Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism

Krupka, Christina; Kufer, Peter; Kischel, Roman; Zugmaier, Gerhard; Lichtenegger, F. S.; Köhnke, Thomas; Vick, Binje; Jeremias, Irmela; Metzeler, Klaus H.; Altmann, Torben; Schneider, Stephanie; Fiegl, Michael; Spiekermann, Karsten; Bäuerle, P A; Hiddemann, Wolfgang; Riethmüller, Gert; Subklewe, Marion

doi:10.1038/leu.2015.214

Cited by 217 publications

(197 citation statements)

References 41 publications

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“…19 Multiple in vitro cytotoxicity assays have showed that, within a reasonable range of E:T ratios (i.e., ≥ 1:80), the effector cells can kill nearly all target cells after a sufficient incubation period. 3,19,24 Accordingly, E max was fixed at 100% in all TBE model analyses. The model-estimated transit time for observable cytotoxicity in the reference system (τ reference ) was 3.49 hours.…”

Section: Resultsmentioning

confidence: 99%

“…In patient samples with E:T ratios > 1:10, the enhancement effect of anti-PD-1 or anti-PD-L1 antibodies on AMG 330-induced target cell lysis was limited, suggesting that the upregulation of PD-1/PD-L1 may be minor at higher E:T ratios (e.g., > 1:10). 24 Since the E:T ratio of the in vitro assay data used in the current model analyses ranged from 20:1 to 1:10, the impact T cell exhaustion (i.e., upregulation of PD-1/PD-L1) was not considered in the current analysis. Multiple in vitro cytotoxicity assays have showed that, within a reasonable range of E:T ratios (i.e., ≥ 1:80), the effector cells can kill nearly all target cells after a sufficient incubation period, 3,19,24 so the E max value for the TBE model was fixed at 100% for all model estimations.…”

Section: Discussionmentioning

confidence: 99%

“…24 Since the E:T ratio of the in vitro assay data used in the current model analyses ranged from 20:1 to 1:10, the impact T cell exhaustion (i.e., upregulation of PD-1/PD-L1) was not considered in the current analysis. Multiple in vitro cytotoxicity assays have showed that, within a reasonable range of E:T ratios (i.e., ≥ 1:80), the effector cells can kill nearly all target cells after a sufficient incubation period, 3,19,24 so the E max value for the TBE model was fixed at 100% for all model estimations. If we want to use this model to project in vivo effects of T-cell redirecting bispecific agents, especially following extended period of treatment, the validity of these simplifications should be carefully evaluated with in vivo data.…”

Section: Discussionmentioning

confidence: 99%

“…In the current analysis, E max was fixed at 100%, since multiple in vitro cytotoxicity assays have showed that, within a reasonable range of E:T ratios (i.e., ≥ 1:80), the effector cells can kill nearly all target cells after a sufficient incubation period. 3,19,24 Base was either estimated or fixed, depending on individual data sets. The dynamics of effector cells (EF) was described with an indirect response model, where k in and k out represent the production and elimination of T cells, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Jiang

Chen

Carpenter

et al. 2018

mAbs

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T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure–response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Jiang

Chen

Carpenter

et al. 2018

mAbs

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show abstract

“…20 In our model system, we used a suboptimal amount of BIS-1 to redirect T cells towards EpCAM + carcinoma cells that was titrated to induce low levels of apoptosis in FaDu and A431 cancer cells. In this setting, addition of PD-L1xEGFR resulted in a potent increase of apoptotic cancer cell death of ∼35% (Fig.…”

Section: Resultsmentioning

confidence: 99%

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

et al. 2018

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PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired antigen-experienced anticancer T cells. However, the efficacy of current PD-L1-blocking antibodies is potentially reduced by ‘on-target/off-tumor’ binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity may induce a generalized activation of all antigen-experienced T cells which may explain the frequent occurrence of autoimmune-related adverse events during and after treatment.To address these issues, we constructed a bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and to more selectively reactivate anticancer T cells. Indeed, the IC50 of PD-L1xEGFR for blocking PD-L1 on EGFR+ cancer cells was ∼140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-γ production, and oncolytic activity of anti-CD3xanti-EpCAM-redirected T cells was enhanced when cocultured with EGFR-expressing carcinoma cells. Similarly, the capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-directed CD8+ effector T cells was enhanced when cocultured with EGFR-expressing CMVpp65-transfected cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in mice xenografted with EGFR-expressing cancer cells 111In-PD-L1xEGFR showed a significantly higher tumor uptake compared to 111In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, thereby promoting the selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies.

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Advances and clinical applications of immune checkpoint inhibitors in hematological malignancies

Sun,

Hu,

Wang

2024

Cancer Communications

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Immune checkpoints are differentially expressed on various immune cells to regulate immune responses in tumor microenvironment. Tumor cells can activate the immune checkpoint pathway to establish an immunosuppressive tumor microenvironment and inhibit the anti‐tumor immune response, which may lead to tumor progression by evading immune surveillance. Interrupting co‐inhibitory signaling pathways with immune checkpoint inhibitors (ICIs) could reinvigorate the anti‐tumor immune response and promote immune‐mediated eradication of tumor cells. As a milestone in tumor treatment, ICIs have been firstly used in solid tumors and subsequently expanded to hematological malignancies, which are in their infancy. Currently, immune checkpoints have been investigated as promising biomarkers and therapeutic targets in hematological malignancies, and novel immune checkpoints, such as signal regulatory protein α (SIRPα) and tumor necrosis factor‐alpha‐inducible protein 8‐like 2 (TIPE2), are constantly being discovered. Numerous ICIs have received clinical approval for clinical application in the treatment of hematological malignancies, especially when used in combination with other strategies, including oncolytic viruses (OVs), neoantigen vaccines, bispecific antibodies (bsAb), bio‐nanomaterials, tumor vaccines, and cytokine‐induced killer (CIK) cells. Moreover, the proportion of individuals with hematological malignancies benefiting from ICIs remains lower than expected due to multiple mechanisms of drug resistance and immune‐related adverse events (irAEs). Close monitoring and appropriate intervention are needed to mitigate irAEs while using ICIs. This review provided a comprehensive overview of immune checkpoints on different immune cells, the latest advances of ICIs and highlighted the clinical applications of immune checkpoints in hematological malignancies, including biomarkers, targets, combination of ICIs with other therapies, mechanisms of resistance to ICIs, and irAEs, which can provide novel insight into the future exploration of ICIs in tumor treatment.

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Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism

Cited by 217 publications

References 41 publications

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

Advances and clinical applications of immune checkpoint inhibitors in hematological malignancies

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