile.…”

Section: Current Il-2-based Fusion Proteins For Cancer Therapymentioning

confidence: 99%

Interleukin 2-Based Fusion Proteins for the Treatment of Cancer

MacDonald

Hung

2021

Journal of Immunology Research

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Interleukin 2 (IL-2) plays a fundamental role in both immune activation and tolerance and has revolutionized the field of cancer immunotherapy since its discovery. The ability of IL-2 to mediate tumor regression in preclinical and clinical settings led to FDA approval for its use in the treatment of metastatic renal cell carcinoma and metastatic melanoma in the 1990s. Although modest success is observed in the clinic, cancer patients receiving IL-2 therapy experience a wide array of side effects ranging from flu-like symptoms to life-threatening conditions such as vascular leak syndrome. Over the past three decades, efforts have focused on circumventing IL-2-related toxicities by engineering methods to localize IL-2 to the tumor or secondary lymphoid tissue, preferentially activate CD8+ T cells and NK cells, and alter pharmacokinetic properties to increase bioavailability. This review summarizes the various IL-2-based strategies that have emerged, with a focus on chimeric fusion methods.

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A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy

Cited by 79 publications

References 55 publications

IL-2 stromal signatures dissect immunotherapy response groups in non-small cell lung cancer (NSCLC)

IL-2 stromal signatures dissect immunotherapy response groups in non-small cell lung cancer (NSCLC)

A forced marriage of IL-2 and PD-1 antibody nurtures tumor-infiltrating T cells

Interleukin 2-Based Fusion Proteins for the Treatment of Cancer

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