CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory

Benonisson, Hreinn; Altıntaş, Işıl; Sluijter, Marjolein; Verploegen, Sandra; Labrijn, Aran F.; Schuurhuis, Danita H.; Houtkamp, Mischa; Verbeek, J. Sjef; Schuurman, Janine; Hall, Thorbald van

doi:10.1158/1535-7163.mct-18-0679

Cited by 68 publications

(82 citation statements)

References 49 publications

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“…flow cytometry. Flow cytometry analysis for tumour infiltrating CD45 + , CD4 + and CD8 + were performed as previously described 20 . In brief, tumours were harvested into 1 mL of non-supplemented IMDM media in 24-well plates and manually dissociated into small pieces with scalpels, incubated with 2.5 mg/mL Liberase TL (Roche) for 20 minutes at 37 °C and single-cell suspensions were made using 70-µm cell strainers (BD Biosciences).…”

mentioning

confidence: 99%

Immunogenicity of rat-neu+ mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment

Sow

Benonisson

Brouwers

et al. 2020

Sci Rep

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The use of Trastuzumab (Herceptin), a monoclonal antibody (mAb) targeting HER2/neu, results in an increased median survival in Her2 + breast cancer patients. the tumour mutational burden and the presence of tumour infiltrating lymphocytes (TILs) clearly correlate with response to trastuzumab. Here, we investigated if the immunogenicity of the transplantable rat-neu + tumour cell line (tUBo) derived from a BALB/c-NeuT primary tumour is associated with the response to anti-neu mAb therapy. We compared the TUBO tumour outgrowth and tumour infiltrating T cells in isogenic (BALB/c-NeuT) and non-isogenic (WT BALB/c) recipient mice. Furthermore, therapeutic efficacy of anti-neu mAb and the contribution of t cells were examined in both mouse strains. the outgrowth of untreated tumours was significantly better in BALB/c-NeuT than WT BALB/c mice. Moreover, tumour infiltrating T cells were more abundantly present in WT BALB/c than BALB/c-NeuT mice, showing that the TUBO tumour was more immunogenic in WT BALB/c mice. In TUBO tumour bearing WT BALB/c mice, anti-neu mAb therapy resulted in an increase of tumour infiltrating T cells and long-term survival. When T cells were depleted, this strong anti-tumour effect was reduced to an outgrowth delay. In contrast, in TUBO tumour bearing BALB/c-NeuT mice, treatment with anti-neu mAb resulted only in tumour outgrowth delay, both in the presence and absence of t cells. We concluded that in immunogenic tumours the response to anti-neu mAb therapy is enhanced by additional t cell involvement compared to the response to anti-neu mAb in non-immunogenic tumours.Overexpression of oncogenic Her2 protein occurs in 15-20% of breast cancers and is associated with highly aggressive disease. Trastuzumab, a humanized IgG1 monoclonal antibody targeting Her2, is the standard therapy for Human epidermal growth factor receptor 2 (HER2/Erbb2/neu) overexpressing breast cancer owing to its apparent efficacy in adjuvant and neoadjuvant uses 1,2 . This antibody was designed to disrupt the ligand-independent HER2-HER2 interaction resulting in rapid inhibition of pro-survival signalling pathways, leading to cell cycle arrest of the cancer cells 3,4 . The clinical success of Trastuzumab has paved the way for devising novel Her2 targeting approaches in breast cancer treatment. To date, two other therapeutic agents are available to inhibit her2 mediated signalling, a monoclonal antibody (pertuzumab) and tyrosine kinase inhibitors (lapatinib, neratinib). However, a recent clinical study has shown that Trastuzumab therapy increases the pathological complete response (pCR) in patients more than laptinib 5 . This can be attributed to the ability of Trastuzumab to engage the immune system to achieve tumor killing. Several preclinical studies have suggested that innate immune responses are essential to anti-Her2/neu mAb cancer therapies through the recruitment of Fcγ receptor (FcγR) expressing immune cells which can mediate antibody-dependent cellular cytotoxicity (ADCC) 6-8 . This is supported by the observation th...

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confidence: 99%

Immunogenicity of rat-neu+ mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment

Sow

Benonisson

Brouwers

et al. 2020

Sci Rep

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“…It raises the possibility that current targeting TAA might not be right strategies. In the presented study, we designed and generate memory immune responses, and tumors eventually relapse despite the initial control 42 . In our syngeneic mouse study, the TAA-targeting BsAb (ErbxCD3) also activated T cells efficiently to kill tumor cells in vitro but had very limited anti-tumor effect in vivo.…”

Section: Discussionmentioning

confidence: 99%

Targeting dendritic cells with a PD-L1 based bispecific antibody rejuvenates specific anti-tumor T cells

Liu

Chen

Bae

et al. 2020

Preprint

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Bispecific T-cell engagers (BiTEs) that preferentially target tumor-associated antigens (TAA) to reengage CD3 signaling have been approved to treat acute B-cell lymphoblastic leukemia. However, their applications in solid tumors have been hampered due to short half-life, weak anti-tumor activity, and severe toxicity at therapeutic doses. To explore new targets, we designed a bispecific antibody (BsAb) which simultaneously targets CD3 and immune checkpoint PD-L1. Compared with conventional TAA based targeting, PDL1xCD3 generates far superior anti-tumor immune responses in vivo. Mechanistically, blockade of PD-L1 on dendritic cells instead of tumor cells can potently rejuvenate preexisting tumor reactive CD8 T cells in a B7-1/2 dependent manner for a durable anti-tumor responses. This study argues that targeting DC-T cell instead of current tumor-T cell can achieve much better T cell rejuvenation in BsAb therapy.

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“…ADCs targeting CD30, CD33, or CD79 have been approved for clinical therapy of lymphomas and AML with the appropriate targets [16][17][18]. BiTEs for solid tumors are under active clinical trials [19,20].…”

Section: Antibodies: More On-target and Less Off-tumor Effectsmentioning

confidence: 99%

CAR-T “the living drugs”, immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy

Liu

2019

J Hematol Oncol

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New advances in the design and manufacture of monoclonal antibodies, bispecific T cell engagers, and antibodydrug conjugates make the antibody-directed agents more powerful with less toxicities. Small molecule inhibitors are routinely used now as oral targeted agents for multiple cancers. The discoveries of PD1 and PD-L1 as negative immune checkpoints for T cells have led to the revolution of modern cancer immunotherapy. Multiple agents targeting PD1, PD-L1, or CTLA-4 are widely applied as immune checkpoint inhibitors (ICIs) which alleviate the suppression of immune regulatory machineries and lead to immunoablation of once highly refractory cancers such as stage IV lung cancer. Tisagenlecleucel and axicabtagene ciloleucel are the two approved CD19-targeted chimeric antigen receptor (CAR) T cell products. Several CART cell platforms targeting B cell maturation antigen (BCMA) are under active clinical trials for refractory and/or relapsed multiple myeloma. Still more targets such as CLL-1, EGFR, NKG2D and mesothelin are being directed in CART cell trials for leukemia and solid tumors. Increasing numbers of novel agents are being studied to target cancer-intrinsic oncogenic pathways as well as immune checkpoints. One such an example is targeting CD47 on macrophages which represents a "do-not-eat-me" immune checkpoint. Fueling the current excitement of cancer medicine includes also TCR-T cells, TCR-like antibodies, cancer vaccines and oncolytic viruses.

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CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory

Cited by 68 publications

References 49 publications

Immunogenicity of rat-neu+ mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment

Immunogenicity of rat-neu+ mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment

Targeting dendritic cells with a PD-L1 based bispecific antibody rejuvenates specific anti-tumor T cells

CAR-T “the living drugs”, immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy

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