Researcher:
Sezen, Duygu

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Duygu

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    Publication
    NLRP3 agonist enhances radiation-induced immune priming and promotes abscopal responses in anti-PD1 resistant model
    (Springer, 2023) Barsoumian, Hampartsoum B.; He, Kewen; Hsu, Ethan; Bertolet, Genevieve; Hu, Yun; Riad, Thomas S.; Cortez, Maria Angelica; Welsh, James W.; Sezen, Duygu; School of Medicine
    Radiotherapy (XRT), a well-known activator of the inflammasome and immune priming, is in part capable of reversing resistance to anti-PD1 treatment. The NLRP3 inflammasome is a pattern recognition receptor which is activated by both exogenous and endogenous stimuli, leading to a downstream inflammatory response. Although NLRP3 is typically recognized for its role in exacerbating XRT-induced tissue damage, the NLRP3 inflammasome can also yield an effective antitumor response when used in proper dosing and sequencing with XRT. However, whether NLRP3 agonist boosts radiation-induced immune priming and promote abscopal responses in anti-PD1 resistant model is still unknown. Therefore, in this study, we paired intratumoral injection of an NLRP3 agonist with XRT to stimulate the immune system in both wild type (344SQ-P) and anti-PD1 resistant (344SQ-R) murine-implanted lung adenocarcinoma models. We found that the combination of XRT + NLPR3 agonist enhanced the control of implanted lung adenocarcinoma primary as well as secondary tumors in a radiological dose-dependent manner, in which 12Gyx3 fractions of stereotactic XRT was better than 5Gyx3, while 1Gyx2 did not improve the NLRP3 effect. Survival and tumor growth data also showed significant abscopal response with the triple therapy (12Gyx3 + NLRP3 agonist + alpha-PD1) in both 344SQ-P and 344SQ-R aggressively growing models. Multiple pro-inflammatory cytokines (IL-1b, IL-4, IL-12, IL-17, IFN-gamma and GM-CSF) were elevated in the serum of mice treated with XRT + NLRP3 or triple therapy. The Nanostring results showed that NLRP3 agonist is capable of increasing antigen presentation, innate function, and T-cell priming. This study can be of particular importance to treat patients with immunologically-cold solid tumors whom are also refractory to prior checkpoint treatments.
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    Systemic inflammation score for predicting radiation-induced trismus and osteoradionecrosis of the jaw rates in locally advanced nasopharyngeal carcinoma patients
    (Akad Doktorlar Yayınevi, 2023) Somay, Efsun; Besen, Ali Ayberk; Mertsoylu, Huseyin; Topkan, Erkan; Sezen, Duygu; Selek, Uğur; School of Medicine
    We sought to determine the predictive value of the systemic inflammation score (SIS) for radiation-induced trismus (RIT) and osteora-dionecrosis of the jaw (ORNJ) in locally advanced nasopharyngeal carcinoma (LA-NPC) patients treated with concurrent chemoradio-therapy (C-CRT). LA-NPC patients (n= 188) who underwent C-CRT and pre-and post-C-CRT oral examinations from August 2010 to January 2022 were included. The three-tiered SIS groups were created using the serum albumin and lymphocyte-to-monocyte ratio (LMR) measures obtained on the first day of C-CRT: SIS-0: Albumin >= 40 g/dL and LMR >= 4.44); SIS-1: Albumin < 40 g/dL and LMR < 4.44 or albumin >= 0 g/dL and LMR >= 4.44; and SIS-2: Albumin < 40 g/dL and LMR <4.44. The primary objective was to ascertain whether there were irrefutable associations between pretreatment SIS groups and the respective post-C-CRT RIT and ORNJ rates. RIT and ORNJ were diagnosed in 33 (17.6%) and 21 (11.1%) patients, respectively. There were 12 (32.4%), 13 (12.7%), and 18 (45.0%) cases diagnosed with RIT in the respective SIS-0, SIS-1, and SIS-2 groups (p< 0.001). Similarly, there were 1 (2.7%), 11 (9.9%), and 9 (22.5%) cases with ORNJ diagnoses in the corresponding SIS groups (p< 0.001). The multivariate analysis's findings revealed that the SIS grouping was an independent predictor of RIT (p< 0.001) and ORNJ incidence rates (p< 0.001). Our study's findings indicate that the novel pretreatment SIS grouping is a dependable biomarker-based system, which can accurately predict the rates of RIT and ORNJ in LA-NPC patients who receive definitive C-CRT.
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    Inhibition of STAT6 with antisense oligonucleotides enhances the systemic antitumor effects of radiotherapy and anti-PD-1 in metastatic non-small cell lung cancer
    (Amer Assoc Cancer Research, 2023) He, Kewen; Barsoumian, Hampartsoum B.; Puebla-Osorio, Nahum; Hu, Yun; Sezen, Duygu; Wasley, Mark D.; Bertolet, Genevieve; Zhang, Jie; Leuschner, Carola; Yang, Liangpeng; Leyton, Claudia S. Kettlun; Fowlkes, Natalie Wall; Green, Morgan Maureen; Hettrick, Lisa; Chen, Dawei; Masrorpour, Fatemeh; Gu, Meidi; Maazi, Hadi; Revenko, Alexey S.; Cortez, Maria Angelica; Welsh, James W.; Sezen, Duygu; School of Medicine
    Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells-such as M2 tumor-associated macrophages (TAM)-thereby establishing an immunosuppressive tumor microenvironment that contri-butes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we tar-geted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung adenocarcinomas). We found that STAT6 ASO plus hRT slowed growth of both primary and abscopal tumors, decreased lung metastases, and extended survival. Interrogating the mech-anism of action showed reduced M2 macrophage tumor infil-tration, enhanced TH1 polarization, improved T-cell and mac-rophage function, and decreased TGFI3 levels. The addition of anti-PD-1 further enhanced systemic antitumor responses. These results provide a preclinical rationale for the pursuit of an alternative therapeutic approach for patients with immune-resistant NSCLC.
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    Preoperative radiosurgical management of brain metastases: evidence and challenges
    (Exon Publication, 2023) Topkan, E.; Kucuk, A.; Pehlivan, B.; Şenyürek, Şükran; Sezen, Duygu; Durankuş, Nilüfer Kılıç; Akdemir, Eyüb Yaşar; Bölükbaşı, Yasemin; Selek, Uğur; School of Medicine; Koç University Hospital
    About 30% of all adult patients with solid tumors will develop brain metastases. The prognosis of patients with brain metastasis is poor, with a median overall survival of 4–7 months. Nevertheless, with efficient systemic and local therapies, some specific patient groups may experience longer survival times. Currently, the options for the management of brain metastasis include surgery, systemic chemotherapy, targeted therapies, stereotactic radiosurgery (SRS), postoperative stereotactic radiosurgery, whole-brain radiotherapy (WBRT), and their combination variants. Given the severe neurotoxic effects of WBRT, increased risk of radionecrosis, leptomeningeal dissemination after postoperative SRS, and the ineligibility of certain patients for SRS during the postoperative period (usually first 21 days), an active search for alternative treatment strategies for such patients ensued. It has been suggested that novel preoperative stereotactic radiosurgery, which has a lower risk of radionecrosis and leptomeningeal dissemination, would provide at least equivalent local control rates in this regard. The purpose of the current chapter is to outline the justification and available evidence for the novel preoperative stereotactic radiosurgery in the management of brain metastasis while accepting the paucity of related literature.
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    Five-year overall survival with ipilimumab and stereotactic ablative radiotherapy for metastatic disease
    (Elsevier Ireland Ltd, 2023) He, Kewen; Hong, David S.; Tang, Chad; Cox, Livia; Maleki, Aurian; Bertolet, Genevieve; Nguyen, Quynh-Nhu; Comeaux, Nathan I.; Schuda, Lily; Chen, Dawei; Welsh, James W.; Sezen, Duygu; School of Medicine
    Purpose: Ipilimumab plus stereotactic ablative radiotherapy (SABR) demonstrate satisfactory short-term clinical benefit and low toxicities in metastatic cancers. Here, we report the 5-year overall survival (OS) rates for patients with metastatic disease treated with this combined-modality therapy in a phase II trial (NCT02239900). Methods and materials: SABR was delivered to patients with metastatic lesions in the liver and lung either during the first dose (concurrent) or 1 week after the second dose (sequential) of ipilimumab (every 3 weeks for 4 cycles). SABR was administered to liver or lung metastases as 50 Gy in 4 fractions or 60 Gy in 10 fractions, considering the tumor location. The OS rates at 12, 36, and 60 months were esti-mated by the Kaplan-Meier method; subgroup analyses of progression-free survival (PFS) and OS by SABR-targeted lesions (liver/lung) were performed by log-rank tests. Results: A total of 106 patients were enrolled in this long-term follow-up analysis. At the median follow-up time of 15.32 months (range, 0.97-82.13 months), the median PFS was 6.52 months (95% CI, 5.86- 7.14) and the median OS was 15.32 months (95% CI,13.03-17.23). The 12-, 36-, and 60-month OS rates were 61%, 23%, and 15%, respectively. There was a significant difference in OS between cohorts (P = 0.039), with a stronger response observed in lung-treated subgroups. Patients who had received sequential fractions (50 Gy/4f) to the lung had improved OS compared to those who had received sequen-tial fractions (18.29 vs 8.9 months, P = 0.043) to the liver. Subgroup analysis of SABR-targeted lesions showed that lung-targeted groups had significantly longer PFS (6.87 months vs. 5.63 months, P = 0.034) and OS (18.67 months vs. 13.63 months, P = 0.013) compared to liver-targeted groups. The sequence did not affect the outcomes of PFS and OS. Exploratory analyses showed that SABR-targeted lesions and smoking history comprised an independent risk factor for OS. Conclusions: Updated 5-year OS data from the phase II trial demonstrate the long-term clinical benefit of ipilimumab and SABR, which warrants further research and cumulative data.
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    Design considerations for clinical trials of radiotherapy combined with immunotherapy
    (Kare Publ, 2023) Welsh, James; Sezen, Duygu; School of Medicine
    The discovery of synergistic effects between radiation and immunotherapy in pre-clinical studies has encouraged researchers to conduct clinical trials testing the effects of combined therapy in patients. The first step in conducting any clinical trial is to define the hypothesis and core objectives. The challenge while developing trials analyzing combinations of immunotherapy and radiation therapy (RT) is to select an appropriate hypothesis that can be tested in the future research, as well as raising new questions for investigation. Here, we review some of the concerns and challenges for designing clinical trials of RT combined with immunotherapy.
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    PublicationOpen Access
    Radiation therapy modulates tumor physical characteristics to reduce intratumoral pressure and enhance intratumoral drug delivery and retention
    (Elsevier Inc, 2023) Barsoumian, Hampartsoum B.; Sheth, Rahul A.; Ramapriyan, Rishab; Hsu, Ethan; Gagea, Mihai; Crowley, Kaitlyn; Williams, Malea; Welsh, James W.; Sezen, Duygu; School of Medicine
    Purpose: High intratumoral pressure, caused by tumor cell-to-cell interactions, interstitial fluid pressure, and surrounding stromal composition, plays a substantial role in resistance to intratumoral drug delivery and distribution. Radiation therapy (XRT) is commonly administered in conjunction with different intratumoral drugs, but assessing how radiation can reduce pressure locally and help intratumoral drug administration and retention is important. Methods and Materials: 344SQ-parental or 344SQ-anti-programmed cell death protein 1-resistant lung adenocarcinoma cells were established in 129Sv/Ev mice, and irradiated with either 1 Gy & POUND; 2, 5 Gy & POUND; 3, 8 Gy & POUND; 3, 12 Gy & POUND; 3, or 20 Gy & POUND; 1. Intratumoral pressure was measured every 3 to 4 days after XRT. Contrast dye was injected into the tumors 3-and 6-days after XRT, and imaged to measure drug retention.Results: In the 344SQ-parental model, low-dose radiation (1 Gy x 2) created an early window of reduced intratumoral pressure 1 to 3 days after XRT compared with untreated control. High-dose stereotactic radiation (12 Gy x 3) reduced intratumoral pressure 3 to 12 days after XRT, and 20 Gy x 1 showed a delayed pressure reduction on day 12. Intermediate doses of radiation did not significantly affect intratumoral pressure. In the more aggressive 344SQ-anti-programmed cell death protein 1-resistant model, low-dose radiation reduced pressure 1 to 5 days after XRT, and 12 Gy x 3 reduced pressure 1 to 3 days after XRT. Moreover, both 1 Gy x 2 and 12 Gy x 3 significantly improved drug retention 3 days after XRT; however, there was no significance detected 6 days after XRT. Lastly, a histopathologic evaluation showed that 1 Gy x 2 reduced collagen deposition within the tumor, and 12 Gy x 3 led to more necrotic core and higher extracellular matrix formation in the tumor periphery. Conclusions: Optimized low-dose XRT, as well as higher stereotactic XRT regimen led to a reduction in intratumoral pressure and increased drug retention. The findings from this work can be readily translated into the clinic to enhance intratumoral injections of various anticancer agents.(http://creativecommons.org/licenses/by-nc-nd/4.0/).
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    FAST- Forward radiotherapy in breast cancer patients from a Turkish cohort: a study on acute skin toxicity
    (Kare Publ, 2024) Bolukbasi, Yasemin; N/A; Durankuş, Nilüfer Kılıç; Sezen, Duygu; Şenyürek, Şükran; School of Medicine; Koç University Hospital
    OBJECTIVE This study aimed to evaluate early skin reactions in patients with breast cancer treated with the FAST-Forward radiotherapy regimen after surgery. METHODS Between December 2019 and August 2022, 60 patients with breast cancer received the FAST-Forward radiotherapy protocol: 26 Gy delivered in five fractions of 5.2 Gy each, using tangential field-in-field techniques.Treatments were administered on consecutive weekdays, and skin reactions were graded using the Radiation Therapy Oncology Group (RTOG) system in the second and sixth weeks after radiotherapy. The radiotherapy area and contralateral breast were photographed, and the patients were asked to report any breast swelling as a subjective symptom. RESULTS The median patient age was 71 years (range: 51-86). All had T1-2 and N0-1 disease and received adju-vant radiotherapy following surgery. In the second week after radiotherapy, 7 patients (11.6%) had grade 1 skin reactions and 1 patient (1.6%) had a grade 2 reaction. By the sixth week, five of the seven grade 1 reactions had resolved, with one remaining in grade 1 and one increasing to grade 2. The initial grade 2 reaction improved to a grade 1 reaction. None of the patients reported breast swelling in the second and sixth weeks after radiotherapy. CONCLUSION Considering the impact of skin reactions on the patients' quality of life, the FAST-Forward protocol appears to be a safe and comfortable option for patients who meet the appropriate criteria. Copyright (c) 2024, Turkish Society for Radiation Oncology
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    Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy
    (BioMed Central Ltd, 2024) He, Kewen; Puebla-Osorio, Nahum; Barsoumian, Hampartsoum B.; Rafiq, Zahid; Riad, Thomas S.; Hu, Yun; Huang, Ailing; Voss, Tiffany A.; Leyton, Claudia S. Kettlun; Schuda, Lily Jae; Hsu, Ethan; Heiber, Joshua; Cortez, Maria-Angelica; Welsh, James W.; Sezen, Duygu; School of Medicine
    Background: Combining interleukin-2 (IL-2) with radiotherapy (RT) and immune checkpoint blockade (ICB) has emerged as a promising approach to address ICB resistance. However, conventional IL-2 cytokine therapy faces constraints owing to its brief half-life and adverse effects. RDB 1462, the mouse ortholog of Nemvaleukin alfa, is an engineered IL-2 with an intermediate affinity that selectively stimulates antitumor CD8 T and NK cells while limiting regulatory T cell expansion. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462, RT, and anti-PD1 in mouse tumor models. Methods: Two bilateral lung adenocarcinoma murine models were established using 344SQ-Parental and 344SQ anti-PD1-resistant cell lines. Primary tumors were treated with RT, and secondary tumors were observed for evidence of abscopal effects. We performed immune phenotyping by flow cytometry, analyzed 770 immune-related genes using NanoString, and performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit. Results: Compared to native IL-2 (RDB 1475), RDB 1462 demonstrated superior systemic antitumoral responses, attributable, at least in part, to augmented levels of CD4 and CD8 T cells with the latter. Our findings reveal substantial reductions in primary and secondary tumor volumes compared to monotherapy controls, with some variability observed among different dosing schedules of RDB 1462 combined with RT. Blood and tumor tissue-based flow cytometric phenotyping reveals an increase in effector memory CD8 and CD4 T cells and a decrease in immunosuppressive cells accompanied by a significant increase in IL-2, IFN-γ, and GM-CSF levels in the combination group. Transcriptomic profiling and TCR sequencing reveal favorable gene expression and T cell repertoire patterns with the dual combination. Furthermore, integrating anti-PD1 therapy with RT and RDB 1462 further reduced primary and secondary tumor volumes, prolonged survival, and decreased lung metastasis. Observations of immune cell profiles indicated that RT with escalating doses of RDB 1462 significantly reduced tumor growth and increased tumor-specific immune cell populations. Conclusion: The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1. Graphical Abstract: (Figure presented.) © The Author(s) 2024.
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    Inhibition of MER proto-oncogene tyrosine kinase by an antisense oligonucleotide enhances treatment efficacy of immunoradiotherapy
    (BMC, 2024) Hu, Yun; Revenko, Alexey; Barsoumian, Hampartsoum; Bertolet, Genevieve; Fowlkes, Natalie Wall; Maazi, Hadi; Green, Morgan Maureen; He, Kewen; Voss, Tiffany A.; Leyton, Claudia S. Kettlun; Masrorpour, Fatemeh; Rafiq, Zahid; Puebla-Osorio, Nahum; Leuschner, Carola; Macleod, Robert; Cortez, Maria Angelica; Welsh, James W.; Sezen, Duygu; School of Medicine
    BackgroundThe combination of radiotherapy and immunotherapy (immunoradiotherapy) has been increasingly used for treating a wide range of cancers. However, some tumors are resistant to immunoradiotherapy. We have previously shown that MER proto-oncogene tyrosine kinase (MerTK) expressed on macrophages mediates resistance to immunoradiotherapy. We therefore sought to develop therapeutics that can mitigate the negative impact of MerTK. We designed and developed a MerTK specific antisense oligonucleotide (ASO) and characterized its effects on eliciting an anti-tumor immune response in mice.Methods344SQR cells were injected into the right legs on day 0 and the left legs on day 4 of 8-12 weeks old female 129sv/ev mice to establish primary and secondary tumors, respectively. Radiation at a dose of 12 Gy was given to the primary tumors on days 8, 9, and 10. Mice received either anti-PD-1, anti-CTLA-4 or/and MerTK ASO starting from day 1 post tumor implantation. The composition of the tumor microenvironment and the level of MerTK on macrophages in the tumor were evaluted by flow cytometry. The expression of immune-related genes was investigated with NanoString. Lastly, the impact of MerTK ASO on the structure of the eye was histologically evaluated.ResultsRemarkably, the addition of MerTK ASO to XRT+anti-PD1 and XRT+anti-CTLA4 profoundly slowed the growth of both primary and secondary tumors and significantly extended survival. The ASO significantly reduced the expression of MerTK in tumor-associated macrophages (TAMs), reprograming their phenotype from M2 to M1. In addition, MerTK ASO increased the percentage of Granzyme B+ CD8+ T cells in the secondary tumors when combined with XRT+anti-CTLA4. NanoString results demonstrated that the MerTK ASO favorably modulated immune-related genes for promoting antitumor immune response in secondary tumors. Importantly, histological analysis of eye tissues demonstrated that unlike small molecules, the MerTK ASO did not produce any detectable pathology in the eyes.ConclusionsThe MerTK ASO can significantly downregulate the expression of MerTK on TAMs, thereby promoting antitumor immune response. The combination of MerTK ASO with immunoradiotherapy can safely and significantly slow tumor growth and improve survival.