Immunotherapy for triple negative breast cancer: the end of the beginning or the beginning of the end?

Wojtukiewicz, Marek Z.; Pogorzelska, Magda; Polityńska, Barbara

doi:10.1007/s10555-022-10060-4

Cited by 9 publications

(5 citation statements)

References 16 publications

(18 reference statements)

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“…TNBC tumors express specific ligands of PD1, LAG3, and TIM3 such as PDL1, Galectin-3, FGL-1, MHCII, Galectin-9, or secreted HMGB1 [52][53][54][55], which offer multiple targets for the improved active drug delivery by NExT. While the presence of other molecules like LAG3 or TIM3 on NExT can improve tumor targeting and accumulation, our focus remained on PD1 due to its consistent retention on NExT (Fig.…”

Section: Discussionmentioning

confidence: 99%

Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy

Blaya-Cánovas,

Griñán-Lisón,

Blancas

et al. 2024

Mol Cancer

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Background Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. Methods NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. Results We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. Conclusions These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.

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Section: Discussionmentioning

confidence: 99%

Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy

Blaya-Cánovas,

Griñán-Lisón,

Blancas

et al. 2024

Mol Cancer

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“…The FDA assessment of changes in the therapeutic landscape of metastatic TNBC concluded in voluntary withdrawal of accelerated approval of this drug combination by Genentech where drug safety and efficacy parameters were not responsible for withdrawal [ 48 ]. The voluntary withdrawal of this accelerated approval of Atezolizumab for this indication accompanied a disappointing phase but continuing extensive research in this field presents a hope of successfully finding an efficacious treatment of TNBC in the near future [ 49 ].…”

Section: Roadmap Of Fda Approvals For Tnbcmentioning

confidence: 99%

Contracting triple-negative breast cancer with immunotherapeutic armamentarium: recent advances and clinical prospects

et al. 2022

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Triple negative breast cancer (TNBC) portraying deficient expression of estrogen receptor (ER), progesterone receptor (PR) and Human epidermal growth factor receptor 2 (HER2) is known to be the most aggressive subtype associated with poor prognosis and interventional strategies limited to chemotherapy and breast conserving surgery. Some TNBC incidences have also been reported with positive circ-HER2 expression thus rendering circ-HER2 a potential immunotherapy target to direct drug development. Resistance and recurrence reported with traditional approaches has led us towards the application of immunotherapeutic interventions owing to their anti-tumor efficacy. This review provides an elaborative insight on potential molecular biomarkers to be targeted by immunotherapy. Additionally, clinical trials proposing the application of immunotherapy in neoadjuvant, adjuvant and metastatic TNBC setting have also been included. The gathered evidence indicates a positive application of immunotherapy in TNBC with therapeutic limitation available only owing to the possibility of adverse events which can be dealt considering risk-to-benefit ratio. Furthermore, potential targets to aim for therapeutic vaccines along with evidence from clinical trials have also been mentioned.

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“…Although conventional chemotherapy remains the standard treatment, immunotherapy is changing the paradigm of anticancer treatment and is emerging as an alternative treatment for TNBC, classified as an immunogenic BC subtype. 2 3 …”

Section: Introductionmentioning

confidence: 99%

A novel Fc-engineered cathepsin D-targeting antibody enhances ADCC, triggers tumor-infiltrating NK cell recruitment, and improves treatment with paclitaxel and enzalutamide in triple-negative breast cancer

Desroys du Roure,

Lajoie,

Mallavialle

et al. 2024

J Immunother Cancer

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IntroductionTriple-negative breast cancer (TNBC) prognosis is poor. Immunotherapies to enhance the antibody-induced natural killer (NK) cell antitumor activity are emerging for TNBC that is frequently immunogenic. The aspartic protease cathepsin D (cath-D), a tumor cell-associated extracellular protein with protumor activity and a poor prognosis marker in TNBC, is a prime target for antibody-based therapy to induce NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). This study investigated whether Fc-engineered anti-cath-D antibodies trigger ADCC, their impact on antitumor efficacy and tumor-infiltrating NK cells, and their relevance for combinatory therapy in TNBC.MethodsCath-D expression and localization in TNBC samples were evaluated by western blotting, immunofluorescence, and immunohistochemistry. The binding of human anti-cath-D F1M1 and Fc-engineered antibody variants, which enhance (F1M1-Fc+) or prevent (F1M1-Fc−) affinity for CD16a, to secreted human and murine cath-D was analyzed by ELISA, and to CD16a by surface plasmon resonance and flow cytometry. NK cell activation was investigated by flow cytometry, and ADCC by lactate dehydrogenase release. The antitumor efficacy of F1M1 Fc-variants was investigated using TNBC cell xenografts in nude mice. NK cell recruitment, activation, and cytotoxic activity were analyzed in MDA-MB-231 cell xenografts by immunophenotyping and RT-qPCR. NK cells were depleted using an anti-asialo GM1 antibody. F1M1-Fc+antitumor effect was assessed in TNBC patient-derived xenografts (PDXs) and TNBC SUM159 cell xenografts, and in combination with paclitaxel or enzalutamide.ResultsCath-D expression on the TNBC cell surface could be exploited to induce ADCC. F1M1 Fc-variants recognized human and mouse cath-D. F1M1-Fc+activated NK cells in vitro and induced ADCC against TNBC cells and cancer-associated fibroblasts more efficiently than F1M1. F1M1-Fc−was ineffective. In the MDA-MB-231 cell xenograft model, F1M1-Fc+displayed higher antitumor activity than F1M1, whereas F1M1-Fc−was less effective, reflecting the importance of Fc-dependent mechanisms in vivo. F1M1-Fc+triggered tumor-infiltrating NK cell recruitment, activation and cytotoxic activity in MDA-MB-231 cell xenografts. NK cell depletion impaired F1M1-Fc+antitumor activity, demonstrating their key role. F1M1-Fc+inhibited growth of SUM159 cell xenografts and two TNBC PDXs. In combination therapy, F1M1-Fc+improved paclitaxel and enzalutamide therapeutic efficacy without toxicity.ConclusionsF1M1-Fc+is a promising immunotherapy for TNBC that could be combined with conventional regimens, including chemotherapy or antiandrogens.

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Immunotherapy for triple negative breast cancer: the end of the beginning or the beginning of the end?

Cited by 9 publications

References 16 publications

Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy

Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy

Contracting triple-negative breast cancer with immunotherapeutic armamentarium: recent advances and clinical prospects

A novel Fc-engineered cathepsin D-targeting antibody enhances ADCC, triggers tumor-infiltrating NK cell recruitment, and improves treatment with paclitaxel and enzalutamide in triple-negative breast cancer

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