scholarly journals P06.12 Combination therapy of CAR-NK-cells and anti-PD-1 antibody results in high efficacy against advanced-stage glioblastoma in a syngeneic mouse model and induces protective anti-tumor immunity in vivo

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A46.2-A47
Author(s):  
F Strassheimer ◽  
MI Strecker ◽  
T Alekseeva ◽  
J Macas ◽  
MC Demes ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Nk Cells ◽  
Tumor Cells ◽  
Combined Treatment ◽  
Checkpoint Blockade ◽  
Great Promise ◽  
Advanced Stage ◽  
Lymphocyte Infiltration ◽  
Term Survival ◽  
Syngeneic Mouse Model

BackgroundCheckpoint inhibitors as well as adoptive cell therapy hold great promise for cancer therapy and encouraging treatment responses have already been demonstrated in different cancer indications. Glioblastoma (GB) is the most common and aggressive primary brain tumor. Standard therapy has very limited efficacy in the majority of patients. Analysis of the GB tumor microenvironment (TME) has shown prominent immunosuppressive features including expression of PD-L1 on tumor cells and increased frequency of FOX-P3 positive regulatory T cells. While the surrounding brain is HER2-negative, GB tumors are frequently HER2-positive, suggesting HER2 as a promising target for adoptive immunotherapy. Previous results from mouse glioma models showed efficacy of CAR-NK cells (NK-92/5.28.z) targeted against HER2 as monotherapy with relatively small tumors, but not with advanced late-stage tumors.Materials and MethodsThe murine glioma cell line GL261 was transfected with HER2. Tumor cells were implanted either subcutaneously or orthotopically into C57BL/6 mice and treated either with HER2-specific NK-92/5.28.z cells alone or in combination with an anti-PD-1 antibody. Effects on tumor growth and survival were determined. Lymphocyte infiltration and immunosuppressive TME were characterized in high-dimensional high-throughput analysis via RNAseq and multiplex IHC.ResultsCombined treatment with NK-92/5.28.z cells and anti-PD-1 checkpoint blockade resulted in synergistic effects with tumor regression and long-term survival even of advanced-stage tumor bearing mice. Analysis of TME showed enhanced cytotoxic lymphocyte infiltration and altered profiles of exhaustion markers in tumor and immune cells, leading to an altered TME after combined treatment with NK-92/5.28.z cells and anti-PD-1 antibody.ConclusionsThese data demonstrate that efficacy of NK-92/5.28.z cells can be enhanced in combination with checkpoint blockade, resulting in successful treatment of advanced tumors refractory to NK-92/5.28.z monotherapy. Furthermore, the combination therapy induces a cytotoxic rather than immunosuppressive TME, leading to a primed immune system. To address this question in a clinical setting, we are preparing a combination therapy cohort as part of our ongoing phase I clinical study (CAR2BRAIN; NCT03383978).Disclosure InformationF. Strassheimer: None. M.I. Strecker: None. T. Alekseeva: None. J. Macas: None. M.C. Demes: None. I.C. Mildenberger: None. T. Tonn: None. P.J. Wild: None. L. Sevenich: None. Y. Reiss: None. P.N. Harter: None. K.H. Plate: None. W.S. Wels: None. J.P. Steinbach: None. M.C. Burger: None.

scholarly journals P12.04 Synergistic effects of combination therapy of CAR-NK cells and anti-PD-1 antibody result in high efficacy against advanced stage orthotopic glioblastoma grafts in a syngeneic mouse model and induce protective anti-tumor immunity in vivo

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii60-iii60
Author(s):  
F Strassheimer ◽  
M I Strecker ◽  
C Zhang ◽  
I C Mildenberger ◽  
P N Harter ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Combined Treatment ◽  
Great Promise ◽  
Advanced Stage ◽  
Lymphocyte Infiltration ◽  
Term Survival ◽  
Syngeneic Mouse Model

Abstract BACKGROUND Checkpoint inhibitors as well as adoptive cell therapy hold great promise for cancer treatment and encouraging treatment responses have already been demonstrated in different cancer indications. Glioblastoma (GB) is the most common and aggressive primary brain tumor. Standard therapy has very limited efficacy in the majority of patients. Analysis of the GB tumor microenvironment (TME) has shown prominent immunosuppressive features including expression of PD-L1 on tumor cells and increased frequency of FOX-P3 positive regulatory T cells. While the surrounding brain is HER2-negative, GB tumors are frequently HER2-positive, suggesting HER2 as a promising target for adoptive immunotherapy. MATERIALS AND METHODS The murine glioma cell line GL261 was transfected with HER2. Tumor cells were orthotopically implanted into C57BL/6 mice and treated either with HER2-specific NK-92/5.28.z cells alone or in combination with an anti-PD-1 antibody. Effects on tumor growth and survival were determined, lymphocyte infiltration and immunosuppressive TME were characterized. RESULTS Combined treatment with NK-92/5.28.z cells and anti-PD-1 antibody resulted in synergistic tumor regression and long-term survival of advanced-stage tumor bearing mice. Analysis of TME showed enhanced cytotoxic lymphocyte infiltration and altered profiles of exhaustion markers in tumor and immune cells. CONCLUSION These data demonstrate that efficacy of NK-92/5.28.z cells can be enhanced by co-therapy with checkpoint inhibitors, resulting in successful treatment of advanced tumors refractory to mono-therapy. Furthermore, this combination therapy induces a cytotoxic rather than immunosuppressive TME, leading to a primed immune system. To address this question in a clinical setting, we are planning a phase I clinical study (CAR2BRAIN-CHECK).

OS12.6.A Combination therapy of CAR-NK-cells and anti-PD-1 results in high efficacy against advanced-stage glioblastoma in a syngeneic mouse model and induces protective anti-tumor immunity in vivo

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii15-ii15
Author(s):  
F Strassheimer ◽  
M I Strecker ◽  
T Alekseeva ◽  
J Macas ◽  
M C Demes ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Cell Therapy ◽  
Nk Cells ◽  
Tumor Cells ◽  
Combined Treatment ◽  
Checkpoint Blockade ◽  
Advanced Stage ◽  
Lymphocyte Infiltration ◽  
Term Survival

Abstract INTRODUCTION Checkpoint inhibitors as well as adoptive cell therapy hold promise for cancer therapy and encouraging treatment responses have already been demonstrated in different cancer indications. Glioblastoma (GB) is the most common and aggressive primary brain tumor. Standard therapy has very limited efficacy in the majority of patients. Analysis of the GB microenvironment (TME) has shown prominent immunosuppressive features, including expression of PD-L1 on tumor cells and increased frequency of FOXP3-positive regulatory T cells. While the surrounding brain is HER2-negative, GB are frequently HER2-positive, suggesting HER2 as a promising target for adoptive immunotherapy. Previous results from mouse glioma models showed efficacy of CAR-NK cells (NK-92/5.28.z) targeted against HER2 as monotherapy with early stage but not with advanced-stage tumors. MATERIALS AND METHODS The murine glioma cell line GL261 was transfected with human HER2. Tumor cells were implanted either subcutaneously or orthotopically into C57BL/6 mice and treated either with HER2-specific NK-92/5.28.z cells alone or in combination with an anti-PD-1 antibody. Effects on tumor growth and survival were determined. Lymphocyte infiltration and immunosuppressive TME were characterized via highplex multi-color flow cytometry (FACS Symphony) and IHC (Phenoptics). Furthermore, gene expression profiles of tumor-infiltrating cells were determined via bulk RNAseq (NanoString). RESULTS Combined treatment with NK-92/5.28.z cells and anti-PD-1 checkpoint blockade resulted in synergistic effects, with tumor regression and long-term survival observed even in advanced-stage tumor bearing mice. Analysis of the TME showed changes in lymphocyte infiltration and increased expression of exhaustion markers in tumor and immune upon combined treatment with NK-92/5.28.z cells and anti-PD-1 antibody resulting in an altered TME. Both, PD-1 and Lag-3 expression are highly upregulated on tumor infiltrating T cells. Total infiltrating lymphocytes show a rather cytotoxic phenotype up combination treatment with NK-92/5.28.z cells and anti-PD-1 antibody CONCLUSION Our data demonstrate that efficacy of NK-92/5.28.z cells can be enhanced by combination with checkpoint blockade, resulting in successful treatment of advanced tumors refractory to NK-92/5.28.z monotherapy. Furthermore, the combination therapy induced a cytotoxic rather than immunosuppressive TME, leading to a primed immune system. To translate the concept of CAR-NK-cell therapy plus checkpoint inhibition to a clinical setting, we are adding a combination therapy cohort to our ongoing phase I clinical study (CAR2BRAIN; NCT03383978).

scholarly journals Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1878 ◽  
Author(s):  
Sami Znati ◽  
Rebecca Carter ◽  
Marcos Vasquez ◽  
Adam Westhorpe ◽  
Hassan Shahbakhti ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combination Therapy ◽  
Cell Lines ◽  
Radiation Treatment ◽  
Combined Treatment ◽  
New Combination ◽  
Migration And Invasion ◽  
Syngeneic Mouse Model

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models. Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown in vitro and in vivo. In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC. Results: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion in vitro. In vivo, combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment. Conclusion: In 2D and 3D studies in vitro and in a syngeneic model in vivo, the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.

scholarly journals Multifunctional PD-L1 Targeted Fe3O4@DOX Nanoparticles Under MRI Monitoring For Combination Therapy of Triple-Negative Breast Cancer

2021 ◽  
Author(s):  
Jie Zhao ◽  
Ming Li ◽  
Jiazhi Duan ◽  
Hang Guo ◽  
Dexin Yu
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Combined Treatment ◽  
Great Promise ◽  
Mri Imaging ◽  
Targeting Therapy ◽  
Magnetic Resonance Imaging Mri

Abstract Background: The triple negative breast cancer (TNBC) is the most difficult subtype of breast cancer to treat, with currently restricted treatment of chemotherapy. However, evidence suggests that immunomotropy is only effective for a small portion of patients. The combination therapy of both immunotherapy and chemotherapy has demonstrated great promise in its treatment efficiency. However, this combination therapy is limited by both the organ toxicity of the chemotherapeutic drugs and the inaccessibility of the in vivo monitoring of individual tumor response to therapies. With the development of the nanomedicine, synchronous targeting therapy, imaging diagnosis and monitoring can be achieved convenientlly using the multifunctional nano-platform for TNBC. Results: In our study, we prepared the DOX loaded Fe3O4 nanoparticles targeting the PD-L1 (PD-L1@Fe3O4-DOX, FPD) to obtain the real-time magnetic resonance imaging (MRI) monitoring and combination therapy of both chemotherapy and immunotherapy for TNBC. The results showed that FPD inhibited tumor growth more effectively than either DOX chemotherapy or PD-L1 immunotherapy alone. Conclusion: Our study demonstrated that FPD has shown a great potential for theranostics and clinical translation in synchronous MRI imaging-guided monitoring and combined treatment of both DOX and immunotherapy of TNBC.

scholarly journals Combination Therapy with Daratumumab and CAR-NK Targeting CS1 for Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1342-1342 ◽  
Author(s):  
Yibo Zhang ◽  
Lichao Chen ◽  
Yufeng Wang ◽  
Xinxin Li ◽  
Tiffany Hughes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
T Cell ◽  
Combination Therapy ◽  
Nk Cells ◽  
Tumor Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Car T ◽  
Ifn Γ

Abstract Daratumumab (Dara), a targeted therapy utilizing a monoclonal antibody against CD38, and its combination with other are becoming a new standard of care treatment in multiple myeloma (MM). Recently, chimeric antigen receptor (CAR) T cell immunotherapy has been successful in the clinic for the treatment of leukemia and lymphoma. Our preliminary data suggest that both CS1-CAR T cells and CS1-CAR NK cells are effective in eradicating MM cells in vitro and in vivo (Chu et al., 2014, Leukemia and Chu et al., 2014, Clinical Cancer Research). In this study, we investigated the combination therapy with Dara and CS1-CAR NK cells for the treatment of relapsed MM. We first showed that that in MM patients, CD38brightCD138─CD34─CD20+CD27+ MM cancer stem-like cells (CSCs) express CS1 at levels much higher than any other cells, and are susceptible to being eradicated by CS1-CAR NK cells. However, CD34+hematopoietic stem cells from bone marrow of healthy donors do not express CS1. These data suggest that CS1-CAR NK cells can target MM CSCs, and thus may prevent relapse of MM, as ample evidence shows that relapsed or recurrent tumor cells are derived from CSCs. We also demonstrated that CD38 is highly expressed on NK and MM cells. Dara triggered IFN-γ and GZMB expression (p< 0.01) in primary human NK cells, even in the absence of crosslinking with tumor cells. Interestingly, the increase IFN-γ expression can be validated in the CD16 (+) haNK-92 (high-affinity natural killer cells), but not in the parental NK-92 cell line. Blocking the recognition between CD16 and Dara (an IgG1 mAb) with an Fc blocking Ab completely impaired Dara-induced IFN-γ and GZMB expression, indicating that Dara-induced NK cell activation is CD16-dependent. Mechanistically, Dara significantly induced phosphorylation of NFkB and STAT1, indicating that Dara induces IFN-γ and GZMB in NK cells, which may occur through CD16 and be mediated downstream by STAT1 and NFkB. We also found that Dara failed to stimulate GZMB and IFN-γ expression in CD38(-) CD16(+) NK cells, while successful in stimulating CD38(+) CD16(+) NK cells, indicating that Dara induces NK cell activation, which requires not only the binding between CD16 and Fc fragment of Dara, but also the CD38 signaling pathway. Furthermore, we found that Dara mediated cytotoxicity of NK cells against MM cells through antibody-dependent cell-mediated cytotoxicity (ADCC) against CD38-positive (e.g., MM1.S), but not CD38-negative (e.g., U266), which can be blocked by CD16 blocking Ab. Moreover, Dara displays ADCC effects in CD16(+) NK cells but not CD16(-) NK cells. When CD16(+) NK cells were armed with the CS1-CAR, ADCC is still observed against CD38(+) MM cells at low effector to target ratios, i.e., Dara still enhances cytotoxicity of CS1-CAR NK cells, which already have enhanced cytotoxicity. We observed that Dara-induced NK cell ADCC against CD38(+) MM MM1.S cells led to increased T cell proliferation and activation in a co-culture system including dendritic cells. This effect was not observed when MM U266 cells were included as the NK cell target. Out data are consistent with that recent discovery by DiLillo and Ravetch showing that engagement of monoclonal antibody can induce an antitumor vaccine effects (David J et al., Cell, 2015). To tested Dara affects NK cell survival, immunoblotting was performed with anti-cleaved Caspase-3 and anti-cleaved PARP-1 antibodies. We demonstrated that apoptotic activity was increased in both CD16(+)NK cells (primary NK and haNK-92) and parental CD16(-)NK-92 cells treated with Dara for 24 h in a dose-dependent manner. Unlike Dara's positive effects on CD16(+) NK cells (i.e. stimulating IFN-γ production and ADCC), induction of apoptosis seems to be CD16-independent, as parental NK-92 cells, which are CD16(-), also showed an increased levels of apoptosis induced by Dara. We are testing whether the apoptosis induction is dependent on the antigen for Dara, because as mentioned above, both primary NK cells, and modified as well as unmodified NK-92 cells, that were CD38 (+). In conclusion, our study demonstrates that the combination of Dara and CS1-CAR NK cells, which target two different tumor-associated antigens, both of which have potent anti-MM efficacy, may show additive or synergistic effects; however due to the positive and negative effects of Dara on NK cells, sequential treatment rather than a concomitant treatment modality should be considered. Disclosures No relevant conflicts of interest to declare.

Bortezomib Enhances the Antitumor Activity of Adoptively Infused Natural Killer Cells In Vivo: A Novel Approach To Override KIR-Mediated Inhibition of NK Cell Cytotoxicity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1786-1786 ◽  
Author(s):  
Andreas Lundqvist ◽  
Sheila Rao ◽  
Aleah Smith ◽  
Maria Berg ◽  
Su Su ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Single Injection ◽  
Combined Treatment ◽  
Malignant Cells ◽  
Tumor Bearing ◽  
Nk Cell Cytotoxicity

Abstract Natural killer (NK) cell killer immunoglobulin-like receptor (KIR) interactions with self MHC class I molecules can regulate NK cell function; such interactions typically inactivate NK cells potentially providing a dominant mechanism through which malignant cells evade host NK cell-mediated immunity. Recently we found that the proteasome inhibitor bortezomib up-regulated surface expression of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) on a variety of different human malignant cells rendering them susceptible to NK cell-mediated apoptosis in vitro; this effect appears to override KIR ligand-mediated NK cell inactivation, overcoming tumor resistance to both allogeneic KIR ligand-matched and autologous NK cell cytotoxicity. We also found that murine tumors were sensitized by bortezomib to the cytotoxic effects of syngeneic NK cells; the killing of RENCA and LLC1 tumors in vitro by syngeneic BALB/c and C57BL/6 NK cells respectively was enhanced when tumors were exposed to 10nM of bortezomib for 18h. Here, we show that the combined treatment of bortezomib followed by syngeneic NK cell infusions significantly delays tumor growth in tumor bearing animals. While treatment with bortezomib or interleukin-2 activated syngeneic NK cells alone had little effect on tumor growth, the combined treatment significantly delayed growth of RENCA tumors in BALB/c mice and LLC1 in C57BL/6 mice (p&lt;0.01;figure). In contrast to human tumor cell lines where an increase in expression of TRAIL-R2 was observed following bortezomib exposure, no change in expression of death receptors was observed in either murine tumor line. Flow cytometry analysis showed caspase-8 activity was significantly enhanced in bortezomib-treated murine tumor cells upon co-culture with NK cells compared to untreated tumor cells. Concanamycin A treatment significantly reduced NK cell-mediated apoptosis (but not neutralizing antibodies to Fas ligand or TRAIL) demonstrating that the sensitizing effect was mediated through perforin. Moreover, bortezomib-treated tumor cells were resistant to killing by perforin-deficient NK cells in vitro and the reduction in tumor growth observed in tumor bearing animals treated with bortezomib and wild-type NK cells was not observed in animals treated with bortezomib and perforin-deficient NK cells. These findings demonstrate that bortezomib-induced tumor sensitization to NK cell perforin and/or TRAIL could be used as a novel strategy to potentiate anti-tumor effects of adoptively infused NK cells in patients with cancer. Figure. Left - BALB/c mice were injected with RENCA tumor cells (100.000 cells i.v) and treated with bortezomib (5ug/mouse i.v) on days 5, 12 and 19 followed by injection of sygeneric NK cells (2×106 i.v) on days 6,13 and 20. All animals received IL-2 (100.000 U i.p on days 6–9,13–16 and 20–23). Animals were euthanized on day 25 and evaluated for pulmonary metastasies. Right - C57BL/6 mice were injected with LLC1 tumor cells (500.000 s.c) and treated with bortezomib (15ug/mouse i.p) on day 14 followed by a single injection of syngeneic NK cells (1×106 i.v) on day 15. All mice were treated with IL-2 (100.000U i.p on days 15–18). Data depicts tumor sizes on day 28 post tumor injection. Figure. Left - BALB/c mice were injected with RENCA tumor cells (100.000 cells i.v) and treated with bortezomib (5ug/mouse i.v) on days 5, 12 and 19 followed by injection of sygeneric NK cells (2×106 i.v) on days 6,13 and 20. All animals received IL-2 (100.000 U i.p on days 6–9,13–16 and 20–23). Animals were euthanized on day 25 and evaluated for pulmonary metastasies. Right - C57BL/6 mice were injected with LLC1 tumor cells (500.000 s.c) and treated with bortezomib (15ug/mouse i.p) on day 14 followed by a single injection of syngeneic NK cells (1×106 i.v) on day 15. All mice were treated with IL-2 (100.000U i.p on days 15–18). Data depicts tumor sizes on day 28 post tumor injection.

scholarly journals Aptamer Targeted Therapy Potentiates Immune Checkpoint Blockade in Triple-Negative Breast Cancer

2020 ◽  
Author(s):  
Simona Camorani ◽  
Margherita Passariello ◽  
Lisa Agnello ◽  
Silvia Esposito ◽  
Francesca Collina ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Lung Metastases ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Syngeneic Mouse Model

Abstract Background: Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy, the current major option for treatment. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers that may allow for novel combination therapies with immune-checkpoint blockade in TNBC. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in mesenchymal invasive TNBC, both on tumor cells and tumor microenvironment (TME). We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC.Methods: The targeting ability of the anti-human PDGFRβ aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays on PDGFRβ-positive cells. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAbs combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed. Results: We show that the PDGFRβ aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAbs-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in a syngeneic mouse model by acting on both TME and cancer cells. Conclusion: Co-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.

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