CD3xPDL1 bi-specific T cell engager (BiTE) simultaneously activates T cells and NKT cells, kills PDL1+ tumor cells, and extends the survival of tumor-bearing humanized mice

Horn, Lucas A.; Ciavattone, Nicholas; Atkinson, Ryan; Woldergerima, Netsanet; Wolf, Julia; Clements, Virginia K.; Sinha, Pratima; Poudel, Munanchu; Ostrand‐Rosenberg, Suzanne

doi:10.18632/oncotarget.19865

Cited by 41 publications

(35 citation statements)

References 44 publications

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“…For instance, α-GalCer-loaded CD1d molecules fused with an antibody fragment specific for HER2 or CEA antigens induced potent antitumor activity in vitro and in vivo ( 258 , 259 ). Recently, Horn et al showed that CD3 × PD-L1 Bi-specific T cell engagers activated both T cells and NKT cells to kill PD-L1 + tumor cells in vitro ( 260 ). Another strategy that was suggested for the treatment of patients with solid tumors is vaccination with NKT-activating agents in combination with tumor antigens.…”

Section: Current Nkt Cell-based Immunotherapy For the Treatment Of Camentioning

confidence: 99%

The Role of Natural Killer T Cells in Cancer—A Phenotypical and Functional Approach

2018

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Natural killer T (NKT) cells are a subset of CD1d-restricted T cells at the interface between the innate and adaptive immune system. NKT cells can be subdivided into functional subsets that respond rapidly to a wide variety of glycolipids and stress-related proteins using T- or natural killer (NK) cell-like effector mechanisms. Because of their major modulating effects on immune responses via secretion of cytokines, NKT cells are also considered important players in tumor immunosurveillance. During early tumor development, T helper (TH)1-like NKT cell subsets have the potential to rapidly stimulate tumor-specific T cells and effector NK cells that can eliminate tumor cells. In case of tumor progression, NKT cells may become overstimulated and anergic leading to deletion of a part of the NKT cell population in patients via activation-induced cell death. In addition, the remaining NKT cells become hyporesponsive, or switch to immunosuppressive TH2-/T regulatory-like NKT cell subsets, thereby facilitating tumor progression and immune escape. In this review, we discuss this important role of NKT cells in tumor development and we conclude that there should be three important focuses of future research in cancer patients in relation with NKT cells: (1) expansion of the NKT cell population, (2) prevention and breaking of NKT cell anergy, and (3) skewing of NKT cells toward TH1-like subsets with antitumor activity.

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Section: Current Nkt Cell-based Immunotherapy For the Treatment Of Camentioning

confidence: 99%

The Role of Natural Killer T Cells in Cancer—A Phenotypical and Functional Approach

2018

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“…The proof-of-concept for this type of T cell engager has been developed in a preclinical model of melanoma using a PD-L1xCD3 BiTE able to redirect T and NKT cells towards PD-L1-positive cells with a promising antitumor activity, especially when combined with the inhibition of other inhibitory immune checkpoints. 92 The direct attack of TME immunosuppressive cells, such as myeloid-derived suppressor cells, is under study using a CD33xCD3 BiTE (AMV564, NCT04128423 ). Inhibitory signals can be also converted into activating signals, for example using a simultaneous multiple interaction T cell engaging (SMITE) strategy.…”

Section: Going Back From Bed To Benchside: Improving Icesmentioning

confidence: 99%

Immune cell engagers in solid tumors: promises and challenges of the next generation immunotherapy

et al. 2021

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In the landscape of cancer immunotherapy, immune cell engagers (ICEs) are rapidly emerging as a feasible and easy-to-deliver alternative to adoptive cell therapy for the antitumor redirection of immune effector cells. Even if in hematological malignancies this class of new therapeutics already hit the clinic, the development of ICEs in solid tumors still represents a challenge. Considering that ICEs are a rapidly expanding biotechnology in cancer therapy, we designed this review as a primer for clinicians, focusing on the major obstacles for the clinical implementation and the most translatable approaches proposed to overcome the limitations in solid tumors.

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“…Importantly, the BiTE-activated healthy donor PBMC were more cytotoxic for PD-L1 + tumor cells than PBMC activated by anti-CD3 mAb by itself, while PD-L1 − cells were not lysed. In vitro depletion studies demonstrated that the CD3xPDL1 BiTE not only activated cytotoxic CD4 + and CD8 + T cells, but also activated CD3 + NKT cells (84).…”

Section: A Bi-specific T Cell Engager (Bite) Activates T Cells That Amentioning

confidence: 99%

“…Approximately 24–60% of the PBMC from these patients consisted of M-MDSC (CD11b + HLA-DR − CD14 + ) plus PMN-MDSC (CD11b + HLA-DR − CD15 + ). Despite the high levels of MDSC, the BiTE activated CD3 + cells that specifically lysed PD-L1 + , but not PD-L1 − human tumor cells (84). MDSC can express PD-L1 (85), so the ability to lyse tumor cells even in the presence of high levels of MDSC is likely due to BiTE-mediated cytotoxicity of the MDSC.…”

Section: A Bi-specific T Cell Engager (Bite) Activates T Cells That Amentioning

confidence: 99%

“…Humanized mice were inoculated with a spontaneously metastatic human melanoma and 7 days later the mice were given CD3xPDL1 BiTE for 4 consecutive days and a final dose of BiTE 2.5 weeks later. BiTE treated, but not control mice, had expanded numbers of human CD3 + cells in their spleens, minimal numbers of MDSC, and significantly extended survival times (84).…”

Section: A Bi-specific T Cell Engager (Bite) Activates T Cells That Amentioning

confidence: 99%

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Radiotherapy Both Promotes and Inhibits Myeloid-Derived Suppressor Cell Function: Novel Strategies for Preventing the Tumor-Protective Effects of Radiotherapy

2019

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Cancer immunotherapies aimed at neutralizing the programmed death-1 (PD-1) immune suppressive pathway have yielded significant therapeutic efficacy in a subset of cancer patients. However, only a subset of patients responds to antibody therapy with either anti-PD-1 or anti-PD-L1 antibodies. These patients appear to have so-called “hot” tumors containing tumor-reactive T cells. Therefore, checkpoint blockade therapy may be effective in a larger percentage of cancer patients if combined with therapeutics that also activate tumor-reactive T cells. Radiotherapy (RT) is a prime candidate for combination therapy because it facilitates activation of both local antitumor immunity and antitumor immunity at non-radiated, distant sites (abscopal response). However, RT also promotes tumor cell expression of PD-L1 and facilitates the development of myeloid-derived suppressor cells (MDSC), a population of immune suppressive cells that also suppress through PD-L1. This article will review how RT induces MDSC, and then describe two novel therapeutics that are designed to simultaneously activate tumor-reactive T cells and neutralize PD-1-mediated immune suppression. One therapeutic, a CD3xPD-L1 bispecific T cell engager (BiTE), activates and targets cytotoxic T and NKT cells to kill PD-L1 + tumor cells, despite the presence of MDSC. The BiTE significantly extends the survival time of humanized NSG mice reconstituted with human PBMC and carrying established metastatic human melanoma tumors. The second therapeutic is a soluble form of the costimulatory molecule CD80 (sCD80). In addition to costimulating through CD28, sCD80 inhibits PD-1 suppression by binding to PD-L1 and sterically blocking PD-L1/PD-1 signaling. sCD80 increases tumor-infiltrating T cells and significantly extends survival time of mice carrying established, syngeneic tumors. sCD80 does not suppress T cell function via CTLA-4. These studies suggest that the CD3xPD-L1 BiTE and sCD80 may be efficacious therapeutics either as monotherapies or in combination with other therapies such as radiation therapy for the treatment of cancer.

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CD3xPDL1 bi-specific T cell engager (BiTE) simultaneously activates T cells and NKT cells, kills PDL1+ tumor cells, and extends the survival of tumor-bearing humanized mice

Cited by 41 publications

References 44 publications

The Role of Natural Killer T Cells in Cancer—A Phenotypical and Functional Approach

The Role of Natural Killer T Cells in Cancer—A Phenotypical and Functional Approach

Immune cell engagers in solid tumors: promises and challenges of the next generation immunotherapy

Radiotherapy Both Promotes and Inhibits Myeloid-Derived Suppressor Cell Function: Novel Strategies for Preventing the Tumor-Protective Effects of Radiotherapy

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