Development of LAG-3/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy.

Aside from antibodies, peptides show great potential as immune checkpoint inhibitors (ICIs) due to several advantages, such as better tumor penetration and lower cost. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-1 (FGL1). Here, we found that LAG-3 expression was higher than programmed cell death protein 1 (PD-1) in multiple human cancers by TCGA databases, and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning, which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/MHC-II. Subsequently, d-amino acids were introduced to substitute the N- and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1, which restores T cell function in vitro and inhibits tumor growth in vivo. Further, a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1 blocking peptide OPBP-1(8-12), which activates T cell with enhanced proliferation and IFN-γ production. More importantly, LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune response. In conclusion, we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function, and the bispecific peptide synergizes with radiotherapy to further enhance the antitumor immune response.

Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy.

BACKGROUND: Targeting the tumor microenvironment (TME) has emerged as a promising strategy in cancer treatment, particularly through the utilization of immune checkpoint blockade (ICB) agents such as PD-1/PD-L1 inhibitors. Despite partial success, the presence of tumor-associated macrophages (TAMs) contributes to an immunosuppressive TME that fosters tumor progression, and diminishes the therapeutic efficacy of ICB. Blockade of the CD47/SIRPα pathway has proven to be an effective intervention, that restores macrophage phagocytosis and yields substantial antitumor effects, especially when combined with PD-1/PD-L1 blockade. Therefore, the identification of small molecules capable of simultaneously blocking CD47/SIRPα and PD-1/PD-L1 interactions has remained imperative. METHODS: SMC18, a small molecule with the capacity of targeting both SIRPα and PD-L1 was obtained using MST. The efficiency of SMC18 in interrupting CD47/SIRPα and PD-1/PD-L1 interactions was tested by the blocking assay. The function of SMC18 in enhancing the activity of macrophages and T cells was tested using phagocytosis assay and co-culture assay. The antitumor effects and mechanisms of SMC18 were investigated in the MC38-bearing mouse model. RESULTS: SMC18, a small molecule that dual-targets both SIRPα and PD-L1 protein, was identified. SMC18 effectively blocked CD47/SIRPα interaction, thereby restoring macrophage phagocytosis, and disrupted PD-1/PD-L1 interactions, thus activating Jurkat cells, as evidenced by increased secretion of IL-2. SMC18 demonstrated substantial inhibition of MC38 tumor growths through promoting the infiltration of CD8+ T and M1-type macrophages into tumor sites, while also priming the function of CD8+ T cells and macrophages. Moreover, SMC18 in combination with radiotherapy (RT) further improved the therapeutic efficacy. CONCLUSION: Our findings suggested that the small molecule compound SMC18, which dual-targets the CD47/SIRPα and PD-1/PD-L1 pathways, could be a candidate for promoting macrophage- and T-cell-mediated phagocytosis and immune responses in cancer immunotherapy.

Deletion of concurrent chemotherapy on the basis of sequential chemoradiotherapy for non-metastatic stage T4 nasopharyngeal carcinoma in IMRT era.

PURPOSE: Intensity-modulated radiotherapy (IMRT) combined with concurrent chemotherapy is deemed as the mainstay treatment in locoregionally advanced nasopharyngeal carcinoma (NPC). Nevertheless, the tolerance of severe acute toxicity of concurrent chemotherapy was unsatisfied. In addition, T4 is the predicting factor of poor prognosis for NPC patients. In this retrospective analysis, the long-term outcomes IMRT combined by induction chemotherapy deleting concurrent chemotherapy with or without adjuvant chemotherapy for T4 non-metastatic NPC were analyzed. MATERIALS AND METHODS: From January 2005 to November 2016, a total of 145 biopsy-proven non-metastatic T4 NPC was treated with IMRT combined by induction chemotherapy with or without adjuvant chemotherapy. The survival and side effects of the patients were analyzed. RESULTS: Median follow-up time was 74 months (ranges, 8-186 months). 10.0%, 61.3%, 27.3%, and 1.3% developed grade 1, 2, 3, and 4 mucositis during IMRT, respectively. 5.5% and 2.0% patients experienced grade 1 and 2 nausea and vomiting; no patients developed grade 3 or 4 nausea and vomiting. Of 145 patients enrolled, 5-year and 10-year overall survival(OS) rates were 73.7% and 53.9%, local progression-free survival(LPFS) rates were 86.1% and 71.6%, regional progression-free survival(RPFS) rates were 96.7% and 92.8%, distant metastasis-free survival (DMFS) rates were 86.7%, 78.2%, respectively. At the last follow-up, five patients developed cranial nerve injury, one patient developed mandibular bone necrosis, four patients developed temporal lobe injury, four patients developed nasopharyngeal massive hemorrhage (three cases after recurrence and one case without recurrence), and five patients developed second primary tumor. CONCLUSION: The survival outcomes of treating T4 NPC IMRT combined by induction chemotherapy deleting concurrent chemotherapy with or without adjuvant chemotherapy are encouraging. Moreover, mucosal reaction, nausea, and vomiting reaction were reduced during IMRT.

Fish oil-based microemulsion can efficiently deliver oral peptide blocking PD-1/PD-L1 and simultaneously induce ferroptosis for cancer immunotherapy.

Peptide immune checkpoint inhibitors in cancer immunotherapy have attracted great attention recently, but oral delivery of these peptides remains a huge challenge due to the harsh gastrointestinal environment, large molecular size, high hydrophilic, and poor transmembrane permeability. Here, for the first time, a fish oil-based microemulsion was developed for oral delivery of programmed death-1/programmed cell death-ligand 1 (PD-1/PD-L1) blocking model peptide, OPBP-1. The delivery system was characterized, in vitro and in vivo studies were conducted to evaluate its overall implication. As a result, this nutraceutical microemulsion was easily formed without the need of co-surfactants, and it appeared light yellow, transparent, good flowability with a particle size of 152 ± 0.73 nm, with a sustained drug release manner of 56.45 ± 0.36% over 24 h and a great stability within the harsh intestinal environment. It enhanced intestinal drug uptake and transportation over human intestinal epithelial Caco-2 cells, and drastically elevated the oral peptide bioavailability of 4.1-fold higher than that of OPBP-1 solution. Meanwhile, the mechanism of these dietary droplets permeated over the intestinal enterocytic membrane was found via clathrin and caveolae-mediated endocytic pathways. From the in vivo studies, the microemulsion facilitated the infiltration of CD8+ T lymphocytes in tumors, with increased interferon-γ (IFN-γ) secretion. Thus, it manifested a promising immune anti-tumor effect and significantly inhibited the growth of murine colonic carcinoma (CT26). Furthermore, it was found that the fish oil could induce ferroptosis in tumor cells and exhibited synergistic effect with OPBP-1 for cancer immunotherapy. In conclusion, this fish oil-based formulation demonstrated great potential for oral delivery of peptides with its natural property in reactive oxygen species (ROS)-related ferroptosis of tumor cells, which provides a great platform for functional green oral delivery system in cancer immunotherapy.

Identification and optimization of peptide inhibitors to block VISTA/PSGL-1 interaction for cancer immunotherapy.

Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients. Here, we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells, especially myeloid derived suppressor cells (MDSCs) and CD8+ T cells. Then, peptide C1 with binding affinity to VISTA was developed by phage displayed bio-panning technique, and its mutant peptide VS3 was obtained by molecular docking based mutation. Peptide VS3 could bind VISTA with high affinity and block its interaction with ligand PSGL-1 under acidic condition, and elicit anti-tumor activity in vivo. The peptide DVS3-Pal was further designed by d-amino acid substitution and fatty acid modification, which exhibited strong proteolytic stability and significant anti-tumor activity through enhancing CD8+ T cell function and decreasing MDSCs infiltration. This is the first study to develop peptides to block VISTA/PSGL-1 interaction, which could act as promising candidates for cancer immunotherapy.

Is radical radiotherapy with/without surgery an effective treatment in the lymphoepithelial carcinoma of the salivary gland？.

BACKGROUND: There is limited information of radical radiotherapy (RT) on lymphoepithelial carcinoma of salivary gland (LECSG) regarding to the rarity of the disease. We conducted this retrospective study that evaluated the feasibility and efficacy of radical RT with/without surgery in LECSG. METHODS: We retrospectively reviewed patients that were pathologically diagnosed of LECSG and had definite or suspicious residual disease. The prescribed dose given to P-GTV and/or P-GTV-LN was 66 to 70.4 Gy. The clinical target volume (CTV) involved ipsilateral salivary gland and corresponding lymph node drainage area. RESULTS: A total of 56 patients were included. With a median follow-up of 60 months (range: 8 to 151 months), the 1-, 5-, and 10-year progression-free survival (PFS) rates were 94.6%, 84.7% and 84.7%; locoregional progression-free survival (LRPFS) rates were 98.2%, 87.4% and 87.4%; distance metastasis-free survival (DMFS) rates were 94.6%, 86.7% and 86.7%; and overall survival (OS) rates were 98.2%, 92.4% and 89.0%, respectively. A total of 7 patients without surgery were included. All patients were alive and only one patient experienced failure of distant metastasis four months after RT. The results of univariate analysis showed that compared with N stage, the number of positive lymph nodes (2 positive lymph nodes) was better prognostic predictor especially in PFS. There were no treatment-related deaths and most toxicities of RT were mild. CONCLUSIONS: Radical RT with/without surgery in LECSG for definite or suspicious residual disease is feasibility and efficacy. Most toxicities of RT were mild due to the target volume involved ipsilateral area.

Development of a novel peptide targeting GPR81 to suppress adipocyte-mediated tumor progression.

GPR81, initially discovered in adipocytes, has been found to suppress lipolysis when activated. However, the current small molecules that target GPR81 carry the risk of off-target effects, and their impact on tumor progression remains uncertain. Here, we utilized phage display technology to screen a GPR81-targeting peptide named 7w-2 and proceeded to demonstrate its bioactivity. Although 7w-2 did not affect the proliferation of tumor cells, it effectively reduced adipocyte catabolism in vitro, consequently restraining the proliferation of co-cultured tumor cells. Furthermore, our findings revealed that 7w-2 could inhibit lipolysis in vivo, leading to a significant impediment in tumor growth and metastasis in the 4T1 murine tumor model. Additionally, 7w-2 exhibited the ability to significantly elevate the proportion and functionality of CD8+ T cells. Our study introduces 7w-2 as the first peptide targeting GPR81, shedding light on its potential role in adipocytes in suppressing tumor progression.

Identification of a novel small-molecule inhibitor targeting TIM-3 for cancer immunotherapy.

PD-1/PD-L1 blockade has achieved substantial clinical results in cancer treatment. However, the expression of other immune checkpoints leads to resistance and hinders the efficacy of PD-1/PD-L1 blockade. T cell immunoglobulin and mucin domain 3 (TIM-3), a non-redundant immune checkpoint, synergizes with PD-1 to mediate T cell dysfunction in tumor microenvironment. Development of small molecules targeting TIM-3 is a promising strategy for cancer immunotherapy. Here, to identify small molecule inhibitors targeting TIM-3, the docking pocket in TIM-3 was analyzed by Molecular Operating Environment (MOE) and the Chemdiv compound database was screened. The small molecule SMI402 could bind to TIM-3 with high affinity and prevent the ligation of PtdSer, HMGB1, and CEACAM1. SMI402 reinvigorated T cell function in vitro. In the MC38-bearing mouse model, SMI402 inhibited tumor growth by increasing CD8+ T and natural killing (NK) cells infiltration at the tumor site, as well as restoring the function of CD8+ T and NK cells. In conclusions, the small molecule SMI402 shows promise as a leading compound which targets TIM-3 for cancer immunotherapy.

Design of a novel chimeric peptide via dual blockade of CD47/SIRPα and PD-1/PD-L1 for cancer immunotherapy.

Although immune checkpoint inhibition has been shown to effectively activate antitumor immunity in various tumor types, only a small subset of patients can benefit from PD-1/PD-L1 blockade. CD47 expressed on tumor cells protects them from phagocytosis through interaction with SIRPα on macrophages, while PD-L1 dampens T cell-mediated tumor killing. Therefore, dual targeting PD-L1 and CD47 may improve the efficacy of cancer immunotherapy. A chimeric peptide Pal-DMPOP was designed by conjugating the double mutation of CD47/SIRPα blocking peptide (DMP) with the truncation of PD-1/PD-L1 blocking peptide OPBP-1(8-12) and was modified by a palmitic acid tail. Pal-DMPOP can significantly enhance macrophage-mediated phagocytosis of tumor cells and activate primary T cells to secret IFN-γ in vitro. Due to its superior hydrolysis-resistant activity as well as tumor tissue and lymph node targeting properties, Pal-DMPOP elicited stronger anti-tumor potency than Pal-DMP or OPBP-1(8-12) in immune-competent MC38 tumor-bearing mice. The in vivo anti-tumor activity was further validated in the colorectal CT26 tumor model. Furthermore, Pal-DMPOP mobilized macrophage and T-cell anti-tumor responses with minimal toxicity. Overall, the first bispecific CD47/SIRPα and PD-1/PD-L1 dual-blockade chimeric peptide was designed and exhibited synergistic anti-tumor efficacy via CD8+ T cell activation and macrophage-mediated immune response. The strategy could pave the way for designing effective therapeutic agents for cancer immunotherapy.

Is postoperative radiotherapy an essential treatment for nonmetastatic lymphoepithelial carcinoma of the salivary gland?

BACKGROUND: Lymphoepithelial carcinoma of salivary gland (LECSG) is a rare malignant tumor. Whether postoperative radiotherapy (PORT) can improve locoregional control and which patients can benefit from PORT are unknown. This study aimed to evaluate the role of PORT and provide individualized suggestions for postoperative therapy in patients with LECSG. PATIENTS AND METHODS: We retrospectively reviewed patients with nonmetastatic LECSG who underwent surgery with or without PORT. Recursive partitioning analysis (RPA) was performed to categorize the patients and predict progression-free survival (PFS). RESULTS: A total of 223 patients were included, 34 (15.2%) received surgery alone, whereas the remaining 189 (84.8%) underwent PORT in the initial treatment. Although patients in the PORT group were with advanced T stage and N stage, the PORT group had an advantage over the non-PORT group on 1-year, 5-year and 10-year PFS and locoregional control (LRC). PORT was an independent prognostic factor for PFS and LRC. Furthermore, compared with T stage and N stage, the size of the primary tumor and the number of positive lymph nodes were better prognostic predictors. The RPA model was generated according to the endpoint of PFS and categorized patients into 3 prognostic groups: low-risk (maximum diameter of primary lesion (≤3 cm) and number of positive lymph nodes (≤2)), intermediate-risk (maximum diameter of primary lesion (>3 cm) and number of positive lymph nodes (≤2)), and high-risk (number of positive lymph nodes (>2)), with corresponding 5-year PFS rates of 90.0%, 75.0%, and 51.0%, respectively. Significant improvement in PFS was observed in the PORT group among intermediate-risk (P = 0.000) and high-risk patients (P = 0.000). CONCLUSIONS: PORT was shown to be a positive prognostic factor for PFS and LRC of LECSG. PORT was an essential treatment especially for patients with >3 cm maximum diameter of primary lesion and/or >2 positive lymph nodes.

Second Primary Lung Adenocarcinoma After Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma.

Objective: The improvement of the efficacy of intensity-modulated radiotherapy (IMRT) for nasopharyngeal cancer (NPC) has prolonged the survival of patients, and the incidence of the second tumor has gradually increased. Among them, second primary lung adenocarcinoma (SPLAC) attributes the highest incidence. This study aimed to determine the long-term risk of SPLAC in NPC patients after IMRT. Methods: From May 2005 to May 2018, a total of 1,102 non-metastatic NPC patients who received IMRT in our hospital were enrolled, and the incidence and efficacy of SPLAC were followed up in the long term. Results: Over a median follow-up period of 66 months, a total of 22 cases of SPLAC were observed, with an incidence of 2.0%. The 1-, 2-, 3-, 4-, and 5-year cumulative risks of SPLAC were 0.4%, 0.7%, 0.8%, 1.1%, and 1.7%, respectively. During follow-up, 90.9% (20/22) of the SPLAC detected was in early stage, and the recurrence rate of surgery alone was 5.3% (1/19). Conclusion: In NPC patients, the proportion of SPLAC after IMRT was similar to that of the normal population, and most of them were found in early stage during follow-up, with good surgical efficacy.

Long-term outcomes of nasopharyngeal carcinoma patients with T1-2 stage in intensity-modulated radiotherapy era.

Objectives: To evaluate long-term outcomes and late toxicities of nasopharyngeal carcinoma (NPC) patients with T1-2N0-3M0 stage in intensity-modulated radiotherapy (IMRT) era. Materials and Methods: From June 2005 to October 2013, 276 patients confirmed T1-2N0-3M0 NPC treated with IMRT were reviewed, with 143 (51.8%) N0-1 disease and 133 (48.2%) N2-3 disease. Among them, 76.4% received chemotherapy. The prescribed doses given to the primary tumor and lymph nodes were 66Gy in 30 fractions. Results: After a median follow-up of 103 months, the 5-year and 10-year overall survival (OS) were 90.6% and 79.2%. The 5-year and 10-year local control (LC) rate, regional control (RC) rate and distant metastasis free survival (DMFS) were 97.0% and 91.9%, 94.1% and 92.2%, 89.4% and 87.0%, respectively. The 5-year and 10-year OS, RC rate and DMFS of N0-1 compared with those of N2-3 were 98.6% vs. 82.0% and 86.8% vs. 70.9% (P=0.000), 99.3% vs. 88.3% and 99.3% vs. 84.1% (P=0.000), 97.9% vs. 80.1% and 95.7% vs. 77.5% (P=0.000). The incidence of 3-4 late toxicities were low and mainly xerostomia and hearing deficit. The rates of radiation-induced cranial nerve palsy and temporal necrosis were 2.5% and 2.5%, respectively. Eighteen patients had the second primary tumor, of whom eight were lung cancer, six were head and neck cancer, four were others. Conclusions: Satisfactory locoregional control was achieved in T1-2N0-3M0 NPC treated with IMRT. Distant metastasis was the main failure cause and N2-3 was the main adverse prognostic factor. Second primary tumor occurred 6.5% and negatively impacted OS in NPC.

Is Immune Therapy Plus Chemotherapy More Effective Than Immune Therapy Alone for Unresectable Recurrent Nasopharyngeal Carcinoma?

Objective: To evaluate whether the combination of immune checkpoint inhibitor (ICI) with chemotherapy is more effective than ICI alone in the treatment of recurrent, locoregionally advanced, unresectable nasopharyngeal carcinoma (RAU-NPC), which has progressed after second line chemotherapy. Methods and materials: Patients with RAU-NPC that progressed after second chemotherapy were prescribed ICI once every 3 weeks, either alone or combined with chemotherapy at the discretion of treating physicians, until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary endpoint was the objective response rate (ORR). The secondary endpoints included safety, duration of response (DOR), and progression-free survival (PFS). Results: From June 2016 to July 2021, 28 patients were enrolled in this study.21 patients received ICI plus chemotherapy, and 7 patients received ICI alone. Altogether, there were 7 (25%) complete response (CR) and 12 (42.8%) partial response (PR), respectively. Stable disease (SD) and progressive disease (PD) were defined in 4 (14.3%) and 5 (17.8%) cases, respectively. The ORR was 19 out of 28 (67.8%). The disease control rate (DCR) was 23 out of 28 (82.1%).Two patients (28.6%) in the ICI alone group and five (23.8%) in the combination group achieved CR (P=0.801). 2 patient (28.6%) in the ICI alone group and 10 (47.6%) in the combination group achieved PR (P=0.378). With a median follow-up of 16 months (2-61 months), five patients terminated ICI due to disease progression, one patient was lost to follow-up, and the remaining 22 patients continued with ICI. Neither the median PFS nor the median DOR was reached. All observed adverse events were defined as ≤ Grade 2. Conclusion: ICI alone or combined with chemotherapy demonstrated promising antitumor activity in RAU-NPC patients that progressed after second line chemotherapy, with a low toxicity profile. Compared with ICI alone, chemotherapy plus ICI did not improve CR or PR in our study.

Long-term outcomes of induction chemotherapy followed by intensity-modulated radiotherapy and adjuvant chemotherapy in nasopharyngeal carcinoma patients with N3 disease.

OBJECTIVES: To evaluate long-term outcomes of induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT) and adjuvant chemotherapy (AC) in nasopharyngeal carcinoma (NPC) patients with N3 disease. MATERIALS AND METHODS: From September 2005 to August 2016, 143 patients confirmed NPC with the 8th AJCC/UICC staging criteria N3 were reviewed. All patients received IC followed by IMRT and AC. RESULTS: After a median follow-up of 67 months, the 5-year and 10-year overall survival (OS), progression-free survival (PFS), distant metastasis free survival (DMFS), local progression-free survival (LPFS) and regional progression-free survival (RPFS) were 75.7% and 61.6%, 61.2% and 53.4%, 73.1% and 72.1%, 92.4% and 87%, 88.9% and 81.8%, respectively. Multivariate analyses indicated that T stage (P = 0.001) appeared to be prognostic factors for OS. T stage (P = 0.001 and P = 0.002) and neck lymph node necrosis (P = 0.015 and P = 0.045) were independent predictors of PFS and DMFS. The acute toxicities were mainly grade 1/2 hematologic toxicities in patients treated with IC+IMRT+AC, and severe toxicities were uncommon. CONCLUSIONS: IC followed by IMRT and AC achieved satisfactory long-term survival outcomes in NPC patients with N3 disease. Neck lymph node necrosis and late T stage served as predictors of poor prognosis for patients.

Metallic Oxide-Induced Self-Assembly of Block Copolymers to Form Polymeric Hybrid Micelles with Tunable Stability for Tumor Microenvironment-Responsive Drug Delivery.

Since block copolymers are able to self-assemble into various polymeric architectures, it is intriguing to explore a unique self-assembly strategy for polymers. Two different metallic oxides [manganese dioxide (MnO2) and zinc oxide (ZnO)] are displayed herein to demonstrate this self-assembly mechanism of polymers. In situ generation of metallic oxides induces self-assembly of block copolymers to form polymeric hybrid micelles with tunable stability in aqueous solutions. These final ZnO-cross-linked polymeric micelles exhibited a high drug loading capacity of 0.41 mg mg-1 toward doxorubicin (DOX), whereas DOX-loaded ZnO-cross-linked polymeric micelles could be broken down into Zn2+ and polymer scraps, which facilitated drug release in tumor microenvironments. Both in vitro and in vivo investigations showed that the drug-loaded ZnO-cross-linked polymeric micelles effectively suppressed tumor growth. Accordingly, the present study demonstrates a novel strategy of polymer self-assembly for fabricating polymeric architectures that can potentially provide insight for developing other polymeric architectures.

Computer-aided design of PVR mutants with enhanced binding affinity to TIGIT.

BACKGROUND: TIGIT, as a novel immune checkpoint molecule involved in T cell and NK cell anergy, could induce the immune tolerance and escape through binding with its ligand PVR. Blockade of TIGIT/PVR is considered as a promising strategy in cancer immunotherapy. However, to facilitate the design of inhibitors targeting TIGIT/PVR, the structural characteristics and binding mechanism still need to be further studied. METHODS: In this study, molecular dynamics (MD) simulations and in silico mutagenesis were used to analyze the interaction between TIGIT and its ligand PVR. Then, PVR mutants were designed and their activities were determined by using TIGIT overexpressed Jurkat cells. RESULTS: The results suggested that the loops of PVR (CC' loop, C'C″ loop, and FG loop) underwent a large intra-molecular rearrangement, and more hydrogen bond crosslinking between PVR and TIGIT were formed during MD simulations. The potential residues for PVR to interact with TIGIT were identified and utilized to predict high affinity PVR mutants. Through the biological activity evaluation, four PVR mutants (PVRS72W, PVRS72R, PVRG131V and PVRS132Q) with enhanced affinity to TIGIT were discovered, which could elicit more potent inhibitory effects compared with the wild type PVR. CONCLUSIONS: The MD simulations analysis provided new insights into the TIGIT/PVR interaction model, and the identified PVR mutants (PVRS72W, PVRS72R, PVRG131V and PVRS132Q) could serve as new candidates for immunotherapy to block TIGIT/PVR. Video Abstract.

Is nasopharyngeal carcinoma in young patients a distinct clinical entity? A single-institution case matched analysis in the era of intensity-modulated radiotherapy.

OBJECTIVES: To compare the treatment outcomes between young and adult patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: We conducted a retrospective case-matched analysis of all patients with non-metastatic NPC ≤20 years treated in our institution between January 2010 and July 2016. Adult patients ≥35 years treated over the same time period were included and matched at a ratio of 1:1 according to N classification, T classification, treatment modality, year of diagnosis, and gender. Survival outcomes and late toxicities were compared between the two groups. RESULTS: Overall 112 young patients with NPC were included, and 112 out of 3105 consecutive patients with NPC aged ≥35 years were matched. The 5-year overall survival (OS), progression-free survival, locoregional control and distant control of young and control cohorts were 89.1% vs. 79.3% (p = 0.03), 80.3% vs. 67.0% (p = 0.02), 96.4% vs. 84.3% (p < 0.01), and 82.9% vs. 82.8% (p = 0.94), respectively. Multi-variate analysis showed that age ≤20 years was the only significant factor predicting for better OS (HR = 0.5, CI 0.3-0.97, p = 0.04). A trend of higher rate of hypothyroidism (grade 1-2) was observed in the young cohort (67.9% vs. 46.2%, p = 0.08). CONCLUSION: Young patients with NPC treated with modern multimodality therapy have better survival outcomes. Age was an independent favorable prognostic factor for NPC in the IMRT era. Further prospective studies are needed to establish optimal management for the young population to minimize and manage long-term side-effects without compromising survival.

Dynamic Changes in Cognitive Function in Patients With Radiation-Induced Temporal Lobe Necrosis After IMRT for Nasopharyngeal Cancer.

Purpose: Radiation-induced temporal lobe necrosis (TLN) was once regarded as a progressive and irreversible disease in the era of two-dimensional radiotherapy. However, in the era of intensity-modulated radiotherapy (IMRT), the long-term development process of TLN remains unknown. We performed a prospective study to evaluate the dynamic changes in cognitive function in patients with TLN after definitive IMRT for nasopharyngeal carcinoma (NPC). Methods: The enrollment criteria were as follows: (1) patients must have had confirmed NPC and must have received only one course of definitive IMRT; (2) patients radiologically diagnosed with TLN during follow-up; (3) patients with TLN who had not undergone surgical resection; and (4) patients with TLN with a follow-up period of more than 2 years. Cognitive function was measured with the mini-mental state examination (MMSE) at an interval of every 3 months. Changes in the size of the necrotic mass in the temporal lobe were evaluated by magnetic resonance imaging. The treatment interventions included the wait-and-see policy or the administration of nerve growth factor (NGF) combined with pulsed steroids. Results: From January 2008 to December 2017, 86 patients with TLN entered this study. With a median follow-up of 32 months (26-50 months), 60 patients (70%) showed normal cognitive function as quantified by MMSE scores (≥27). Twenty-six patients (30%) demonstrated obvious cognitive impairment (MMSE scores ≤ 26) during follow-up. However, after receiving NGF combined with pulsed steroids, cognitive function improved significantly, and 21 of 26 patients demonstrated recovery to normal levels. Magnetic resonance imaging studies demonstrated that 10 patients had a complete response (CR), 13 had a partial response, and 3 had stable disease. Conclusions: In the IMRT era, TLN is not always a progressive disease. Most patients remain stable both in their cognitive function and in the size of the necrotic mass. For patients with progressive TLN, active intervention with the administration of NGF and pulsed steroids not only can improve cognitive function but also can decrease the size of the necrotic mass.

Radiotherapy in the treatment of primary or recurrent unresectable desmoid tumors of the neck.

Purpose: Desmoid tumors are locally aggressive nonmalignant soft tissue tumors, which frequently recur after therapy. The optimal treatment is still controversial because of the lack of large research. A few studies have reported the effects of other treatments in one lesion when surgery is not possible or would cause notable functional impairment. Our aim was to examine the outcome of radiotherapy (RT) in the treatment of primary or recurrent unresectable desmoid tumors of the neck. Materials: A retrospective analysis was performed on 30 patients between 1/2008 and 12/2017, with 3 primary and 27 recurrent unresectable desmoid tumors of the neck. All cases were reviewed by pathologists. Results: The median follow-up time was 50.5 months (range 2-126 months). Radiotherapy doses varied from 50 to 66 Gy (median 60 Gy, 23/30 patients) with all fraction size of 2 Gy. The objective response rate (ORR: CR or PR) to definitive RT was 56.7% (17/30 patients). On Chi-square statistic, ORR was significantly influenced by tumor size (≤5 cm versus >5 cm) (p = .046). Age (≤ 40 versus >40 years) (p = .804), gender (p = .629), and RT dose (≤60 versus >60 Gy) (p = .613) were not significantly associated with ORR. The most common acute side effects of the radiation-related complication were grade 1-2 skin toxicities. Conclusion: Radiotherapy is a valuable option in the management of primary or recurrent unresectable DTs of the neck with good local control. Multi-institutional and prospective studies are warranted to further validate our findings.