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).

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.

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 Biological therapies in nonsmall cell lung cancer

2017 ◽  
Vol 49 (3) ◽  
pp. 1601520 ◽  
Author(s):  
Jon Zugazagoitia ◽  
Sonia Molina-Pinelo ◽  
Fernando Lopez-Rios ◽  
Luis Paz-Ares
Keyword(s):  
Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Nonsmall Cell Lung Cancer ◽  
Advanced Stage ◽  
Biological Therapies ◽  
Term Survival ◽  
Treatment Benefits ◽  
Medical Disciplines

Biological therapies have improved survival outcomes of advanced-stage nonsmall cell lung cancer (NSCLC). Genotype-directed therapies have changed treatment paradigms of patients withEGFR-mutant andALK/ROS1-rearranged lung adenocarcinomas, and the list of druggable targets with demonstrated clinical actionability (BRAF, MET, RET, NTRK1andHER2) continues to expand. Furthermore, we have incrementally understood the mechanisms of cancer immune evasion and foresee ways to effectively circumvent them, particularly at the immune checkpoint level. Drugs targeting the tumour immune-evasive PD-1 pathway have demonstrated remarkable treatment benefits in this disease, with a non-negligible fraction of patients potentially receiving long-term survival benefits. Herein, we briefly discuss the role of various medical disciplines in the management of advanced-stage NSCLC and review the most relevant biological therapies for this disease, with particular emphasis in genotype-directed therapies and immune checkpoint inhibitors.

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 Radiation for Oligometastatic Lung Cancer in the Era of Immunotherapy: What Do We (Need to) Know?

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2132
Author(s):  
Stephanie T. H. Peeters ◽  
Evert J. Van Limbergen ◽  
Lizza E. L. Hendriks ◽  
Dirk De Ruysscher
Keyword(s):  
Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Metastatic Cancer ◽  
Combined Treatment ◽  
Progression Free Survival ◽  
Phase Ii Trials ◽  
Consensus Definition ◽  
Term Survival ◽  
Oligometastatic Disease

Oligometastatic cancer is recognized as a separate entity within the spectrum of metastatic disease. It was suggested that patients with oligometastatic disease can obtain long-term survival by giving local ablative therapy (LAT) to all visible disease locations. However, the true extent from which metastatic cancer should be called “oligometastatic” is unknown, although a consensus definition for oligometastatic disease is proposed by research organizations, such as the EORTC (maximum of five metastases in three organs). Different states of the oligometastatic disease are defined, such as synchronous vs. metachronous, oligopersistent vs. oligoprogressive disease. All clinical trials including patients with non-small cell lung cancer (NSCLC) are small and most are not randomized. Two small randomized phase II trials on synchronous disease showed an improvement in progression free survival, with the addition of LAT, and one also demonstrated an overall survival benefit. Immune checkpoint inhibitors (ICI) were not part of the treatment in these trials, while ICI significantly improved long-term outcomes of patients with metastatic NSCLC. Radiotherapy might improve the prognosis of patients treated with ICI because of its immunostimulatory effects and the possibility to eradicate metastatic deposits. Here, we summarize the data for adding ablative radiotherapy to the treatment of oligometastatic NSCLC, especially in the ICI era, and discuss the challenges of combined treatment.

scholarly journals Systemic Therapy for Hepatocellular Carcinoma: Latest Advances

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 412 ◽  
Author(s):  
Masatoshi Kudo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Combination Therapy ◽  
Systemic Therapy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Phase Iii ◽  
Term Survival ◽  
Targeted Agent

Systemic therapy for hepatocellular carcinoma (HCC) has changed drastically since the introduction of the molecular targeted agent sorafenib in 2007. Although sorafenib expanded the treatment options for extrahepatic spread (EHS) and vascular invasion, making long-term survival of patients with advanced disease achievable to a certain extent, new molecular-targeted agents are being developed as alternatives to sorafenib due to shortcomings such as its low response rate and high toxicity. Every single one of the many drugs developed during the 10-year period from 2007 to 2016 was a failure. However, during the two-year period from 2017 through 2018, four drugs—regorafenib, lenvatinib, cabozantinib, and ramucirumab—emerged successfully from clinical trials in quick succession and became available for clinical use. The efficacy of combination therapy with transcatheter arterial chemoembolization (TACE) plus sorafenib was also first demonstrated in 2018. Recently, immune checkpoint inhibitors have been applied to HCC treatment and many phase III clinical trials are ongoing, not only on monotherapy with nivolumab, pembrolizumab, and tislelizumab, but also on combination therapy with checkpoint inhibitors, programmed death-1 (PD-1) or PD-ligand 1 (PD-L1) antibody plus a molecular targeted agent (bevacizumab) or the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, tremelimumab. These combination therapies have shown higher response rates than PD-1/PD-L1 monotherapy alone, suggesting a synergistic effect by combination therapy in early phases; therefore, further results are eagerly awaited.

scholarly journals Combining Immune Checkpoint Inhibitors with Anti-Angiogenic Agents

2020 ◽  
Vol 9 (3) ◽  
pp. 675 ◽  
Author(s):  
Paola Ciciola ◽  
Priscilla Cascetta ◽  
Cataldo Bianco ◽  
Luigi Formisano ◽  
Roberto Bianco
Keyword(s):  
Tumor Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Synergistic Effects ◽  
Combined Therapy ◽  
Large Fraction ◽  
Combined Treatment ◽  
Growth Factor Receptor ◽  
Clinical Settings ◽  
Tumor Vessels

Immunotherapy has recently emerged as a novel strategy for treating different types of solid tumors, with promising results. However, still a large fraction of patients do not primarily respond to such approaches, and even responders sooner or later develop resistance. Moreover, immunotherapy is a promising strategy for certain malignancies but not for others, with this discrepancy having been attributed to a more immunogenic microenvironment of some tumors. As abnormal and augmented tumor vessels often occur in cancerogenesis, anti-angiogenic drugs have already demonstrated their effectiveness both in preclinical and in clinical settings. By targeting abnormal formation of tumor vessels, anti-angiogenetic agents potentially result in an enhanced infiltration of immune effector cells. Moreover, crosstalks downstream of the immune checkpoint axis and vascular endothelial growth factor receptor (VEGFR) signaling may result in synergistic effects of combined treatment in tumor cells. In this review, we will describe and discuss the biological rationale of a combined therapy, underlying the modification in tumor microenvironment as well as in tumor cells after exposure to checkpoint inhibitors and anti-angiogenic drugs. Moreover, we will highlight this strategy as a possible way for overcoming drug resistance. By first discussing potential prognostic and predictive factors for combined treatment, we will then turn to clinical settings, focusing on clinical trials where this strategy is currently being investigated.

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