Dual targeting of CTLA-4 and CD47 on T
            <sub>reg</sub>
            cells promotes immunity against solid tumors

Zhang, Anli; Ren, Zhenhua; Tseng, Kuo‐Fu; Liu, Xiaojuan; Li, Huiyu; Lu, Changzheng; Cai, Yu; Minna, John D.; Fu, Yang–Xin

doi:10.1126/scitranslmed.abg8693

Cited by 43 publications

(39 citation statements)

References 54 publications

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“…Of note, previous studies have identified combination inhibition of CD47 and PD-L1 could lead to a synergistic inhibition effect on tumor growth in some pancreatic cancer cell lines 38 . Combination blockade of CD47 and PD1, CTLA4 also achieved better anti-tumor effect 34 , 37 . Furthermore, a couple of ongoing clinical trials are targeting dual immune checkpoints such as CD47/PD-1(HX009), CD47/CD137 (DSP107), CD47/PD-L1 (IBI322, PF-07257876), CD47/CD20 (IMM0306), CD47/CD19 (TG-1801) 49 .…”

Section: Discussionmentioning

confidence: 97%

“…Targeting CD47 in combination with PD-1 may potentially improve the outcomes of patients with anaplastic thyroid carcinoma 36 . Similarly, Dual targeting CD47 and CTLA-4 promotes immunity against colon cancers 37 . Anti-CD47 targeting in pancreatic cancer could remodel tumor- infiltrating immune cells 38 and enhance CD19/CD3-bispecific T cell engager antibody-mediated lysis of B cell malignancies 39 .…”

Section: Introductionmentioning

confidence: 99%

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Role of CD47 in tumor immunity: a potential target for combination therapy

Huang

Liu

et al. 2022

Sci Rep

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CD47 performs a vital function in cancer therapy by binding to different SIRPα, thrombospondin 1, and integrin. However, its role in tumor immunity and its correlation with prognosis among many cancer types remain unknown. The raw mRNA expression data of CD47 in cancer patients was downloaded from TCGA and GTEx datasets. The protein expression of CD47 was detected using a microarray. Kaplan Meier analysis and forest plot were performed to compare the effects of high and low expression of CD47 on overall survival in different cancers. In addition, the correlations between CD47 expression and immune cell infiltration, stromal components, immune checkpoint genes, tumor mutational burden (TMB), and microsatellite instability (MSI) were analyzed from the public database. The gene function was determined by Gene Set Enrichment Analysis (GSEA). The expressions of CD47 in CHOL, COAD, ESCA, HNSC, KIRC, STAD, and THCA were higher compared with normal tissues. Elevated expression of CD47 predicted poor prognosis in ACC, KICH, KIRP, LGG, PAAD and UCEC. CD47 expression was strongly associated with immune infiltrating cells among KICH, KIRP, LGG, and PAAD. In addition, significant positive correlations with most immune checkpoint genes including PDCD 1 (PD-1), CD274 (PD-L1), CTLA4 in BLCA, DLBC, KICH, KIRC, LUAD, LUSC, PAAD, PCPG, SKCM, STAD, UCEC, and UVM was noted for the expression of CD47. GSEA analysis demonstrated that CD47 was a key regulator in metabolism-related pathways. These findings provide novel evidence that CD47 could be utilized as a promising prognostic biomarker and combination treatment target in various cancers.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Role of CD47 in tumor immunity: a potential target for combination therapy

Huang

Liu

et al. 2022

Sci Rep

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“…IL-2 was fused with Fc with a GGGGS linker and cloned into pEE6.4. Heterodimerization of Ab–IL-2 was achieved by the knobs-into-holes approach ( 52 ). Plasmids encoding Ab-Fc and IL-2–Fc were cotransfected into FreeStyle 293-F cells (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity

Ren¹,

Zhang²,

Sun³

et al. 2022

Journal of Clinical Investigation

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PD-1 signaling on T cells is the major pathway that limits T cell immunity, but the efficacy of anti–PD-1 therapy has been limited to a small proportion of patients with advanced cancers. We fortuitously observed that anti–PD-1 therapy depends on IL-2 signaling, which raises the possibility that a lack of IL-2 limits anti–PD-1–induced effector T cell expansion. To selectively deliver IL-2 to PD-1 + CD8 + tumor-infiltrating lymphocytes (TILs), we engineered a low-affinity IL-2 paired with anti–PD-1 (PD-1–laIL-2), which reduced affinity to peripheral Treg cells but enhanced avidity to PD-1 + CD8 + TILs. PD-1–laIL-2 exerted better tumor control and lower toxicity than single or mixed treatments. Mechanistically, PD-1–laIL-2 could effectively expand dysfunctional and tumor-specific CD8 + T cells. Furthermore, we discovered that presumably dysfunctional PD-1 + TIM3 + TILs are the dominant tumor-specific T cells responding to PD-1–laIL-2. Collectively, these results highlight that PD-1–laIL-2 can target and reactivate tumor-specific TILs for tumor regression as a unique strategy with stronger efficacy and lower toxicity.

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“…Based on the high expression of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on regulatory T (Treg) cells and abundant Fc receptor-expressing active phagocytes inside the TME, preclinical study had been done by combining anti-CTLA-4 mAbs with the SIRPα, targeting Treg cells and selectively blocking CD47 on intratumoral Treg cells, respectively. The results demonstrated that simultaneously modulating both "eat me" and “do not eat me” signals induced Treg cell depletion inside the TME and could be an effective strategy for treating solid tumors [ 81 ].…”

Section: Cd47 Combination Therapiesmentioning

confidence: 99%

Targeting CD47 for cancer immunotherapy

et al. 2021

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Much progress has been made in targeting CD47 for cancer immunotherapy in solid tumors (ST) and hematological malignancies. We summarized the CD47-related clinical research and analyzed the research trend both in the USA and in China. As of August 28, 2021, there are a total 23 related therapeutic agents with 46 clinical trials in the NCT registry platform. Among these trials, 29 are in ST, 14 in hematological malignancies and 3 in both solid tumor and hematological malignancy. The ST include gastric cancer, head and neck squamous cell carcinoma and leiomyosarcoma, while the hematological malignancies include non-Hodgkin's lymphoma, acute myeloid leukemia, myelodysplastic syndrome, multiple myeloma and chronic myeloid leukemia. Majority of the CD47-related clinical trials are at the early phases, such as 31 at phase I, 14 at phase II and 1 at phase III in the USA and 9, 6, 1, in China, respectively. The targets and spectrums of mechanism of action include 26 with mono-specific and 20 with bi-specific targets in the USA and 13 with mono-specific and 3 with bi-specific targets in China. The new generation CD47 antibodies have demonstrated promising results, and it is highly hopeful that some candidate agents will emerge and make into clinical application to meet the urgent needs of patients.

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Dual targeting of CTLA-4 and CD47 on T _reg cells promotes immunity against solid tumors

Cited by 43 publications

References 54 publications

Role of CD47 in tumor immunity: a potential target for combination therapy

Role of CD47 in tumor immunity: a potential target for combination therapy

Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity

Targeting CD47 for cancer immunotherapy

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Dual targeting of CTLA-4 and CD47 on T reg cells promotes immunity against solid tumors

Cited by 43 publications

References 54 publications

Role of CD47 in tumor immunity: a potential target for combination therapy

Role of CD47 in tumor immunity: a potential target for combination therapy

Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity

Targeting CD47 for cancer immunotherapy

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Product

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Dual targeting of CTLA-4 and CD47 on T _reg cells promotes immunity against solid tumors