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

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eric J. Hsu ◽  
Xuezhi Cao ◽  
Benjamin Moon ◽  
Joonbeom Bae ◽  
Zhichen Sun ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Interleukin 2 ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Targeting Therapy ◽  
Protease Substrate ◽  
Reduced Toxicity ◽  
Infiltrating Lymphocytes ◽  
Receptor Beta

AbstractAs a potent lymphocyte activator, interleukin-2 (IL-2) is an FDA-approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, we address these issues by engineering an IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.

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

2020 ◽  
Author(s):  
Eric Hsu ◽  
Xuezhi Cao ◽  
Benjamin Moon ◽  
joonbeom Bae ◽  
Zhichen Sun ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Interleukin 2 ◽  
Body Weight Loss ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Targeting Therapy ◽  
Protease Substrate ◽  
Reduced Toxicity ◽  
Receptor Beta

Abstract Interleukin-2 (IL-2) is an FDA approved treatment for multiple metastatic cancers. However, while IL-2 is a potent activator of CD8 and NK cells, its clinical use is limited by short in vivo half-life, low potency, and severe in vivo toxicity. Current strategies of reducing IL-2 receptor alpha binding and increasing IL-2 receptor beta binding reduce efficacy or increase toxicity. Here, we address these issues by engineering a novel IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferred IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it is efficiently cleaved and expands CD8 T cells. This significantly reduces IL-2 associated cytokine storm, body weight loss, and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can effectively eliminate metastatic cancer by inducing an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.

Clinical application of retroviral gene transfer in oncology: results of a French study with tumor-infiltrating lymphocytes transduced with the gene of resistance to neomycin.

1995 ◽  
Vol 13 (2) ◽  
pp. 410-418 ◽  
Author(s):  
Y Merrouche ◽  
S Negrier ◽  
C Bain ◽  
V Combaret ◽  
A Mercatello ◽  
...  
Keyword(s):  
Adoptive Immunotherapy ◽  
Human Lymphocytes ◽  
Marker Gene ◽  
Interleukin 2 ◽  
Tumor Infiltrating Lymphocytes ◽  
Pcr Analysis ◽  
Gene Marker ◽  
Gene Transduction ◽  
Infiltrating Lymphocytes

PURPOSE Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and interleukin-2 (IL-2) has been reported to mediate tumor regression in some human cancers. To define better the biologic characteristics of TIL, especially survival and distribution in vivo, we performed a gene-marker study in patients with advanced malignancies. PATIENTS AND METHODS We treated five patients with metastatic melanoma or renal cell carcinoma with adoptive immunotherapy. TIL were genetically modified, before their infusion, using a recombinant retroviral vector that contained the marker gene coding for resistance to neomycin (NeoR). RESULTS All of the patients tolerated the treatment well and none of the theoretic safety hazards due to the retroviral gene transduction was observed. The presence of the NeoR gene in TIL was detected by Southern blot analysis, with an efficiency of transduction that ranged from 1% to 26%. With polymerase chain reaction (PCR) analysis, we demonstrated that gene-modified TIL can survive for several months after reinjection, since positive blood samples were observed up to day 260 following reinjection. Eight malignant biopsy specimens were obtained from three patients after cell infusion. TIL were detected in only four of these eight tumor deposits on days 7 and 260. CONCLUSION These results confirm the feasibility and safety of using in vitro retroviral gene transduction in human lymphocytes to analyze their in vivo distribution for further therapeutic applications. However, a selective and prolonged retention of TIL at the tumor site was not found in this study.

Tumor-Infiltrating Lymphocytes and Interleukin-2: Dose and Schedules of Administration in the Treatment of Metastatic Cancer

2004 ◽  
Vol 19 (6) ◽  
pp. 730-737 ◽  
Author(s):  
Robert Dillman ◽  
Patric Schiltz ◽  
Carol De Priest ◽  
Neil Barth ◽  
Linda Beutel ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Interleukin 2 ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

scholarly journals C4b-binding protein α-chain enhances antitumor immunity by facilitating the accumulation of tumor-infiltrating lymphocytes in the tumor microenvironment in pancreatic cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Kosuke Sasaki ◽  
Shigetsugu Takano ◽  
Satoshi Tomizawa ◽  
Yoji Miyahara ◽  
Katsunori Furukawa ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Binding Protein ◽  
Combined Treatment ◽  
Tumor Infiltrating Lymphocytes ◽  
Pdac Cell ◽  
Α Chain ◽  
Infiltrating Lymphocytes

Abstract Background Recent studies indicate that complement plays pivotal roles in promoting or suppressing cancer progression. We have previously identified C4b-binding protein α-chain (C4BPA) as a serum biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). However, its mechanism of action remains unclear. Here, we elucidated the functional roles of C4BPA in PDAC cells and the tumor microenvironment. Methods We assessed stromal C4BPA, the C4BPA binding partner CD40, and the number of CD8+ tumor-infiltrating lymphocytes in resected human PDAC tissues via immunohistochemical staining. The biological functions of C4BPA were investigated in peripheral blood mononuclear cells (PBMCs) and human PDAC cell lines. Mouse C4BPA (mC4BPA) peptide, which is composed of 30 amino acids from the C-terminus and binds to CD40, was designed for further in vitro and in vivo experiments. In a preclinical experiment, we assessed the efficacy of gemcitabine plus nab-paclitaxel (GnP), dual immune checkpoint blockades (ICBs), and mC4BPA peptide in a mouse orthotopic transplantation model. Results Immunohistochemical analysis revealed that high stromal C4BPA and CD40 was associated with favorable PDAC prognosis (P=0.0005). Stromal C4BPA strongly correlated with the number of CD8+ tumor-infiltrating lymphocytes (P=0.001). In in vitro experiments, flow cytometry revealed that recombinant human C4BPA (rhC4BPA) stimulation increased CD4+ and CD8+ T cell numbers in PBMCs. rhC4BPA also promoted the proliferation of CD40-expressing PDAC cells. By contrast, combined treatment with gemcitabine and rhC4BPA increased PDAC cell apoptosis rate. mC4BPA peptide increased the number of murine T lymphocytes in vitro and the number of CD8+ tumor-infiltrating lymphocytes surrounding PDAC tumors in vivo. In a preclinical study, GnP/ICBs/mC4BPA peptide treatment, but not GnP treatment, led to the accumulation of a greater number of CD8+ T cells in the periphery of PDAC tumors and to greater tumor regression than did control treatment. Conclusions These findings demonstrate that the combination of GnP therapy with C4BPA inhibits PDAC progression by promoting antitumor T cell accumulation in the tumor microenvironment.

EXTH-48. NOVEL COMBINATION THERAPY IN PRECLINICAL GLIOMA MODELS USING THE CELL CYCLE STABILIZING COMPOUND ARGYRIN F AND CHECKPOINT INHIBITION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi174-vi174
Author(s):  
Bianca Walter ◽  
Denis Canjuga ◽  
Simge G Yuez ◽  
Michael Ghosh ◽  
Przemyslaw Bozko ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Clonogenic Survival ◽  
Autologous Tumor ◽  
Cycle Arrest ◽  
Resected Tissue ◽  
Infiltrating Lymphocytes

Abstract Glioblastoma are incurable aggressive tumors and remain a therapeutic challenge. Glioblastoma frequently harbor alterations in the retinoblastoma pathway with subsequent cell cycle abnormalities. Here, we aimed to investigate the anti-glioma activity of the cell cycle-stabilizing compound Argyrin F and its potential treatment-induced vulnerabilities to exploit possibilities for novel combination therapies. We investigated cell viability, clonogenic survival, cell cycle status and immunoblots of human and murine glioma cells treated with Argyrin F. Moreover, we established an ex vivo glioma model using residual freshly resected tissue from patients, i.e. patient-derived microtumors (PDMs). Additionally, we extracted autologous tumor infiltrating lymphocytes (TILs) to perform co-culturing experiments. We performed mass spectrometry-based immunopeptidomics and used the orthotopic syngeneic SMA560/VM/Dk glioma mouse model. Argyrin F displayed anti-glioma efficacy in glioma cell lines in vitro and in PDM models ex vivo. Moreover, Argyrin F treatment induced cell cycle arrest, reduced clonogenic survival in vitro and prolonged survival in vivo. Argyrin F-treated SMA560 glioma displayed 4.6-fold more glioma-infiltrating CD8+ T cells. We discovered a distinctive treatment-induced immunopeptidome. Combination of Argyrin F plus PD-1 antibody increased cellular toxicity in PDM/TILs co-cultures ex vivo and prolonged overall survival compared with monotherapies in vivo. We conclude that our experimental data suggest a novel combination of Argyrin F plus PD-1 blockade and its clinical translation.

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