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We investigated whether uptake of 18F-AlF-NOTA-FAPI-04 on positron emission tomography/computed tomography (PET/CT) could predict treatment response and survival in patients with pancreatic adenocarcinoma (PAAD). We prospectively evaluated 47 patients with histopathologically confirmed primary PAAD and pretreatment 18F-FAPI PET/CT scans to determine uptake of fibroblast activation protein (FAP) and compare the findings with those from blood tests and immunohistochemically stained tumor specimens. Cox regression and Kaplan-Meier methods were used to assess relationships between disease progression and potential predictors. Receiver operating characteristic (ROC) curve analysis was used to define the optimal cutoff points for distinguishing patients according to good response vs poor response per RECIST v. 1.1. The FAPI PET variables maximum and mean standardized uptake values (SUV max , SUV mean); metabolic tumor volume (MTV); and total lesion FAP expression (TLF) were positively correlated with cancer-associated fibroblast (CAF) markers (FAP, α-smooth muscle actin, vimentin, S100A4, and platelet-derived growth factor receptor α/β, all P <0.05). MTV and Log2 TLF were associated with survival in patients with inoperable PAAD (all P <0.05). Analyses controlling for sex, age, cTNM, and performance status showed that MTV and Log2 TLF were associated with overall survival (MTV hazard ratio [HR] = 1.016, P = 0.016 and Log2 TLF HR = 4.093, P = 0.003). ROC cutoff analysis indicated that elevated MTV and TLF were associated with poorer survival. Greater changes from before to after chemotherapy in SUV max , MTV, and TLF were associated with good treatment response (all P <0.05). ΔMTV, ΔTLF and ΔSUV max had larger areas under the curve than ΔCA19-9 for predicting treatment response. Kaplan-Meier analysis showed that the extent of change in MTV and TLF from before to after treatment predicted progression-free survival, with cutoff values (based on medians) of –4.95 for ΔMTV (HR = 8.09, P = 0.013) and –77.83 for ΔTLF (HR = 4.62, P = 0.012). Higher baseline MTV on 18F-FAPI-04 PET/CT scans was associated with poorer survival in patients with inoperable PAAD. ΔMTV was more sensitive for predicting response than ΔCA19-9. These results are clinically meaningful for identifying patients with PAAD who are at high risk of disease progression. [ABSTRACT FROM AUTHOR]

Tumor-associated fibroblasts (CAF) are expressed in tumor stroma and play an important role in tumor proliferation, invasion, metastasis and drug resistance. Fibroblast activating protein inhibitor (FAPI) is a new type of PET tracer, which can be used to evaluate the expression of FAP in CAF. We aimed to explore whether biological distribution of [18F]Alf-NOTA-FAPI-04-positron emission tomography/computed tomography (PET/CT) reflected the expression of CAF related markers and immune markers in cancer tissues based on pathology. The study included 20 patients with rectal cancer who underwent [18F] AlF-NOTAFAPI-04PET/CT scans 3 days before surgery. The following FAPI uptake variables were generated using nuclear medicine information system: maximum standardized uptake value [SUVmax], SUVpeak, SUVmean, and total lesion glycolysis (TLG). The tumor specimens were stained with immunohistochemistry after operation, including CAF related markers, FAP, S100A4, Vimentin, PDGFRα/β and α-SMA as well as including immune markers, CD8 and CD163. FAPI uptake variables including SUVmax, SUVmean, SUVpeak, TLG were positively correlated with FAP (all p < 0.05), α-SMA (all p < 0. 05), Vimentin (all p < 0. 05), S100A4 (all p < 0.05) and PDGFRα/β, all p < 0.001). FAPI uptake variables were negatively correlated with CD8 (all P < 0.05) and CD163 (all p < 0.05). There were significant differences between T stages and SUVmax as well as SUVmean (all p < 0.05). [18F] AlF-NOTAFAPI-04PET/CT uptake variables can reflect the expression of CAF-related markers and correlated with immune markers, which may have the potential to identify high-risk patients for early intensifying treatment and identify patients for receiving immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Identifying suspicious cancer metastasized lymph nodes (GTV is an essential task in esophageal cancer radiotherapy. Manual delineation requires high-level sophisticated clinical reasoning in multi-modality imaging, which is challenging and suffers from high subjectivity and inter-observer variability. We propose an automated esophageal GTV_LN detection method via integrating a distance-based decision stratification into a multi-task deep network, which is able to effectively learn the GTV_LN oncology features. This is inspired by the fact that lymph node involvements often follow certain distance patterns from the primary tumors.Materials/methods: We collected and curated 2 esophageal cancer datasets with PET and RTCT images. The 1st dataset contained 141 patients and 651 annotated GTV_LN for training and evaluating our deep network (60%, 10% and 30% for training, validation and testing), while the 2nd dataset contained 10 patients aiming for the multi-user agreement analysis. A distance-based decision stratification is designed to divide GTV_LN into "tumor-proximal" and "tumor-distal" categories and a multi-branch deep network is proposed to solve each of them. The multi-branch network has a shared encoder and separate decoders to detect and segment two GTV_LN subcategories, respectively. The distance-based decision stratification enables the automated multi-branch method to specialize in GTV_LN oncology features of each subcategory. We use both PET and RTCT as the network inputs to exploit the complementary information in each imaging modality.Results: In the testing set of the 1st esophageal cancer dataset (34 patients with 138 GTV_LNs), our method achieves a sensitivity of 73.8% and 79.1% at 6 and 12 false positives (FPs) per patient as compared to 72.0% and 75.9% by MULAN, the state-of-the-art deep learning based universal lesion detection algorithm. On the 2nd dataset containing 10 patients, 3 radiation oncologists annotated 53 GTV_LNs in total, among which 42 GTV_LNs were agreed with all 3 physicians leading to 79.2% multi-user agreement. Our method achieves a sensitivity of 77.4% at 6 FPs per patient on the 2nd dataset. This shows that the sensitivity achieved by our automated deep learning approach can be close to the multi-user agreement.Conclusion: We proposed a multi-task deep learning method with distance-based decision stratification to effectively detect and segment the GTV_LN in esophageal cancer radiotherapy. It significantly improves on previous state-of-the-art and the achieved performance has potential clinical values considering the large multi-user variability in this challenging task. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase 1 (IDH1) mutations confer gain-of-function activity by converting α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG). IDH mutant tumors have fewer tumor-infiltrating CD8+ T cells and reduced PD-L1 expression compared with their wild type (WT) counterparts. In addition, 2-HG can directly inhibit the killing and proliferative functions of CD8+ T lymphocytes, and suggesting that 2-HG promotes an immunosuppressive TME. Several studies have shown that 2-HG can inhibit homologous recombination (HR) and weaken the DNA damage response (DDR), making them more sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors and radiotherapy (RT). At the same time, RT and PARP inhibition (PARPi) have been considered to be a new direction to stimulate antitumor immunity. Therefore, our study intends to use RT + PARPi to reverse the immunosuppressive microenvironment caused by IDH1 mutations, thereby promoting the therapeutic effect of immune checkpoint inhibitors. We compared the immune responses of clinical tissue samples and TCGA data from either IDH1 mut or IDH1 WT low-grade gliomas. We then established IDH1 mut-overexpressing MC38 and GL261 cell lines to determine the antitumor effect of RT + PARPi. Apoptosis and immunogenic death markers were detected by flow cytometry, western blot (WB) and ELISA in these cell lines. Tumor growth and mouse survival curves were observed in both an MC38 subcutaneous and GL261 orthotopic tumor model. Changes in the composition of the immune microenvironment were assessed using flow cytometry. The mechanisms underpinning these compositional shifts were then further interrogated using various techniques, including WB, immunofluorescence, qRT-PCR, CRISPR/Cas9, and CD8+ T cell migration experiments. We observed that CD8+ T cell infiltration and expression of the chemokines CXCL10 and CCL5 of CD8+ T cells in IDH1 mut tumors were significantly downregulated by immunohistochemistry and TCGA analysis. Gene enrichment analysis using the TCGA database found that IDH1 mutations downregulated interferon (IFN)-related signaling pathways. RT + PARPi induces more DNA damage and actives the CGAS-STING pathway compared with monotherapy, leading to more expression of IFN-β, CXCL10 and CCL5 at mRNA and protein level. In the MC38 subcutaneous tumor model, we found that RT + PARPi increased the infiltration of CD8+ T cells while enhancing the killing function of CD8+ T cells. We observed these same effects in the GL261 orthoma model, as well as increased proliferation function of CD8+ T cells. In addition, RT + PARPi increased the expression of PD-L1 and enhanced the therapeutic effect of immune checkpoint inhibitors. RT + PARPi reshapes the IDH1 mut tumor immune suppression microenvironment, thereby potentiating the antitumor effect and efficiency of immune checkpoint inhibitor. [ABSTRACT FROM AUTHOR]

Consolidation durvalumab has become the standard of care in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) without disease progression after concurrent chemoradiation therapy (cCRT) based on the PACIFIC study. However, there are still about 44% of patients experiencing disease progression or recurrence within one year. New regimens for consolidation treatment are worth exploring to further improve survival for this population. Tislelizumab, an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis (a potential mechanism of resistance), has shown improved efficacy in advanced NSCLC with a tolerable safety profile. Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (Tyro3, Axl, and Mer) and split tyrosine-kinase domain-containing receptors (VEGFR2, KIT), which may potentially augment immune checkpoint blockade through reducing the number of myeloid-derived suppressor cells/regulatory T cells and increasing the ratio of M1/M2 polarized macrophages. An early trial of tislelizumab plus sitravatinib showed acceptable tolerability and promising antitumor activity in advanced NSCLC. STELLAR (NCT05176925) is evaluating tislelizumab plus sitravatinib as consolidation treatment in patients with unresectable, locally advanced, stage III NSCLC after cCRT. This phase II, open-label, single-arm, prospective study is enrolling patients aged from 18-75 years with histologically/cytologically confirmed, locally advanced, unresectable, stage III NSCLC who have not progressed following definitive, platinum-based cCRT, and with ECOG PS of 0 or 1. Patients will be excluded if they have a mixed histological type of small cell lung cancer and NSCLC, or receive prior anti-VEGF mAb, VEGFR TKI or ICI therapy. Patients will receive tislelizumab (200 mg, IV, d1, Q3W) combined with sitravatinib (starting dose 70 mg, po, qd; escalating to 100 mg, qd, after 2 cycles) for up to 1 year until disease progression, intolerable toxicity, withdrawal of consent or death. The primary endpoint is 1-year progression-free survival (PFS) rate by investigator assessment per RECIST v1.1. Secondary end points are PFS, objective response rate, duration of response and disease control rate assessed by investigators per RECIST 1.1, overall survival, time to distant metastasis, and safety. AEs will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Enrollment begins in January 2022, and approximately 36 patients will be enrolled. N/A N/A [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Several PD-1/PD-L1 inhibitors have been approved, with or without chemotherapy, in advanced non-small cell lung cancer (NSCLC). However, the objective response rate (ORR) remains limited in unselected population. Accumulating data indicated that adding SBRT to PD-1/PD-L1inhibitors could improve treatment efficacy in NSCLC and the anti-tumor immune response induced by SBRT may be enhanced by GM-CSF, which plays a pivotal role in dendritic cell differentiation and maturation. Nevertheless, the safety and efficacy of triple combination of XX (a PD-1 inhibitor), SBRT and GM-CSF in advanced NSCLC remain unknown.Materials/methods: This is a prospective, multicenter, phase II study. Eligible patients (pts) were advanced EGFR/ALK negative NSCLC pts who had failed first-line standard chemotherapy. Pts received SBRT (8 Gy*3) to one lesion, followed by XX (200 mg d1, every 3 weeks) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 3 weeks after SBRT. XX would be given continuously until disease progression, unacceptable toxicity, or up to 35 cycles. To determine the tolerability of the triple combination therapy, a safety run-in phase was conducted in the first 20 enrolled pts by monitoring the dose-limiting toxicities (DLTs). Primary end point is ORR. Secondary end points are safety, out-of-field response rate, overall survival (OS), progression free survival (PFS). Here, we report the preliminary results of the safety run-in phase.Results: From 2019/10/16 to 2020/8/8, 20 pts were enrolled from 3 academic centers. The majority of pts were male, smoker, ECOG 1 and non-squamous NSCLC, with a median age of 61 (range, 32-71). Baseline brain, liver and bone metastasis were present in 2, 4 and 8 pts, respectively. All of the pts had more than 5 lesions at baseline, and the sites of SBRT included lung (n = 11), mediastinal lymph node (n = 5), liver (n = 1), abdominal lymph node (n = 1), pleural nodule (n = 1) and vertebra (n = 1). There were no DLTs. Treatment-related adverse event (TRAE) occurred in 18 pts. The most common TRAEs were fatigue (50%), fever (30%), and ostealgia (20%), and all were grade1. Only 2 grade 3 TRAEs were observed. 1 pt had G3 ALT and AST elevation, and the other experienced transient (recovered within 7 days) acute heart failure which was considered GM-CSF related. No grade 4 or 5 AE occurred. Median follow-up was 7.9 (range,1.6-16.5) months by data cut-off (2021/02/28). Partial response occurred in 7 and stable disease in 5 pts, the confirmed ORR was 35%. Median PFS was 6.9 (95% CI, 2.76-NA) months with 12 events and 1-year OS rate was 75.0% (95% CI, 58.2%-96.6%).Conclusion: Triple combination of XX, SBRT and GM-CSF is safe and shows promising efficacy as a novel second-line treatment for advanced EGFR/ALK negative NSCLC. The trial continues to recruit participants. [ABSTRACT FROM AUTHOR]