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Radiation and immunotherapy combined-induced myocardial injury has potentially related to CD8+ T cells, but the mechanism is unclear. This study aims to explore the effects of on the expression of PD-L1 in cardiomyocytes and its role in the occurrence of myocardial injury induced by radiation and anti-programmed death-1 (PD-1) antibody combined. Human ventricular cardiomyocytes (AC16) were irradiated at varying doses and time points, and PD-L1 levels were assessed using flow cytometry, real-time qPCR, Western blot, and immunofluorescence staining. A cell counting kit cell viability assay, flow cytometry apoptosis, and ELISA detection were performed on AC16 cells before and after radiation. Subsequently, siRNA knockdown of PD-L1 was used to verify its role in radiation-induced myocardial injury. Then, simulation of radiation and PD-1 antibody-induced myocardial injury was conducted in vitro. Activated and inactivated human CD8+ T cells were prepared and co-cultured with cardiomyocytes, with or without PD-L1 knockdown, before and after radiation with PD-1 antibody, the vitality of cardiomyocytes in each group was detected by a cell counting kit, and the expression of PD-1, IFN-γ, and granzyme B of co-culture CD8+ T cells were detected by flow cytometry and ELISA, respectively. 10Gy radiation significantly upregulated PD-L1 expression in AC16 cells in a time-dependent manner (p<0.001), while PD-L2 expression was not significantly expressed. and PD-L1 was enriched in the nucleus after 72h of radiation. Following radiation, AC16 cells viability decreased, apoptosis increased, and the expression of IL-6, CCL5, and CXCL10 increased, while IL-10 expression decreased. siRNA knockdown of PD-L1 had no significant effect on the viability and apoptosis (P > 0.05), but significantly upregulated the expression of IL-6, CCL5, CXCL10 (p<0.0001), suggesting the chemotaxis of CD8+ T cells had enhanced. Co-culture of activated and inactivated CD8+ T cells with AC16 cells before and after radiation therapy showed that the cytotoxicity of the activated group was significantly higher than that of the inactivated group. The co-culture of activated CD8+ T cells with AC16 cells demonstrated that AC16 cell vitality was lowest in the combined group, followed by the single radiation therapy group, then the single PD-1 antibody group, and all were lower than the normal co-culture group (p < 0.01). SiPD-L1 co-culture revealed that the PD-L1 knockdown group exhibited lower vitality than the control group, regardless of radiation (p < 0.01). Additionally, PD-1, IFN-γ, and granzyme B expression in CD8+ T cells was higher in the co-culture radiation group compared to the non-radiation and control CD8+ T cell groups. Radiation increases PD-L1 expression in ventricular cardiomyocytes AC16, enhancing CD8+ T cell chemotaxis. The exacerbation of myocardial injury in combined radiation and PD-1 antibody treatment may be due to PD-1/PD-L1 pathway blockade and upregulation of CD8+ T cell function. [ABSTRACT FROM AUTHOR]

PD-1/PD-L1 inhibitors combined with chemotherapy have been established as the standard first-line options in metastatic non-small cell lung cancer (NSCLC). Consolidative thoracic radiotherapy (cTRT) after systematic therapy significantly improved patient survival and was widely used in clinical practice in the pre-immunotherapy era. However, whether cTRT following first-line chemoimmunotherapy can improve patient outcome is still controversial. More importantly, the subpopulation who can benefit from cTRT is unknown. Metastatic NSCLC patients who received first-line chemoimmunotherapy with or without subsequent cTRT from three cancer centers were retrospectively enrolled in the real-world study. Based on PD-L1 expression, they were further divided into three groups: PD-L1 negative (TPS score＜1%), PD-L1 low (TPS score 1-49%), and PD-L1 high (TPS score≥50%) groups. Propensity score matching (PSM) with a 1:1:1 ratio was applied in three groups. The efficacy and safety were evaluated. A total of 424 patients were included, with 333 and 91 and patients in cTRT and no cTRT groups, respectively. Compared with patients in no cTRT group, those in cTRT group showed significantly improved median progression-free survival (mPFS) (15.8 months vs 12.2 months, P = 0.002) and overall survival (mOS) (NA vs 27.73-month, P = 0.023). After PSM, a total of 30 pairs of patients were enrolled in PD-L1 negative group, 29 pairs in PD-L1 low group, and 32 pairs in PD-L1 high group. For patients with negative PD-L1 expression, cTRT markedly prolonged PFS (median: 14.72 months vs 9.56 months, P = 0.008), and numerically improved OS (median: 30.06 months vs 21.09 months, P = 0.21). In those with low PD-L1 expression, cTRT significantly improved both PFS (median: 16.59 months vs 12.32 months, P = 0.042) and OS (median: NA vs 24.97 months, P = 0.034). However, in patients with high PD-L1 expression, no significant PFS (median: 18.81 months vs 15.8 months, P = 0.913) and OS (P = 0.892) differences were observed between cTRT and no cTRT groups. Further analysis on adverse events (AEs) revealed that patients receiving cTRT or not showed comparable AE occurrence. However, for those with high PD-L1 expression, cTRT generated higher rate of grade III-V pneumonia compared with no cTRT (18.8% vs. 3.1%). cTRT following first-line chemoimmunotherapy prolongs PFS and OS in patients with negative and low PD-L1 expression. In those with high PD-L1 expression, cTRT cannot bring survival benefit which might due to increased pneumonia occurrence. [ABSTRACT FROM AUTHOR]

For locally advanced rectal cancer (LARC), previous STELLAR study has shown that a new total neoadjuvant therapy (TNT) paradigm of short-course radiotherapy (SCRT) followed by chemotherapy can achieve higher complete response (CR) rate compared to standard chemoradiotherapy (CRT), meanwhile, the 3-year DFS is not inferior to CRT. Recent studies have shown that, PD-1/PD-L1 inhibitors may improve the complete response of LARC and have strong synergistic potential with radiotherapy, especially hypo-fractionated mode. Thus, the STELLAR II trial aims to investigate whether SCRT-based TNT combined with PD-1 inhibitor could further improve prognosis. The outcomes of the initial 100 enrolled patients are presented. This is a prospective, multicenter, two-arm randomized controlled, seamless phase II/III trial for pMMR/MSS LARC. Patients will receive the TNT regimen and be randomly assigned to two groups: the iTNT group and the TNT group. Patients in both groups will receive SCRT (25 Gy/5 fx) followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX, with the iTNT group receiving the same chemotherapy in combination with Sintilimab. TME surgery or W&W strategy will be performed after neoadjuvant therapy and then 2 cycles of same regimen as before are recommended. The primary endpoints are the complete response (CR) rate for phase II trial and 3-year DFS for phase III trial. The initial 100 patients enrolled from 10 hospitals were analyzed for tolerability and toxicity as planned, of which 54 and 46 patients are in the iTNT and TNT groups, respectively. 75% of the patients were men and the median age was 69 years (range = 21-73). Most of them had T3-4 (97%), N1-2 (92%) and lower location (79%) tumors, with half of MRF+ (50%) and EMVI+ (51%). 2 patients withdrew before treatment. 98 patients completed SCRT, and the 4-cycle chemotherapy ± Sintilimab completion rates were 83.3% and 95.5% in the iTNT and TNT groups, respectively. In the iTNT group, 7 patients did not receive immunotherapy, 5.6%, 9.3% and 72.2% received 2, 3 and 4 cycles of PD-1 inhibitor respectively. The rates of grade 3-5 toxicities were 33.3% in the iTNT group versus 20.5% in the TNT group, and thrombocytopenia was the most common in both groups. A total of 13.5% irAEs were observed, including 3 grade 3 cases. 7 patients in each group achieved cCR and opted for W&W strategy. The pCR rates and CR rates were 40.0% (12/30) versus 18.8% (6/32) and 40.4% versus 31.0% in the iTNT and TNT groups, respectively. This trial is a head-to-head, SCRT-based study that can definitively explore the value and toxicity of PD-1 inhibitors combined with TNT for LARC. The acute toxicity was tolerable from the initial results, and the iTNT group showed a surprising CR rate to look forward to. Clinical trial information: NCT05484024. [ABSTRACT FROM AUTHOR]

The inefficacy of PD-1/PD-L1 monotherapy in glioblastoma (GBM) underscores the necessity for enhanced therapeutic strategies. This study hypothesizes that precise, real-time monitoring of PD-L1 expression using a novel peptide-based immuno-PET/CT tracer, [18F]AlF-PCP2, could optimize the timing and effectiveness of radioimmunotherapy. [18F]AlF-PCP2 was synthesized and characterized for its binding affinity to PD-L1 using surface plasmon resonance (SPR). Its specificity and uptake were evaluated in vitro and in vivo in various GBM cell lines and orthotopic xenograft models. The tracer's effectiveness in detecting PD-L1 expression changes post-radiotherapy (RT) treatment was assessed, along with its potential in identifying candidates for combination immunotherapy. In vitro and in vivo, [18F]AlF-PCP2 exhibited specific, high-affinity binding to PD-L1, with a binding constant (K D) of 0.24 nM. PET/CT imaging in the orthotopic U251MG model revealed a significant accumulation of [18F]AlF-PCP2 in tumors (9.51 ± 0.4%ID/cc), correlating with blood-brain barrier disruption as observed in Gd-DTPA-enhanced MRI. However, there was a 5.56 ± 0.03% decrease in uptake compared to subcutaneous tumors. Remarkably, after 15 Gy of RT, [18F]AlF-PCP2 uptake in tumors increased to 12.04 ± 1.43%ID/cc from 9.51 ± 0.73%ID/cc in controls, indicating enhanced PD-L1 expression consistent with immunohistochemistry findings. Fractionated RT (5 Gy × 3 fractions) further amplified PD-L1 upregulation (13.9 ± 1.54 %ID/cc) compared to a single dose (11.48 ± 1.05 %ID/cc). Identifying mice with significant PD-L1 upregulation after RT (IFN-γ intervention) and then recruiting them to receive combination anti-PD-L1 therapy improved survival (P = 0.0279). [18F]AlF-PCP2 immuno-PET/CT enables precise, non-invasive monitoring of PD-L1 expression dynamics in glioblastoma post-radiation, offering a strategic advantage in optimizing radioimmunotherapy. This study's findings suggest that patients with early PD-L1 upregulation during radiotherapy could benefit significantly from subsequent anti-PD-L1 therapy, underlining the importance of tailored treatment strategies. [ABSTRACT FROM AUTHOR]

Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC). KRAS G12C , the most frequent KRAS variant, is found in ∼13% of patients (pts) with NSCLC. KRAS is a GTPase that regulates cell signaling pathways necessary for proliferation, differentiation, and survival. KRAS mutation reduces the intrinsic GTPase activity of the enzyme, allowing for the accumulation of active, GTP-bound KRAS and hyperactivation of downstream signaling, driving tumorigenesis. JDQ443 is a potent, selective KRASG12C inhibitor that irreversibly traps KRASG12C in its inactive, GDP bound state and blocks downstream signaling. In preliminary data from the Phase Ib part of the KontRASt-01 study (NCT04699188), JDQ443 showed promising antitumor activity and an acceptable safety profile in previously treated pts with KRAS G12C -mutated advanced NSCLC. Pts with KRAS G12C -mutated NSCLC currently receive the same first-line (1L) treatment as those without driver mutations, consisting of immunotherapy alone or combined with chemotherapy; however, ∼30% of pts with NSCLC present with programmed death-ligand 1 (PD-L1) expression <1%, and ∼10-20% of pts harbor an STK11 mutation, both indicators of poor response to immunotherapy. Therefore, alternative 1L treatment options are needed for these pts. Of note, PD-L1 expression and STK11 mutation do not affect responsiveness to KRASG12C inhibitors, raising interest in the evaluation of these targeted therapies as 1L alternatives to immunotherapy for pts with KRAS G12C -mutated NSCLC. KontRASt-06 (NCT05445843) is an open-label, Phase II, single-arm, multicenter study evaluating JDQ443 monotherapy (200 mg JDQ443 twice daily in 21-day cycles) as a 1L treatment for two cohorts of adult pts with locally advanced or metastatic, KRAS G12C -mutated NSCLC. Cohort A (n = 90) includes pts whose tumors have PD-L1 expression <1%, regardless of STK11 mutation status, while Cohort B (n = 30) includes pts whose tumors have PD-L1 expression ≥1% and an STK11 co-mutation. Local testing for PD-L1 status and KRAS and STK11 mutations is accepted; KRAS and STK11 mutations may be assessed in blood samples. A tissue sample is required for retrospective biomarker status confirmation and exploratory study. The study is currently enrolling pts into both cohorts. The primary endpoint is the overall response rate (ORR) per RECIST version 1.1, assessed by a blinded independent review committee, in Cohort A. Key secondary endpoints are ORR in Cohort B and duration of response in both cohorts. Other secondary endpoints include progression-free survival, overall survival, safety, pharmacokinetics, and pt-reported outcomes. A comprehensive biomarker strategy aims to investigate predictors of treatment response and resistance in the study population. TBD TBD [ABSTRACT FROM AUTHOR]

To investigate efficacy and safety of PD-1/PD-L1 inhibitors plus radiotherapy in patients that brain metastases (BMs) from non-small cell lung cancer (NSCLC). All 234 eligible patients were divided into PD-1/PD-L1 inhibitors plus intracranial radiotherapy (BM-RT) group and immunotherapy (non-BM-RT) group. 144 patients in BM-RT group were divided into patients received extracranial radiotherapy for NSCLC (extra-RT) group and had not (non-extra-RT) group. According to the Lung Immune Prognostic Index (LIPI), patients were stratified into good, intermediate, and poor groups. The toxicity was assessed with Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Kaplan-Meier method and Log-rank test were used to analyze intracranial progression-free survival (iPFS) and overall survival (OS). The median iPFS (11.6 months vs. 9.9 months, P = 0.001) and median OS (17.3 months vs. 14.6 months, P = 0.029) had a significant difference in BM-RT group and non-BM-RT group. Meanwhile, median iPFS (15.7 months vs. 10.5 months, P <0.001) and median OS (20.2 months vs. 15.1 months, P = 0.024) in extra-RT group were longer than non-extra-RT group. The median iPFS (12.9 months vs. 10.4 vs. 8.4 months, P = 0.001) and median OS (20.1 months vs. 16.7 months vs. 12.6 months, P = 0.025) were longer in good group than intermediate group and poor group in LIPI. Our data suggested there was a significant difference in iPFS and OS with or without radiotherapy in patients of BMs from NSCLC, and with safety profiles. LIPI helped predict prognosis of BMs in NSCLC. [ABSTRACT FROM AUTHOR]

With the extensive use of PD-1/PD-L1 inhibitor, more patients with advanced solid tumors obtain tumor regression and long-term survival. Despite the characteristic durability of response to PD-1/PD-L1 inhibitor, unfortunately some patients may develop acquired resistance after an initial response. Finding an effective treatment to rescue with resistance of PD-1/PD-L1 inhibitor has been an urgent problem. The PRaG trial as a salvage therapy in advanced solid tumors has obtained satisfactory results. With great surprise we found that patients with PD-1/PD-L1 inhibitors acquired resistance are more likely to benefit from the PRaG regimens (PD-1 inhibitors combined with radiotherapy and GM-CSF with or not IL-2). This is the PRaG regimen rechallenge that could represent an attractive option in advanced solid tumors. We retrospectively analyzed the clinical efficacy and safety of PRaG regimen rechallenge to treat immunotherapy-refractory advanced solid tumors. A total of 15 patients who showed initial resistance to PD-1/PD-L1 inhibitor were retrospectively collected from PRaG serial trails. They received stereotactic body radiation therapy or hypofractionated radiotherapy (2-3 doses of 5-8Gy) to a target metastatic site, PD-1 inhibitor was dosing within one week after completion of radiotherapy, and GM-CSF subcutaneous (SC) injection once daily for 14 days after radiotherapy (the PRaG 2.0 regimen, GM-CSF 200µg SC d1-7, sequentially IL-2 2million IU d8-14.). Pooled analysis of response rate (ORR), median progression-free survival (mPFS), and treatment-related adverse events were calculated. By February 2022, a total of 15 multi-metastatic patients were examined. Thirteen patients showed acquired resistance and underwent first-time assessment, involving in lung cancer, renal cancer, liver cancer, colon cancer and sarcoma. The ORR was 18.2%, and the disease control rate (DCR) was 90.9%. The mPFS was 9.03 months (95%CI, 1.5 to 16.5 months). One lung cancer achieved complete remission, with PFS over 17 months. Treatment-related adverse events of any grade occurred in 11 of 15(73.3%) patients. While there was no grade 3 or higher adverse events. Our preliminary results suggested that PRaG regimens rechallenge was an active and feasible strategy in PD-1/PD-L1 inhibitors acquired resistance. The therapy was well tolerated with acceptable toxicity. A III phase prospective study is in the plan to clarify the role of rechallenge after acquired resistance. The PRaG trial was registered in chictr.org.cn (No. ChiCTR1900020175) and the PRaG 2.0 trial was registered at www.clinicaltrials.gov (No. NCT04892498). [ABSTRACT FROM AUTHOR]

The molecular detection and tumor microenvironment research give insights into the mechanism of cancer initiation and progression. Meanwhile, the progress of anticancer therapy tends to focusing on pan-cancer analysis, targeted therapy and immunotherapy. Evidence has shown that radiotherapy can induce a systemic anti-tumor immune response, which may potentially sensitize PD-1/PD-L1 inhibitors. Previous phase II trial showed that radiotherapy combined with PD-1 inhibitor and GM-CSF (PRaG regimen) has obtained promising results. RC48-ADC is a novel HER2-targeting antibody-drug conjugate (ADC). Preclinical studies indicated that ADC elicit immunogenic cell death and selectively radiosensitize to tumors. An exploratory multi-center, single-arm phase II trial was conducted to assess the initial clinical efficacy and safety of PRaG3.0 regimen (RC48-ADC combined with radiotherapy, PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2) for treatment of HER2-expressing pan-cancer. Patients with advanced, confirmed HER2-expressing (IHC3+, 2+ or 1+) solid tumors that had progressed after the standard of care or intolerance were enrolled. In the cycle, those received RC48-ADC (2.0 mg/kg d1), then stereotactic body radiation therapy or hypofractionated radiotherapy (2-3 doses of 5-8Gy) was delivered for one metastatic lesion every other day, followed by GM-CSF (200μg d3-7), sequential IL-2(2million IU d8-12), and PD-1/PD-L1 inhibitor was dosing within one week after completion of radiotherapy. PRaG3.0 regimen was repeated every 3 weeks for at least 2 cycles. After RC48-ADC combined with PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 for at least 6 cycles, then maintenance with PD-1/PD-L1 inhibitor was administered until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). By February 2022, a total of 8 patients were enrolled. The median number of metastatic lesions was 5.0 (95%CI, 3.0 to 14.0). Six patients had at least one tumor assessment, involved gastric cancer, breast cancer, cervical cancer, pancreatic cancer. The most common treatment-related adverse events were alopecia (37.5%), fatigue (25.0%), hepatic damage (25.0%) and rash (25.0%). No Grade 3 and higher adverse events occurred. The ORR was 66.7% and disease control rate was 83.3% (RECIST 1.1). One cervical cancer and one pancreatic cancer achieved complete remission. The PRaG3.0 regimen is tolerated with acceptable toxicity. Our data suggest the PRaG3.0 regimen further improve the synergistic antitumor effects; this precise paradigm may provide a promising salvage treatment of HER2-expressing advanced solid tumors. This trial is registered with ClinicalTrials.gov, No. NCT05115500. [ABSTRACT FROM AUTHOR]

To determine the clinical significance of serum soluble (s)PD-1 and sPD-L1 in hepatocellular carcinoma (HCC) received radiotherapy (RT). In cohort 1, 144 HCC patients treated with liver RT were obtained from a prospectively collected database. Blood samples were collected 1 day before and 2 weeks after RT. In cohort 2, formalin-fixed paraffin-embedded samples were obtained from 46 patients with HCC, among whom 23 received preoperative RT and the other 23 received direct surgery. The relationship of sPD-1/sPD-L1 in serum or PD-L1 expression in tumor tissues and clinicopathological features were evaluated. In cohort 1, patients with tumor thrombosis (p = 0.01) and advanced stage (p = 0.00) had significantly higher serum sPD-L1 concentrations. Higher sPD-L1 level was negative predictor of progression-free survival (PFS) (HR = 1.53, p= 0.042). In addition, RT significantly increased the expression of sPD-L1 (p = 0.000), which negatively associated with content of serum CD8+ T cells (R = -0.24, p = 0.033). Moreover, no significant associations were found between clinicopathological features and sPD-1. In cohort 2, we confirmed the phenomenon that RT could increase the expression of PD-L1 in tumor tissues (p = 0.001) and the expression level of PD-L1 in tumor tissues was related to decreased cytotoxic T-cell infiltration and a trend of poor prognosis. High PD-L1 expression was associated with poor prognoses in HCC treated with RT. The increases in PD-L1 induced by RT indicated the combined treatment with RT and immune therapy may be promising strategy for HCC. [ABSTRACT FROM AUTHOR]