Overcoming the challenges associated with CD3+ T-cell redirection in cancer

Singh, Ajit Kumar; Dees, Sundee; Grewal, Iqbal S.

doi:10.1038/s41416-020-01225-5

Cited by 65 publications

(52 citation statements)

References 93 publications

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“…Considering the observed in vivo differences in intratumoral vascular leakage, CD3, CD31, and CD45 were selected as markers to further assess endothelial changes and immune-cell response (36)(37)(38). Semi-automated quantification of CD31 immunohistology within the annotated area of the tumor tissue harvested at the end of the experiment was not significantly different in RTX-pretreated and non-pretreated control animals (1.449 vs 1.599 relative mask area (rMA) (%); Figures 6A, B, D).…”

Section: Unaltered Levels Of Cd31 Cd3 and Cd45 Immunoreactivity In The 4t1 Breast Tumor Tissue In Desensitized Micementioning

confidence: 99%

Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth via Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer

et al. 2021

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There is growing interest in the role of nerve-driven mechanisms in tumorigenesis and tumor growth. Capsaicin-sensitive afferents have been previously shown to possess antitumoral and immune-regulatory properties, the mechanism of which is currently poorly understood. In this study, we have assessed the role of these terminals in the triple negative 4T1 orthotopic mouse model of breast cancer. The ultrapotent capsaicin-analogue resiniferatoxin (RTX) was used for the selective, systemic desensitization of capsaicin-sensitive afferents. Growth and viability of orthotopically implanted 4T1 tumors were measured by caliper, in vivo MRI, and bioluminescence imaging, while tumor vascularity and protease enzyme activity were assessed using fluorescent in vivo imaging. The levels of the neuropeptides Calcitonin Gene-Related Peptide (CGRP), Substance P (SP), and somatostatin were measured from tumor tissue homogenates using radioimmunoassay, while tumor structure and peritumoral inflammation were evaluated by conventional use of CD31, CD45 and CD3 immunohistology. RTX-pretreated mice demonstrated facilitated tumor growth in the early phase measured using a caliper, which was coupled with increased tumor vascular leakage demonstrated using fluorescent vascular imaging. The tumor size difference dissipated by day seven. The MRI tumor volume was similar, while the intratumoral protease enzyme activity measured by fluorescence imaging was also comparable in RTX-pretreated and non-pretreated animals. Tumor viability or immunohistopathological profile was measured using CD3, CD31, and CD45 stains and did not differ significantly from the non-pretreated control group. Intratumoral somatostatin, CGRP, and SP levels were similar in both groups. Our results underscore the beneficial, antitumoral properties of capsaicin sensitive nerve terminals in this aggressive model of breast cancer, which is presumed to be due to the inhibition of tumor vascular bed disruption. The absence of any difference in intratumoral neuropeptide levels indicates non-neural sources playing a substantial part in their expression.

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Section: Unaltered Levels Of Cd31 Cd3 and Cd45 Immunoreactivity In The 4t1 Breast Tumor Tissue In Desensitized Micementioning

confidence: 99%

Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth via Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer

et al. 2021

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“…T cell engaging bispecific antibodies have raised major interest for the treatment of hematological and solid tumors. [1][2][3] We have developed T cell bispecific antibodies (TCBs), for example, cibisatamab (CEA-TCB) 4 5 or glofitamab (CD20-TCB), 6 harboring a 2+1 format with one binder to the CD3ε chain and two binders to specific tumor antigens (figure 1A). Crosslinking of CD3 with tumor antigens triggers T cell activation and proliferation, cytokine release and tumor cell killing.…”

Section: Introductionmentioning

confidence: 99%

JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy

Leclercq-Cohen

Haegel

Zimmermann

et al. 2022

J Immunother Cancer

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BackgroundT cell engaging therapies, like chimeric antigen receptor T cells and T cell bispecific antibodies (TCBs), efficiently redirect T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing, a process that is accompanied by the release of cytokines. Despite their promising efficacy in the clinic, treatment with TCBs is associated with a risk of cytokine release syndrome (CRS). The aim of this study was to identify small molecules able to mitigate cytokine release while retaining T cell-mediated tumor killing.MethodsBy screening a library of 52 Food and Drug Administration approved kinase inhibitors for their impact on T cell proliferation and cytokine release after CD3 stimulation, we identified mTOR, JAK and Src kinases inhibitors as potential candidates to modulate TCB-mediated cytokine release at pharmacologically active doses. Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of mTOR, JAK and Src kinase inhibitors combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB and CD19-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. The combination of mTOR, JAK and Src kinase inhibitors together with CD19-TCB was evaluated in vivo in non-tumor bearing stem cell humanized NSG mice in terms of B cell depletion and in a lymphoma patient-derived xenograft (PDX) model in humanized NSG mice in terms of antitumor efficacy.ResultsThe effect of Src inhibitors differed from those of mTOR and JAK inhibitors with the suppression of CD19-TCB-induced tumor cell lysis in vitro, whereas mTOR and JAK inhibitors primarily affected TCB-mediated cytokine release. Importantly, we confirmed in vivo that Src, JAK and mTOR inhibitors strongly reduced CD19-TCB-induced cytokine release. In humanized NSG mice, continuous treatment with a Src inhibitor prevented CD19-TCB-mediated B cell depletion in contrast to mTOR and JAK inhibitors, which retained CD19-TCB efficacy. Ultimately, transient treatment with Src, mTOR and JAK inhibitors minimally interfered with antitumor efficacy in a lymphoma PDX model.ConclusionsTaken together, these data support further evaluation of the use of Src, JAK and mTOR inhibitors as prophylactic treatment to prevent occurrence of CRS.

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“…Furthermore, the epitope and the affinity of the CD3 binding site have been shown to affect efficacy and safety of bispecific T-cell engagers 56 , thus providing a rational for further improvement of the safety properties of HER3-targeting T-cell engagers. Especially in the context of solid tumors, redirecting CD3 + T-cells has been reported to be associated with a number of challenges probably limiting or reducing the anti-tumor efficacy, including the recruitment of counterproductive CD3 + T-cell subsets, dose limiting cytokine storm, the presence of an immunosuppressive tumor microenvironment and on-target and off-tumor binding 22 , 57 . Several disadvantages are associated with polyclonal T-cell activation, including the recruitment of naïve, exhausted or regulatory T-cells 58 , 59 .…”

Section: Discussionmentioning

confidence: 99%

A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells

Beha

Steinlein

Kühl

et al. 2021

Sci Rep

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HER3 is a member of the EGF receptor family and elevated expression is associated with cancer progression and therapy resistance. HER3-specific T-cell engagers might be a suitable treatment option to circumvent the limited efficacy observed for HER3-blocking antibodies in clinical trials. In this study, we developed bispecific antibodies for T-cell retargeting to HER3-expressing tumor cells, utilizing either a single-chain diabody format (scDb) with one binding site for HER3 and one for CD3 on T-cells or a trivalent bispecific scDb-scFv fusion protein exhibiting an additional binding site for HER3. The scDb-scFv showed increased binding to HER3-expressing cancer cell lines compared to the scDb and consequently more effective T-cell activation and T-cell proliferation. Furthermore, the bivalent binding mode of the scDb-scFv for HER3 translated into more potent T-cell mediated cancer cell killing, and allowed to discriminate between moderate and low HER3-expressing target cells. Thus, our study demonstrated the applicability of HER3 for T-cell retargeting with bispecific antibodies, even at moderate expression levels, and the increased potency of an avidity-mediated specificity gain, potentially resulting in a wider safety window of bispecific T-cell engaging antibodies targeting HER3.

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Overcoming the challenges associated with CD3+ T-cell redirection in cancer

Cited by 65 publications

References 93 publications

Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth via Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer

Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth via Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer

JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy

A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells

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