37 results on '"*PROGRAMMED death-ligand 1"'
Search Results
2. Phase II Trial Assessing Safety, Efficacy and Immune Correlates of Heterologous Prime-Boost with pBI-11 (IM) and TA-HPV (IM) Plus Pembrolizumab for Advanced, PD-L1 CPS≥1, hrHPV+ Oropharyngeal Cancer.
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Gibson, M., Savvides, P., Worden, F., Gopalakrishnan, R., Wu, T., Roden, R., Heimann-Nichols, E.K., and Chang, Y.N.
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OROPHARYNGEAL cancer , *HEAT shock proteins , *VIRAL antigens , *PROGRAMMED death-ligand 1 , *BIOMARKERS , *GENITAL warts , *MOVEMENT disorders - Abstract
HPV-related OPSCC occurs in younger patients, has a significantly better prognosis, and is most often caused by HPV subtype 16. There is a 90% overall survival for HPV+/p16+ OPSCC (40% for HPV-/p16- OPSCC), which can be cured with multimodality care. For patients with R/M disease, treatment with pembrolizumab (P) +/- chemotherapy is palliative, with a median OS of approximately 12 months for patients with PD-L1 combined positive score (cps) >1 treated with pembrolizumab (P) alone. Heterologous prime boost with DNA priming followed by vaccinia-based boosting against HPV16 viral antigens will be studied using the priming of pBI-11 DNA [pNGVL4a DNA construct encoding HPV16 E7(detox)/ HPV18 E7(detox)/HPV16 E6(detox)/HPV18 E6(detox) fusion protein linked to mycobacteria tuberculosis heat shock protein 70] followed by boosting of TA-HPV (recombinant vaccinia-human papillomavirus (denoted TA-HPV) derived from the Wyeth strain of vaccinia which carries modified E6 and E7 genes from HPV types 16 and 18). This study is approved by the Vanderbilt University IRB and is open (NCT NCT05799144). Additional sites will include the University of Michigan, Mayo Clinic Scottsdale and Mount Sinai Medical Center Miami Beach Patients with R/M, HPV positive OPSCC without prior therapy for R/M disease, without contraindications to immunotherapy and with a PD-L1 cps > 1 will be screened. There is a 6 patient safety run-in. Treatment with pBI-11 vaccine (2 IM injections on weeks 1 and 4) plus one IM administration of TA-HPV on week 7 will be given in combination with P IV on weeks 1, 4, and 7). Following restaging, all patients will continue (including those with PD) with 3 more cycles of P followed by restaging. The primary clinical outcome is RR to addition of vaccine in the 50% of predicted P non-responders (NR) who proceed to Part II (ie conversion to responders). All responders will continue to receive P until progression. Approximately 54 patients with be enrolled. Two research tumor biopsies and blood draws will be obtained pre- and on treatment (week7-9). Tumor tissue cores will be utilized for immunohistochemical and molecular tests (e.g., expression of immune cell and viral markers, TCR sequencing and total transcripts). Blood with be tested for HPV16/18 E6, E7 antibodies and vaccinia virus neutralizing antibodies; proliferative responses of peripheral blood lymphocytes to stimulation by HPV16/18 E6 and E7; HPV16/18 E6- and E7-Specific T cells; and HPV DNA in plasma. 2 patients enrolled. Accrual ongoing. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Zanzalintinib Plus Pembrolizumab Versus Pembrolizumab Alone In Patients with PD-L1 Positive Metastatic Head And Neck Squamous Cell Carcinoma (STELLAR-305): A Double-Blind, Randomized, Placebo-Controlled, Phase 2/3 Study.
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Saba, N.F., Harrington, K., Licitra, L., Machiels, J.P., Huang, M., Xu, F., Patel, P., and Haddad, R.I.
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SQUAMOUS cell carcinoma , *PROGRAMMED death-ligand 1 , *IMMUNOTHERAPY , *IMMUNE checkpoint inhibitors , *PEMBROLIZUMAB , *CANCER chemotherapy - Abstract
Pembrolizumab as monotherapy or in combination with chemotherapy is a standard of care in patients (pts) with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) and PD-L1 CPS ≥1. While pembrolizumab monotherapy results in low response rates, the addition of 5FU/cisplatin adds significant toxicity for pts. Rational combinations which improve outcomes while avoiding cytotoxic chemotherapy are needed. HNSCC is associated with overexpression of VEGFR, MET, and AXL, and there are preclinical data supporting the antitumor effect of inhibition of these kinases through suppressing tumor growth and angiogenesis, and promoting an immune-permissive tumor microenvironment. In a phase 2 study, pembrolizumab plus the multi-kinase inhibitor cabozantinib demonstrated encouraging clinical activity and safety in pts with R/M HNSCC (Saba et al. Nat Med 2023), suggesting that targeting kinases including VEGFR, MET, and AXL has antitumor effect in this population and may enhance responses to immune checkpoint inhibitor (ICIs). Zanzalintinib (XL092) is a novel, multi-targeted kinase inhibitor that inhibits VEGFR, MET, and the TAM kinases (TYRO3, AXL, MER). STELLAR-305 (NCT06082167) is a randomized, double-blind, phase 2/3 study that will evaluate the efficacy and safety of zanzalintinib plus pembrolizumab vs pembrolizumab plus placebo in pts with previously untreated, PD-L1-positive, R/M HNSCC. Eligible pts are aged ≥18 years and have histologically or cytologically confirmed R/M HNSCC that is incurable with local therapy and has not been treated with systemic therapy, unless completed >6 months before randomization and given as part of multimodal treatment for locally advanced disease. Pts must have a primary tumor location of the oropharynx (HPV testing required), oral cavity, hypopharynx, or larynx; pts with nasopharynx, salivary gland, or occult primary sites are excluded. Other eligibility criteria include a PD-L1 CPS ≥1; measurable disease per RECIST v1.1; and an ECOG performance status of 0–1. Prior treatment with ICIs or zanzalintinib is not allowed. Patients will be randomized 1:1 to either zanzalintinib plus pembrolizumab or placebo plus pembrolizumab. The dual primary endpoints are PFS per RECIST v1.1 by blinded independent radiology committee and overall survival. Secondary endpoints include safety, PFS per RECIST v1.1 by investigator, objective response rate, and duration of response. If minimum efficacy requirements are met in phase 2, the study will proceed to phase 3. In total, approximately 500 pts will be enrolled across phase 2 and 3. The study is ongoing with enrollment planned across sites in US, Europe, and the Asia-Pacific region. TBD TBD [ABSTRACT FROM AUTHOR]
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- 2024
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4. Prognostic and Predictive Role of PD-L1 Expression in Stage III Non-small Cell Lung Cancer Treated With Definitive Chemoradiation and Adjuvant Durvalumab.
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Bryant, Alex K., Sankar, Kamya, Strohbehn, Garth W., Zhao, Lili, Daniel, Victoria, Elliott, David, Ramnath, Nithya, and Green, Michael D.
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NON-small-cell lung carcinoma , *PROGRAMMED death-ligand 1 , *CHEMORADIOTHERAPY - Abstract
Purpose: It is unclear whether programmed death ligand 1 (PD-L1) expression is prognostic or predictive of immunotherapy benefit among patients with stage III non-small cell lung cancer (NSCLC) treated with definitive chemoradiation and adjuvant durvalumab.Methods and Materials: We determined pretreatment tumor PD-L1 expression for 312 patients with stage III NSCLC treated with definitive chemoradiation and at least 1 dose of adjuvant durvalumab between November 2017 and April 2021 across the national Veterans Health Administration. Progression-free survival (PFS) and overall survival (OS) in PD-L1 expression subgroups (<1%, 1%-49%, and 50%-100%) were compared with 994 patients with stage III NSCLC treated without adjuvant durvalumab from 2015 to 2016.Results: PD-L1 expression was <1%, 1% to 49%, and 50% to 100% in 109 (34.9%), 96 (30.7%), and 107 (34.3%) patients, respectively. Increasing PD-L1 expression was associated with longer PFS (adjusted hazard ratio [aHR], 0.84 per 25% absolute increase in expression; 95% confidence interval [CI], 0.75-0.94; P = .003) and OS (aHR, 0.86 per 25% absolute increase in expression; 95% CI, 0.74-0.99; P = .036). Compared with the no-durvalumab group, PFS was longer for PD-L1 50% to 100% (aHR, 0.44; 95% CI, 0.32-0.60; P < .001) and PD-L1 1% to 49% (aHR, 0.64; 95% CI, 0.47-0.86; P = .003) but not PD-L1 <1% (aHR, 0.84; 95% CI, 0.64-1.10; P = .19). Similar results were found for OS, with no significant difference between the no-durvalumab group and PD-L1 <1% (aHR, 0.81; 95% CI, 0.58-1.13; P = .22).Conclusions: Increasing tumor PD-L1 expression is prognostic for PFS and OS among patients with stage III NSCLC treated with adjuvant durvalumab, and patients with PD-L1 expression <1% may have limited benefit from adjuvant durvalumab. [ABSTRACT FROM AUTHOR]- Published
- 2022
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5. A Phase II Trial of JDQ443 in KRAS G12C-Mutated NSCLC with PD-L1 Expression <1% or PD-L1 Expression ≥1% and an STK11 Co-Mutation.
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Lindsay, C., Veluswamy, R., Junior, G. Castro, Tan, D.Y.H., Caparica, R., Glaser, S., Malhotra, S., Felip, E., and Chan, E.
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PROGRAMMED cell death 1 receptors , *RAS oncogenes , *PROGRAMMED death-ligand 1 , *NON-small-cell lung carcinoma - Abstract
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]
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- 2024
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6. Radiation Therapy Promotes Hepatocellular Carcinoma Immune Cloaking via PD-L1 Upregulation Induced by cGAS-STING Activation.
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Du, Shi-Suo, Chen, Gen-Wen, Yang, Ping, Chen, Yi-Xing, Hu, Yong, Zhao, Qian-Qian, Zhang, Yang, Liu, Rong, Zheng, Dan-Xue, Zhou, Jian, Fan, Jia, and Zeng, Zhao-Chong
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PROGRAMMED death-ligand 1 , *CYCLIC guanylic acid , *HEPATOCELLULAR carcinoma , *RADIOTHERAPY , *SMALL interfering RNA , *IONIZING radiation - Abstract
Purpose: Radiation therapy (RT) is one of the main treatments for patients with unresectable hepatocellular carcinoma (HCC). Emerging evidence indicates that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) stimulator of interferon gene (STING) pathway is crucial in RT-induced antitumor immune responses. Here, we discovered that activation of the cancer cell-intrinsic cGAS-STING pathway mediated immune cloaking after RT-induced DNA damage.Methods and Materials: Key regulatory proteins in the cGAS-STING signaling pathway in human and murine HCC cell lines were knocked out or down using CRISPR and CRISPR-associated protein 9 or small interfering RNA. The underlying mechanism of immune cloaking and clinical significance of cGAS-STING-induced programmed cell death ligand 1 (PD-L1) expression were studied with both ex vivo analyses and in vitro experiments.Results: RT upregulated PD-L1 in patients with HCC, which correlated with poor survival. RT activated cGAS-STING, increasing immune-checkpoint PD-L1 expression in human and mouse liver cancer cells. Ionizing radiation activated the STING-TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) innate immune pathway, leading to PD-L1 upregulation in HCC cells and inhibiting cytotoxic T-lymphocyte activity and protecting tumor cells from immune-mediated eradication. Knockdown of cGAS, STING, TBK1, and IRF3 reversed the antitumor effect of cytotoxic T-lymphocyte-mediated cytotoxicity after ionizing radiation in vitro or in vivo. RT potentiated the antitumor effect of programmed cell death protein 1 and PD-L1 axis blockade and augmented cytotoxic T-cell (CTL) infiltration in HCC tumors in immunocompetent mice. CD8 depletion compromised the synergetic antitumor effect of combined RT and anti-PD-L1 blockade, demonstrating that CD8+ CTLs are required for antitumor immunity induced by combination therapy.Conclusions: Our results identified an immune-cloaking mechanism for RT-activated, innate immune cGAS-STING and suggested that RT enhances HCC immunotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2022
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7. The Predictive Value of Circulating Exosomal PD-L1 in Cervical Cancer Immunotherapy.
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Tang, W., Guo, Q., Chen, J., Wu, Q., Zhang, T., Wang, Q., Zhang, X., and Xie, P.
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PROGRAMMED death-ligand 1 , *IMMUNE checkpoint inhibitors , *CERVICAL cancer , *EXOSOMES , *TRANSMISSION electron microscopes , *GRANZYMES - Abstract
Programmed death ligand 1 (PD-L1) expression was wildly used as a predictor of immune Check-Point Inhibitors (ICIs) efficiency. However, emerging results showed that PD-L1 was of great heterogeneity in sampling time and site. Recently, some studies found that exosomal PD-L1(ExoPD-L1) was related to ICIs response. In this study, we aimed to explore the predictive value of ExoPD-L1 in ICIs treatment of cervical cancer (CC) for the first time. A total of 40 primarily diagnosed CC patients who accepted radical radiotherapy (RT) from March 2021 to October 2022 were included. The consecutive tumor sample were collected before and during RT. Another 37 advanced CC patients who accepted ICIs combination therapy from June 2020 to October 2022 were enrolled in this study. Blood samples were collected from each participant before and during treatment. Exosomes were derived by differential centrifugation, which was further identified by Western blot (WB) (CD9/TSG101/Calnexin), transmission electron microscope analysis and nanoparticle tracking analysis. ExoPD-L1 detection was conducted by enzyme-linked immuno-sorbent assay (ELISA). The knockout of PD-L1 was conducted via CRISPR/Cas9 assay and the overexpress of PD-L1 was conducted by lentiviral transfection. CD8+ T cells were extracted from murine spleen by CD8+ T Cell Isolation Kit. Immune cells and cytokines markers were detected by multicolor flow cytometry. The consecutive detection of PD-L1 showed a dynamic change during RT. Compared with the level before RT, PD-L1 expression elevated in most patients (87.5%, 35/40) after RT. And the responders (n = 18) had elevated ExoPD-L1 level at the first two circles in the ICIs combination therapy (P<0.001). Whereas the level of pre-treatment ExoPD-L1 couldn't stratified clinical responders and non-responders (P = 0.181). The median follow-up time was 14.13 months. The mPFS in increased group vs. decreased group: not reach vs.11.02 months (P = 0.025, HR: 0.218, 0.052-0.913). Continuous blood sampling of mice models also found that effective therapeutic intervention could increase ExoPD-L1 in the early stage. The combination of exosome inhibitor GW4869 and anti-PD-1 further inhibited tumor growth. Mice were injected with external ExoPD-L1OE and ExoPD-L1KO. The results showed that ExoPD-L1OE suppressed body immunity and promoted tumor growth. The results of flow cytometry showed that ExoPD-L1OE inhibited CD8+ T cells from releasing interferon-and granzyme B. And ExoPD-L1OE also suppressed the CD8+ T cells proliferation in murine spleen. The coculture of CD8+ T cells and exosomes in vitro also confirmed the above conclusion. Compared with unstable and impressionable tumoral PD-L1, ExoPD-L1 seems to be better predictor for the efficacy of immunotherapy in CC, which was with easy accessibility and continuation. Exosome PD-L1 played an immunosuppressive role by inhibiting the proliferation and functional factor release of CD8+ T cell. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Radiotherapy Combined with PD-L1 Antibody Exerts a Synergistic Anti-tumor Effect in a Mouse Model of Esophageal Squamous Cell Carcinoma.
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Yin, Z., Zhang, H., Zhang, K., Ying, H., and Liu, B.
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ESOPHAGEAL cancer , *SQUAMOUS cell carcinoma , *IMMUNOLOGIC memory , *PROGRAMMED death-ligand 1 , *REGULATORY T cells , *LABORATORY mice - Abstract
The combination of radiotherapy and immune checkpoint inhibitors (ICIs) has been shown to exert synergistic anti-tumor effects in various tumors. In esophageal squamous cell carcinoma (ESCC), several clinical trials of radiotherapy combined with ICIs are undergoing or have been finished. However, the efficacy and action mechanisms of radiotherapy combined with ICIs is still not clear in ESCC. Our study aimed to investigate whether radiotherapy improved the anti-cancer effect of PD-L1 antibody and the effect of this combination therapy on tumor-immune microenvironment. The mouse esophageal cancer cell line mEC25 was implanted into the armpits of female C57 mice. When the tumor volume grew to 150-250 mm3, the mice were randomly divided into different groups including control group (administration of IgG antibody), radiotherapy group (12 Gy at 4 Gy per fraction), PD-L1 antibody group (200 mg/kg i.p. for three times) and combination group (fractionated radiation combined with PD-L1 antibody was delivered on day 1, day 4 and day 7, the day when fractionated radiation began was recorded as day 1).The mice were sacrificed on the 1st, 3rd and 7th day after the treatment was ended. The tumor, spleen and draining lymph nodes of the mice were collected and analyzed using flow cytometry (FCM), and the tumor volume and survival time of mice were calculated. Compared with radiotherapy or PD-L1 antibody alone, the combination therapy significantly prolonged the survival time of mice and decreased the growth rate of xenograft tumors FCM analysis showed that the combination therapy significantly increased the infiltration and cytotoxicity of effector T cells and reduced the proportion of M2 macrophages in tumor, spleen and lymph nodes. In addition, in tumor and spleen, the proportion of regulatory T cells (Tregs) decreased in the group of combination therapy. In tumor, spleen, and lymph nodes, the proportion of central memory T cell (TCM) was increased in the group of combination therapy. The anti-tumor effect of radiotherapy combined with PD-L1 antibody is superior to single treatment in the mouse model of esophageal cancer. Radiotherapy can shape tumor-immune microenvironment, allowing the infiltration of effector T cells and exclusion of immune-suppressive cells such as M2 macrophages and Tregs. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Molecular Status Predicts for Local Control in Patients with Non-Small Cell Lung Cancer Spinal Metastases Following Spine Stereotactic Body Radiotherapy.
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Shor, D., Zeng, K.L., Chen, H., Louie, A.V., Menjak, I., Atenafu, E., Tseng, C.L., Detsky, J., Larouche, J., Zhang, B., Soliman, H., Maralani, P., Myrehaug, S.D., and Sahgal, A.
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NON-small-cell lung carcinoma , *STEREOTACTIC radiotherapy , *PROGRAMMED death-ligand 1 , *VERTEBRAL fractures , *EPIDERMAL growth factor , *EPIDURAL abscess - Abstract
We report outcomes after spine stereotactic body radiotherapy (SBRT) in patients with metastatic non-small cell lung cancer (NSCLC), to determine the significance of programmed death-ligand 1 (PD-L1) status and epidermal growth factor (EGFR) mutation on local failure (LF) rate. A total of 165 patients and 389 spinal segments were retrospectively reviewed from 2009 to 2021. Baseline patient characteristics, treatment and outcomes were abstracted. Primary endpoint was LF and secondary outcomes included overall survival (OS) and vertebral compression fracture (VCF) rates. OS was estimated using the Kaplan-Meier method. Cumulative LF and VCF rates were calculated using competing risk analysis method. Multivariable analysis (MVA) evaluated factors predictive of LF and VCF. Median follow-up was 13 months (range, 0.5-95 months). Median OS was 18.4 months (95% CI 11.4-24.6). Median age was 67 years (range, 28.2-89.9). 52% were female, 76% had an adenocarcinoma histology and 61% had a smoking history. 49/165 (29%) had an EGFR mutation. PD-L1 status was analyzed in 109/165 (66%) patients with 16% PD-L1 ≥ 50%, 20% PD-L1 1-49% and 35% PD-L1 <1%. Of 389 segments, 79% were de novo and 21% were previously radiated. At baseline, 35% had a VCF, 27% had epidural disease, 27% had paraspinal extension, and 49% were Spinal Instability in Neoplasia Score (SINS) stable. 239/389 (61%) were treated with either 24 or 28 Gy in 2 SBRT fractions. Within 1 month of SBRT, 39/165 (24%) had a tyrosine kinase inhibitor, 27/165 (16%) immunotherapy (IO) with or without chemotherapy, and 31/165 (19%) chemotherapy alone. LF cumulative incidence at 1- and 2-years was 16.3% (95% CI 12.8-20.3%) and 25.4% (95% CI 20.9%-30%), respectively. EGFR positivity (p<0.0001), PD-L1≥50% (p = 0.013) and treatment with IO within 1 month of SBRT (p = 0.004) predicted for improved local control on MVA. The 1- and 2-year LF rate in EGFR-positive vs. negative patients were 12.9% vs. 16.6% and 17.7% vs. 28.8%, respectively, and in those PD-L1 ≥50% vs PD-L1<50% were 7.8% vs. 19.6% and 7.8% vs. 38.1% respectively. Cumulative incidence of VCF at 1- and 2-years were 6.6% (95% CI 4.4-9.4%) and 8.8% (95% CI 6.1-12.0%). MVA identified prior SBRT to the same treated segment (P<0.0001) and a baseline VCF (p<0.0001) as significant predictors. 18/389 (4.6%) had radiation-induced radiculopathy and no radiation myelopathy events detected. We identify the predictive utility of EGFR mutation and PD-L1 ≥50% status on local control in NSCLC patients with spinal metastases treated with spine SBRT, and a therapeutic benefit with peri-SBRT IO. [ABSTRACT FROM AUTHOR]
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- 2023
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10. PD-L1 Inhibitors Combined with Thoracic Radiotherapy in First-Line Treatment of Extensive Stage Small Cell Lung Cancer: A Propensity Score-Matched, Real-World Study.
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Peng, J., Zhang, L., Wang, L., Feng, H., Yao, D., Meng, R., Liu, X., Li, X., Liu, N., Tan, B., Huang, Z., Li, S., and Meng, X.
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SMALL cell lung cancer , *PROGRAMMED death-ligand 1 , *PEMETREXED , *PROPENSITY score matching , *RADIOTHERAPY , *PROGNOSIS - Abstract
The CREST study showed that the addition of thoracic radiotherapy (TRT) could improve the survival of extensive stage small cell lung cancer (ES-SCLC), but whether TRT can bring survival benefit in the era of immunotherapy is controversial. This study aims to explore the efficacy and safety of adding TRT to the combination of PD-L1 inhibitors and chemotherapy. Thepatients who received PD-L1 inhibitors combined with platinum-based chemotherapy as the first-line treatment of ES-SCLC from January 2019 to December 2021 were retrospectively collected. According to whether they received TRT, they were divided into two groups, and the follow-up analysis was performed. Propensity score matching (PSM) in with a 1:1 ratio was performed to balance the baseline characteristics of the two cohorts. The endpoints were progression-free survival (PFS) and OS. A total of 211 patients with ES-SCLC were enrolled, of whom 70 (33.2%) patients received standard therapy plus TRT as first-line treatment, and 141 (66.8%) patients in the control group received PD-L1 inhibitors plus chemotherapy. After PSM, a total of 65 pairs of patients were enrolled in the analysis. There were no significant differences in baseline characteristics between the two groups of patients who received TRT and those who did not. In all patients, the median PFS (mPFS) in the TRT group and the non-TRT groupwere 9.5 months and 7.2 months, respectively, with HR = 0.60 (95% CI 0.41-0.87, p = 0.007). The median OS (mOS) in the TRT group was also significantly longer than that in the non-TRT group (24.1 months vs. 18.5 months, HR = 0.53, 95% CI 0.32-0.85, p = 0.009). Multivariable analysis showed that baseline liver metastasis and bone metastasis were independent prognostic factors for OS. In terms of safety, immunotherapy combined with thoracic radiotherapy increased the incidence of treatment-related pneumonia (p <0.001), most of which were grade 1-2. This real-world study shows that adding TRT to durvalumab or atezolizumab plus chemotherapy significantly improves survival in ES-SCLC. It leads to more treatment-related pneumonia, but most of them can be relieved after symptomatic treatment. This treatment model deserves to be explored in prospective clinical trials. [ABSTRACT FROM AUTHOR]
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- 2023
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11. A Randomized Phase 2 Study of Pembrolizumab With or Without Radiation in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma.
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Mahmood, Umair, Bang, Andrew, Chen, Yu-Hui, Mak, Raymond H., Lorch, Jochen H., Hanna, Glenn J., Nishino, Mizuki, Manuszak, Claire, Thrash, Emily M., Severgnini, Mariano, Sanborn, Matthew, Sridharan, Vishwajith, Margalit, Danielle N., Tishler, Roy B., Busse, Paul M., Willers, Henning, Mamon, Harvey J., Yoo, Hyung-Jin, Pai, Sara I., and Wirth, Lori J.
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ADENOID cystic carcinoma , *PROGRAMMED death-ligand 1 , *METASTASIS , *LIVER enzymes , *PEMBROLIZUMAB , *PROGRESSION-free survival , *THERAPEUTIC use of monoclonal antibodies , *RESEARCH , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *TREATMENT effectiveness , *DISEASE relapse , *COMPARATIVE studies , *RANDOMIZED controlled trials , *SURVIVAL analysis (Biometry) , *COMBINED modality therapy - Abstract
Purpose: We evaluated the safety and efficacy of pembrolizumab (pembro) ± radiation therapy (RT) in a phase 2 study among patients with progressive, metastatic adenoid cystic carcinoma (ACC).Methods and Materials: Eligible patients had metastatic ACC with progression within the last year and ≥1 measurable lesion. Patients were randomized to pembro alone or with RT to 30 Gy in 5 fractions (pembroRT). The primary endpoint was objective response rate outside the RT field. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and local RT responses.Results: We randomized 20 patients (10 per arm) from 2017 to 2018. We did not observe objective response outside of the radiation treatment field; stable disease (SD) was the best response in 12 (60%) patients and was not different per arm (7 pembro, 5 pembroRT, P = .65). A tumor growth rate decrease (TGR) of >25% was noted among 7 of 12 patients and >75% in 4 patients. There were local responses in the irradiated field among all evaluable pembroRT patients. Median PFS and OS were 4.5/not reached for pembroRT and 6.6 / 27.2 months for pembro patients. One patient developed grade 3 liver enzyme elevation after 27 cycles of therapy. Correlative analyses confirm low levels of programmed death-ligand 1 expression (PD-L1), and CD8 infiltrating T-cells. We identified associations between local response and both MYB/NFIB translocation and PD-L1 expression and between changes in systemic immune populations and RT.Conclusions: Pembrolizumab and pembroRT were well tolerated. We observed no objective responses, but 60% of patients with PD before the study achieved SD, the majority with decreased TGR and half (n = 10) with clinical benefit (SD >6 months). We observed favorable local responses within the RT field. Additional strategies are needed to further delay progression and effect response. [ABSTRACT FROM AUTHOR]- Published
- 2021
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12. Programmed Death Receptor Ligand One Expression May Independently Predict Survival in Patients With Non-Small Cell Lung Carcinoma Brain Metastases Receiving Immunotherapy.
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Hulsbergen, Alexander F.C., Mammi, Marco, Nagtegaal, Steven H.J., Lak, Asad M., Kavouridis, Vasileios, Smith, Timothy R., Iorgulescu, Julian B., Mekary, Rania A., Verhoeff, Joost J.C., Broekman, Marike L.D., and Phillips, John G.
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DEATH receptors , *BRAIN metastasis , *NON-small-cell lung carcinoma , *PROPORTIONAL hazards models , *PROGRAMMED death-ligand 1 , *BRAIN tumor treatment , *LUNG cancer , *LUNG tumors , *PROGNOSIS , *RETROSPECTIVE studies , *BRAIN tumors , *GENES , *SURVIVAL analysis (Biometry) , *IMMUNOTHERAPY - Abstract
Purpose: Programmed death receptor ligand 1 (PD-L1) expression is known to predict response to PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC). However, the predictive role of this biomarker in brain metastases (BMs) is unknown. The aim of this study was to assess whether PD-L1 expression predicts survival in patients with NSCLC BMs treated with PD-1/PD-L1 inhibitors, after adjusting for established prognostic models.Methods and Materials: In this multi-institutional retrospective cohort study, we identified patients with NSCLC-BM treated with PD-1/PD-L1 inhibitors after local BM treatment (radiation therapy or neurosurgery) but before intracranial progression. Cox proportional hazards models were used to assess the predictive value of PD-L1 expression for overall survival (OS) and intracranial progression-free survival (IC-PFS).Results: Forty-eight patients with BM with available PD-L1 expression were identified. PD-L1 expression was positive in 33 patients (69%). Median survival was 26 months. In univariable analysis, PD-L1 predicted favorable OS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.19-1.02; P = .055). This effect persisted after correcting for lung-graded prognostic assessment and other identified potential confounders (HR, 0.24; 95% CI, 0.10-0.61; P = .002). Moreover, when modeled as a continuous variable, there appeared to be a proportional relationship between percentage of PD-L1 expression and survival (HR, 0.86 per 10% expression; 95% CI, 0.77-0.98; P = .02). In contrast, PD-L1 expression did not predict IC-PFS in uni- or multivariable analysis (adjusted HR, 0.54; 95% CI, 0.26-1.14; P = .11).Conclusions: In patients with NSCLC-BMs treated with PD-1/PD-L1 checkpoint inhibitors and local treatment, PD-L1 expression may predict OS independent of lung-graded prognostic assessment. IC-PFS did not show association with PD-L1 expression, although the present analysis may lack power to assess this. Larger studies are required to validate these findings. [ABSTRACT FROM AUTHOR]- Published
- 2020
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13. Changes in Indoleamine 2,3-Dioxygenase 1 Expression and CD8+ Tumor-Infiltrating Lymphocytes after Neoadjuvant Chemoradiation Therapy and Prognostic Significance in Esophageal Squamous Cell Carcinoma.
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Zhou, Sha, Yang, Hong, Zhang, Jun, Wang, Juncheng, Liang, Zhaohui, Liu, Songran, Li, Yong, Pan, Yanpeng, Zhao, Lei, and Xi, Mian
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INDOLEAMINE 2,3-dioxygenase , *SQUAMOUS cell carcinoma , *ESOPHAGEAL cancer , *BIOMARKERS , *LYMPHOCYTE count , *PROGRAMMED death-ligand 1 , *CHEMORADIOTHERAPY , *CARDIAC pacing , *LYMPHOCYTE metabolism , *RESEARCH , *RESEARCH methodology , *PROGNOSIS , *MEDICAL cooperation , *EVALUATION research , *LYMPHOCYTES , *COMPARATIVE studies , *GENES , *OXIDOREDUCTASES , *COMBINED modality therapy , *ESOPHAGEAL tumors - Abstract
Purpose: Despite good preclinical evidence, clinical data on the effect of neoadjuvant chemoradiation therapy (CRT) on expression of immune markers in esophageal cancer are limited. This study aimed to evaluate the changes in indoleamine 2,3-dioxygenase 1 (IDO1) expression, programmed cell death-ligand 1 (PD-L1) expression, and CD8+ tumor-infiltrating lymphocyte status after neoadjuvant CRT and the prognostic significance in esophageal squamous cell carcinoma (ESCC).Methods and Materials: Between 2003 and 2017, 138 patients with ESCC who underwent neoadjuvant CRT and esophagectomy without achieving pathologic complete response were included for analysis. Both pre-CRT biopsies and post-CRT surgical specimens were available in 82 patients. Immunohistochemistry of IDO1, PD-L1, and CD8 density were analyzed.Results: Among 82 paired samples, the expression levels of IDO1 and PD-L1 and CD8 density increased significantly after neoadjuvant CRT (P < .01 for all). Patients with high IDO1 expression after CRT had poorer overall survival (P = .001) and recurrence-free survival (P < .001) than those with low IDO1 expression. High post-CRT CD8 density was significantly correlated with more favorable overall survival (P = .01) and recurrence-free survival (P = .008). Neither pre- nor post-CRT PD-L1 expression was an independent prognostic factor for survival. Stratification analysis revealed that patients with combined low IDO1 expression and high CD8 density after CRT were significantly associated with better survival than other subgroups. The major findings were reproducible in an independent validation cohort.Conclusions: IDO1 and PD-L1 expression and CD8 density increased significantly after neoadjuvant CRT in ESCC. The post-CRT IDO1 expression and CD8 density could serve as prognostic biomarkers for survival. [ABSTRACT FROM AUTHOR]- Published
- 2020
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14. HPV Infection and Immunohistochemical Analysis of P16, P53, and PD-L1 Expression as Prognostic Biomarkers in Squamous Cell Anal Cancer Patients Receiving Definitive Radiotherapy/Chemoradiotherapy.
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Topuz, B. Balci, Sert, F., Sezak, M., Soylu, M., Yalman, D., and Ozkok, S.
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ANAL cancer , *SQUAMOUS cell carcinoma , *IMMUNOHISTOCHEMISTRY , *PROGNOSIS , *PROGRAMMED death-ligand 1 , *HUMAN papillomavirus , *KI-67 antigen , *ANDROGEN drugs - Abstract
The treatment of anal squamous cell carcinoma (SCC) with definitive radiotherapy (RT)/chemoradiotherapy (CRT) has a high likelihood of success; nevertheless, treatment resistance and recurrence rates cannot be ignored. Therefore, we aimed to identify the relationship between immunohistochemical (IHC) evaluation, treatment response, and prognosis. This retrospective study included 42 patients with anal SCC treated with definitive RT/CRT at a single institution between 2006 and 2020. Detection of high-risk HPV-DNA and IHC analysis of p16, p53, and PD-L1 expression was performed from diagnostic formalin-fixed, paraffin-embedded (FFPE) biopsies. Positive staining was accepted as >5% in tumor cells for p16 and p53 expression in addition to ≥1% combined positive score (CPS) [(PD-L1 positive tumor, lymphocyte, macrophage count/total viable cell count) x100] for PD-L1 expression. Thirty patients (71.4%) had a complete response to definitive RT/CRT. Recurrence was observed in 16 (38.1%) patients, with 3 (7.1%) having locoregional recurrence (LRR), 6 (14.3%) having distant metastases (DM), and 7 (16.7%) having both LRR and DM. Twenty-four (57.1%) patients were alive. Thirty (71.4%) patients were HPV+, while 12 (28.6%) were HPV-. There was a significant correlation between HPV+ and p16+ status (p<0.001). HPV- status was associated with the male gender (p = 0.001). HPV- and p16- status were significantly associated with a lack of complete response to definitive RT/CRT (p<0.001, p<0.001, respectively). Furthermore, there was a significant relationship between lack of complete response and increased recurrence (p = 0.016) and distant metastases (p = 0.015). Ten of the 16 patients with recurrence were p53+; a significant correlation was found between recurrence and p53+ status (p = 0.006). Similarly, p53+ status was associated with increased LRR (p = 0.014). PD-L1 CPS ≥ 1% was found in 31 (73.8%) patients. PD-L1 positivity was significantly correlated with HPV+ (p = 0.026) and p16+ (p = 0.013) status. All 10 (23.8%) patients with LRR were PD-L1+; PD-L1 CPS ≥ 1% was associated with poor local control (p = 0.031). In univariate analysis, age [<65] (p = 0.049), complete response (p = 0.015), and HPV+ status (p = 0.010) were related to increased 5-year (y) overall survival (OS); complete response (p = 0.001), HPV+ status (p = 0.025) and p53- status (p = 0.010) were associated with increased 5-y disease-free survival (DFS). In multivariate analysis, age [<65] (p = 0.010) and HPV+ status (p = 0.002) were significant prognostic factors for 5-y OS, whereas complete response (p = 0.007) and p53- status (p = 0.038) were significant prognostic factors for 5-y DFS. Patients with HPV- status and/or poor prognostic biomarkers should be identified at diagnosis. Thus, better outcomes can be achieved with different treatment options, such as combining immunotherapy and standard CRT. [ABSTRACT FROM AUTHOR]
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- 2023
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15. Efficacy and Safety of PD-1/PD-L1 Inhibitors Combined with Radiotherapy in Patients with Brain Metastases Caused by Non-Small Cell Lung Cancer: A Multi-Center Retrospective Analysis.
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Wang, X.
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NON-small-cell lung carcinoma , *PROGRAMMED cell death 1 receptors , *PROGRAMMED death-ligand 1 - Abstract
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]
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- 2023
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16. PD-1 Inhibitor Combined with Hypofractionated Radiotherapy and GM-CSF with or without IL-2 (PRaG Regimens) Rechallenge for Acquiring Resistance to PD-1/PD-L1 Inhibitor in Advanced Solid Tumors.
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Xu, M., Xing, P., Kong, Y., Zhang, C., Zhao, X., Zhang, J., and Zhang, L.
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PROGRAMMED death-ligand 1 , *PROGRAMMED cell death 1 receptors , *STEREOTACTIC radiotherapy , *GRANULOCYTE-macrophage colony-stimulating factor , *ADVERSE health care events , *PULMONARY alveolar proteinosis - Abstract
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]
- Published
- 2022
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17. The Impact of KRAS Mutation and PD-L1 Status on Outcomes of Definitive Stereotactic Body Radiation (SBRT) for Stage I Non-Small Cell Lung Cancer (NSCLC).
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Stephans, K.L., Reddy, C.A., and Videtic, G.M.
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NON-small-cell lung carcinoma , *PROGRAMMED death-ligand 1 , *RAS oncogenes , *COLORECTAL liver metastasis - Abstract
Mutational and PD-L1 status of non-small cell lung cancer (NSCLC) correlate with response to systemic therapy. KRAS mutations have been implicated in radio-resistance of both colorectal liver metastasis as well as NSCLC after stereotactic body radiation (SBRT), while the effect of PD-L1 status on outcomes after SBRT is unknown. Here we examine the relationship of these molecular markers on outcomes after SBRT for stage I NSCLC. Reflexive testing for mutations associated w NSCLC (EGFR, ALK, KRAS, ROS1, BRAF, RET, HER2, MET) was gradually implemented at our institution beginning in 2016, followed by PD-L1 testing in 2018, provided biopsy samples were obtained internally and adequate tissue for molecular testing was available. We cross-referenced an institutional database of all patients treated with definitive intent SBRT for stage I NSCLC from 1/2015-12/2020 in order to correlate mutational/PD-L1 testing along with other patient, tumor and treatment factors on local recurrence (LR), disease recurrence (AR) and overall survival (OS) after SBRT. Gray's test was used to compare cumulative incidence rates of LR and AR, and OS rates were compared using the log rank test. No patients received adjuvant systemic therapy of any kind. 148 patients with known mutational status were identified, of which 62 (41.9%) had known KRAS mutations. Other mutations (EGFR 16, ALK 3, BRAF 9, MET 4, ROS1 1, RET 1, and HER2 0) were identified too infrequently for analysis. PD-L1 status was known for 161 patients and was analyzed in the following groups (0% in 58, 1-49% in 60, and 50-100% in 43 patients) as well as a continuous variable. SBRT regimen was at physician discretion; 34 Gy/1 fx in 30.6%, 48-50 Gy/4-5 fx in 30.6%, 54-60 Gy/ 3 fx in 37.1%, and 60 Gy/8fx in 1.6% of patients. KRAS and PD-L1 groups were balanced for known prognostic factors, except KRAS mutated was a/w higher SBRT dose. At median follow-up of 25.7 months 55% of patients were living. By Gray's test KRAS mutation status was not associated with a difference in LR (2-year cumulative incidence of 1.3% versus 1.6%, p=0.25), AR (2-year cumulative incidence of 27.2% v 24.8%, p=0.70) or OS (5-year survival 44.9% v 49.1%, p=0.34) for wild-type versus mutant status respectively. There was a trend towards higher LR in the PD-L1 0% group with 2y LR of 10.2%, 5.2%, and 2.9% and 5y LR of 19.5, 10.9 and 9.2% in the three PD-L1 groups respectively (P=0.085), however PD-L1 did not correlate with LR as a continuous variable (p=0.15). The PD-L1 1-49% group experienced the lowest risk of 2y AR (28% v 20% v 36%, p=0.11) and greatest 5y OS (37% v 44.% v 28%, p=0.06) however PD-L1 was not correlated to AR (p=0.79) or OS (p=0.25) as a continuous variable. Unlike prior series suggesting increased LF after SBRT in KRAS mutated adenocarcinoma, KRAS status was not correlated with LF in this series of patients of whom 70% received BED 149 or higher dose SBRT. Whether PD-L1 status is correlated with LR, AR or OS after SBRT for stage I NSCLC requires a larger sample for study. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Radiation Immunodynamics as the Foundation of Immune-Guided Radiotherapy: Changes in Peripheral CD14+PD-L1+ Myeloid Cells over the Course of Chemoradiation and Association with Survival for New Diagnosis of Glioblastoma.
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Sloan, L., Sen, R., Hu, C., Liu, C., Doucet, M., Blosser, L., Thompson, E., Katulis, L., Kamson, D., Grossman, S., Holdhoff, M., Redmond, K.J., Quon, H., Lim, M., Eberhart, C., Pardoll, D.M., Ganguly, S., and Kleinberg, L.R.
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MYELOID-derived suppressor cells , *MYELOID cells , *PROGRAMMED death-ligand 1 , *CHEMORADIOTHERAPY , *BIOMARKERS - Abstract
Radiation immunodynamics, or the understanding of immune markers over a fractionated course of radiotherapy (RT), is a critical intermediate step in developing personalized RT approaches, including Immune-guided Radiotherapy (IM-GRT). Peripheral-origin myeloid cells are a major component of the glioblastoma (GBM) tumor microenvironment. The effect of adjuvant chemoradiation (CRT) on programmed death-ligand 1 (PD-L1)-expressing suppressive myeloid cells is unknown. We hypothesize that PD-L1+ monocytes increase from baseline in the peripheral blood of patients with GBM undergoing CRT. Tumor and peripheral blood were collected from a prospective, single-institution, biospecimen protocol of newly diagnosed GBM participants undergoing CRT. A neuropathologist selected regions of interest within baseline formalin-fixed, paraffin-embedded tissue for digital spatial profiling. Expression for PD-L1 on CD163+ regions of interest is quantified relative to isotype and presented as fold change. Flow cytometry was performed on peripheral blood immune cells at seven time points in relation to CRT: one prior to start, five weekly during, and one month after completion. Flow cytometry data are expressed as percent frequency (%fx) of CD14+ monocytes. Correlative studies focusing on plasma analytes, metabolic proteins, and bulk RNA sequencing were also performed. Relationships between PD-L1 and overall survival (OS) or progression-free survival (PFS) were assessed by Cox model. "Survivors" were alive 2 years after diagnosis. A total of 15 cases with baseline PD-L1 assessment are included. Digital spatial profiling (n=10) of tumor identified PD-L1 expression within regions of interest with CD163+ myeloid cells is increased in non-survivors compared to survivors (log2FC=0.28; padj<0.05). The median %fx of peripheral blood CD14+ PD-L1+ cells at the pre-CRT baseline is 39.2% among survivors and 16.0% among non-survivors, and not associated with OS (HR=0.98, p=0.36) or PFS (HR=0.99, p=0.7). Comparing to baseline, the %fx of CD14+PD-L1+ cells at week 4 during CRT decreases (median fold change 0.49, range 0.08-0.92) in survivors but increases (median fold change 1.86, range 0.31-4.32) in non-survivors. Such a mid-CRT change (in terms of fold change) is significantly associated with OS (HR=2.21, p=0.008) but not PFS (HR=1.33, p=0.17). One month after CRT, the median %fx is 4.9% in survivors and 19.7% in non-survivors, and not associated with OS (HR=1.04, p=0.11) or PFS (HR=1.02, p=0.33). This is the first study to demonstrate changes in peripheral CD14+PD-L1+ myeloid cells over the course of CRT and to associate these changes with survival outcome. Dynamic biomarker assessments, like radiation immunodynamics, may identify patients who would benefit from immune adjuvants while undergoing CRT in neuro-oncology and other disease sites. [ABSTRACT FROM AUTHOR]
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- 2022
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19. The LMP1/Lgals1-NF-Kb-IRF1-PDL1 Axis Promotes Immune Escape in Nasopharyngeal Carcinoma.
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Yixing, C., Xie, F., Chen, J., Dayu, L., Li, Z., Luo, Q., and Lin, Q.
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NASOPHARYNX cancer , *CANCER relapse , *PROGRAMMED death-ligand 1 , *CELLULAR signal transduction , *FLOW cytometry - Abstract
Recurrence and metastasis of nasopharyngeal carcinoma (NP) is closely related to immune escape. It is known that LMP1 promotes the immune escape of nasopharyngeal carcinoma cells (NPCs) by controlling the expression of PD-L1. However, the underlying molecular mechanisms remain to be fully characterized. At first, we screened the transcription factor which LMP1 can induce, to find the transcription factor regulates PD-L1, and further proved LMP1 can elevated the expression of IRF-1 in nasopharyngeal carcinoma cells. We further confirmed the presence of the LMP1/Lgals1 complex, and demonstrated that LMP1/Lgals1 can regulate IRF-1 through the NF-κB signaling pathway. We also confirmed the involvement of Lgals1 in the immune escape of nasopharyngeal carcinoma cells by T-cell killing assay, ELISA and flow cytometry. In this study, we demonstrated that LMP1 interacts with Lgals1, a beta (β)-galactoside-binding protein, to regulate IRF1 via NF- k B signaling pathway, promoting the expression of PD-L1 in NPCs. LMP1 and Lgals1 are both found to be tightly linked to recurrence and metastasis of NPC based on clinical data. Targeting Lgals1 by using OTX008, a specific Lgals1 inhibitor, is able to restore the immunogenic environment in NPCs. Our findings reveal a regulatory axis for programmed death ligand 1 (PD-L1) expression in NPC cells, and targeting one component in this axis, Lgals1, is effective in boosting the immunogenicity of NPCs, providing a therapeutic avenue for treating NPC in clinic. [ABSTRACT FROM AUTHOR]
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- 2022
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20. A Multicenter, Single-Arm, Phase II Trial of RC48-ADC Combined with Radiotherapy, PD-1/PD-L1 Inhibitor Sequential GM-CSF and IL-2 (PRaG3.0 regimen) for the Treatment of HER2-Expressing Advanced Solid Tumors.
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Xu, M., Kong, Y., Xing, P., Chen, R., Ma, Y., Shan, C., and LiYuan, Z.
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PROGRAMMED cell death 1 receptors , *PROGRAMMED death-ligand 1 , *GRANULOCYTE-macrophage colony-stimulating factor , *STEREOTACTIC radiotherapy , *CANCER remission , *PANCREATIC tumors , *RADIOTHERAPY - Abstract
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]
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- 2022
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21. High Serum sPD-L1 Level Predicts Poor Outcome in Hepatocellular Carcinoma Patients Treated with Radiotherapy.
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Zhang, Y., Li, Z., Du, S., and Zeng, Z.
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PROGRAMMED death-ligand 1 , *HEPATOCELLULAR carcinoma , *RADIOTHERAPY , *PROGRAMMED cell death 1 receptors , *PROGRESSION-free survival , *T cells - Abstract
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]
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- 2022
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22. 18F-AlF-NOTA-PCP1 PET/CT Imaging Visualize Radiation-Induced PD-L1 Expression in Glioblastoma Subcutaneous Xenograft Mouse Models.
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Chen, Y., Liu, Z., Zhang, Y., Man, H., and Yu, J.
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COMPUTED tomography , *PROGRAMMED death-ligand 1 , *LABORATORY mice , *IMMUNE checkpoint proteins , *POSITRON emission tomography - Abstract
Remarkable clinical benefits from radiotherapy combined with PD-1/PD-L1 immune checkpoint blockades were reported across several cancer patients. However, the optimal time window of combining treatment remains undefined, which may be correlated with the timing of upregulation of PD-L1 expression. PD-L1 antibody-based PET/CT imaging was difficult to translate into clinical settings secondary to the long interval before the scan. We therefore generated a peptide-based PET radiotracer to monitor radiation-induced PD-L1 expression in a non-invasive manner, which could be used to assess the optimal time window of combining radio- and immunotherapy. Peptide targeting PD-L1 (PCP1) was conjugated with NOTA and radiolabeled with 18F ([18F]-AlF-NOTA-PCP1). The Binding assay was performed in U87MG and GL261 glioblastoma cell lines with different levels of PD-L1 expression. [18F]-AlF-NOTA-PCP1 PET/CT imaging was prepared in U87MG and GL261 xenografts and syngeneic tumor models. In vivo imaging data was confirmed by ex vivo biodistribution and immunohistochemistry (IHC). To evaluate the radiation-induced PD-L1 upregulation, [18F]-AlF-NOTA-PCP1 PET/CT scan was prepared 3 days after U87MG tumor on mice subjecting to 20 Gy × 1F external radiation therapy. [18F]-AlF-NOTA-PCP1 was developed with high radiochemical purity and stability. The Binding assay showed more than 20 folds [18F]-AlF-NOTA-PCP1 binding to U87MG compared with GL261 cell line (p = 0.0495). The U87MG and GL261 tumors and excretory organs were identified by [18F]-AlF-NOTA-PCP1 PET/CT imaging. [18F]-AlF-NOTA-PCP1 PET/CT data showed different %ID/cc (percentage of injected dose per cubic centimeter of tissue) values of ROIs (regions of interest) among tumor models as evaluated by ex vivo methods. Preliminary results demonstrated the increase in PD-L1 expression of irradiated tumors on [18F]-AlF-NOTA-PCP1 PET/CT, showing a %ID/cc value of nearly 4 folds development post-radiation. PET imaging with [18F]-AlF-NOTA-PCP1 is an effective approach for specific and non-invasive visualization of tumor PD-L1 level. PD-L1 expression can be induced by radiotherapy treatments and [18F]-AlF-NOTA-PCP1 PET can quantify these changes in glioblastoma subcutaneous xenograft mouse models. [ABSTRACT FROM AUTHOR]
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- 2022
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23. Role of TMB and PD-L1 as Prognostic Factors and Predictors of Response to Immunotherapy in Head and Neck Squamous Cell Cancer.
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Porosnicu, M., Burcher, K., Lantz, J.W., Gavrila, E., Burcher, J.T., Hughes, R.T., Lycan, T., Bunch, P.M., Zhang, W., and D'Agostino, R.
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HEAD & neck cancer , *SQUAMOUS cell carcinoma , *PROGRAMMED death-ligand 1 , *PROGNOSTIC models , *PROGNOSIS , *PROGRESSION-free survival - Abstract
Immunotherapy with checkpoint inhibitors (ICI) improved survival in HNSCC. Response rates to ICIs remain low, in part due to lack of effective predictors of response to guide patients' selection. PD-L1, as the only biomarker used in prospective research of ICI in HNSCC has generated inconsistent results. Developments in Precision Oncology in HNSCC brings the prospect for new biomarkers. Tumor mutational burden (TMB) is under investigation in many solid tumors and this study assessed the significance and potential role of TMB and PD-L1 in the immunotherapy of HNSCC. This single institution retrospective review includes HNSCC patients (pts) with tumor tissue evaluated for PD-L1 (IHC 22C3 pharmDx kit) and TMB by FoundationOne. PD-L1 was reported as TPS score (prior to 2018) or CPS score (thereafter). TMB and PD-L1 were analyzed for individual association with demographics, disease characteristics and survival, and with progression free survival (PFS) and response to ICI. Pts tested for TMB (mut/Mb) were grouped as TMB(1-5) and TMB(6+) and pts tested for PD-L1 were grouped as PD-L1(0), PD-L1(1-19) and PD-L1(20+). 139 pts were included, 128 pts had TMB, 95 pts had PD-L1 and 92 pts had both results. TMB(6+) was associated with smoking (p=0.03) and with tumor location, with laryngeal cancer pts having higher TMB (p<0.01) and oropharyngeal cancer pts having lower TMB (p p<0.01). PD-L1 was higher in African Americans (p=0.04), in never smokers (p=0.04) and never drinkers (p=0.01), and in pts with earlier cancer stage (p=0.03) and lower tumor stage (p p<0.01). There was no correlation of TMB or PD-L1 with HPV status. TMB(6+) was associated with improved survival in univariate analysis (p=0.02) and in Cox proportional hazards regression model adjusted for age, tobacco, tumor site, nodal stage, previous chemo/radiotherapy and PD-L1 level (p<0.01). No correlation was found between PD-L1 level and prognosis. There was no correlation between TMB and PD-L1 level. Treatment efficacy with ICI was evaluated in 51 pts, of whom 40 pts had TMB and 36 pts had PD-L1 results. There was significant association of continuous TMB score with PFS (p=0.013) and with response to ICI (mean TMB=11.2 in responders and 4.9 in non-responders; p=0.01). Similarly, in categorical analysis, PFS was 538 days in TMB(6+) and 261 days in TMB(1-5) (p=0.04). There was no association between response to ICI or PFS and PD-L1 analyzed as categorical (p=0.89 and p=0.62) or continuous variable (p=0.99 and p=0.66). Inadequate PD-L1 results in this study could be explained by inconsistence in methods. The association of TMB with prognosis and response to ICI in this study warrants further investigations, and prompts a methodology harmonization effort and advancement of TMB in future prospective studies. The recent availability of circulating TMB makes it a further attractive biomarker. [ABSTRACT FROM AUTHOR]
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- 2022
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24. Plasma Cell-Free RNA PD-L1 Expression and Clinical Outcomes With Immunotherapy.
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Jayananda, S., Muzaffar, M., Namireddy, P., Sharma, N., and Walker, P.
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PROGRAMMED death-ligand 1 , *TREATMENT effectiveness , *IMMUNE checkpoint inhibitors , *NON-small-cell lung carcinoma , *IMMUNOTHERAPY - Abstract
Programmed death ligand-1 (PD-L1) expression is predictive of immunotherapy benefit. However, tissue PD-L1 protein immunohistochemical testing can be fraught with tissue acquisition and heterogeneity limitations. PD-L1 expression by RNA sequencing can be performed by both tissue and plasma with tissue PD-L1 protein correlations. What has not been well characterized is the correlation of plasma cfRNA PD-L1 and clinical outcomes with immunotherapy. Plasma cfRNA PD-L1 expression was evaluated and correlated with immunotherapy benefit in advanced non-small cell lung cancers (NSCLC). Patients with advanced NSCLC undergoing plasma next-generation sequencing including plasma cfRNA PD-L1 testing in a CLIA and CAP accredited laboratory were retrospectively identified and evaluated at a single institution. Plasma PD-L1 positive patients underwent a de-identified chart abstraction to identify those patients with advanced NSCLC treated with front line immunotherapy regimens and those who received cytotoxic chemotherapy alone. 16 patients with plasma PD-L1 expression treated with front line immunotherapy regimens including single-agent immune checkpoint inhibitors and combinatorial chemo-immune or chemo-immune-bevacizumab regimens, were assessed for overall survival (OS). 11 patients with plasma PD-L1 expression who received chemotherapy alone were identified and evaluated as a non-immunotherapy OS comparison. Median OS for the immunotherapy treated patients was 13 months with a 30% 3-year landmark OS versus 4 months median OS and a 10% 3-year landmark OS for those treated with chemotherapy alone. Comparative log-rank test p-value 0.0091 and a hazard ratio of 0.36 (95%-CI 0.13-0.99). Plasma cfRNA PD-L1 expression is predictive of a statistically significant survival benefit from immunotherapy treatment compared to chemotherapy in the first line treatment of advanced NSCLC. The 3-year landmark OS of 30% parallels tissue PD-L1 directed immunotherapy-based treatment outcomes. The clinical utility of plasma cfRNA PD-L1 to overcome tissue acquisition and PD-L1 protein heterogeneity limitations and to study the dynamic nature of PD-L1 expression with non-immune cancer treatments and potential immunotherapy response monitoring are undergoing ongoing research. [ABSTRACT FROM AUTHOR]
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- 2022
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25. A Radiomics Approach for Prediction of PD-L1 Expression in Cervical Cancer Patients: An Initial Result.
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Cai, M., Tang, H., Tan, X., Guo, W., LI, Y., Ma, Y., Xu, W., Zhu, X., Luo, J., Liu, Z., Chen, H., Lu, J., Zhang, Y., Shi, F., Wang, J., Su, J., and Ma, J.
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PROGRAMMED death-ligand 1 , *CERVICAL cancer , *CANCER patients , *FORECASTING - Published
- 2020
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26. Safety and Tolerability Evaluation of Sintilimab in Combination with Low Dose Radiation and SBRT in Treatment Naive Stage IV PD-L1 Positive NSCLC Patients.
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Li, R., Chen, L., Zhang, Y., Mei, L.Y., Zhou, L., Zhu, X., Yu, M., Yin, L., Gong, Y., Xue, J., and Lu, Y.
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PROGRAMMED death-ligand 1 , *RADIATION doses , *NON-small-cell lung carcinoma , *BLOOD testing - Published
- 2020
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27. Stereotactic Radiosurgery (SRS) for Non-Small Cell Lung Cancer (NSCLC) in the Setting of PDL1 and EGFR: An Analysis of Patient Outcomes.
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Butler-Xu, Y.S., Botteron, H., Tennapel, M.J., and Wang, F.
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NON-small-cell lung carcinoma , *STEREOTACTIC radiosurgery , *PROGRAMMED death-ligand 1 - Published
- 2020
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28. Identifying Optimal First-Line Interventions for Advanced Non-Small Cell Lung Carcinoma According to PD-L1 Expression: A Systematic Review and Network Meta-Analysis.
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Liu, J., Yu, J., and Meng, X.
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PEMETREXED , *PROGRAMMED death-ligand 1 , *IMMUNE checkpoint inhibitors , *META-analysis , *LUNGS , *CARCINOMA - Published
- 2020
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29. The Change of Soluble Programmed Cell Death Ligand-1 (sPD-L1) in Patients with Glioma during Radiotherapy and Impact on Clinical Outcome.
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Ding, X., Zhu, Y., Zhang, X., Nie, S., Zhou, Z., Guo, Y., Yu, J., and Hu, M.
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APOPTOSIS , *GLIOMAS , *PROGRAMMED death-ligand 1 , *IMMUNE checkpoint inhibitors , *OLIGODENDROGLIOMAS - Published
- 2020
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30. Soluble Programmed Death-Ligand 1 (sPD-L1) as a Novel Biomarker for the Combination of Anti-PD-L1 Antibody and Radiotherapy for Glioma Patients.
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Ding, X., Zhou, Z., Ge, Z., Guo, Y., Chen, Y., Nie, S., Yu, J., and Hu, M.
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PROGRAMMED death-ligand 1 , *GLIOMAS , *CELL analysis , *ENZYME-linked immunosorbent assay , *IMMUNE checkpoint inhibitors - Abstract
Purpose/objective(s): In our previous study, it has been proven that high level of soluble programmed death-ligand 1 (sPD-L1) is considered a predictor of negative clinical outcomes in glioma. However, the expression of sPD-L1 can change dynamically during radiotherapy (RT), and the effect of sPD-L1 has not been thoroughly elucidated. The purpose of this study was to uncover the dynamics of circulating sPD-L1 levels in glioma patients undergoing RT and to investigate the significance of plasma sPD-L1 levels as a biomarker for combining anti-PD-L1 antibody and RT.Materials/methods: Glioma patients treated with RT between October 2019 and September 2020 were prospectively recruited and sPD-L1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Blood samples were obtained before RT (0f), during RT (15 ± 2f) and RT end (30 ± 2f). Flow cytometry were used to address whether circulating sPD-L1 molecules can affect the CD8+ T cells activation and function in the adaptive immune response. Glioma murine model were used to validate whether combine RT and anti-PD-L1 antibody can be a promising therapeutic strategy in gliomas.Results: Thirty-two GBM patients treated with RT were included. The proportions of grade I, II, III, and IV gliomas were 6.2%, 28.1%, 21.9%, and 43.8%. RT significantly increased the mean level of sPD-L1 (0f vs. 15 ± 2f: 55.7 ± 19.2 vs.76.7 ± 38.8, P = 0.008; 0f vs. 30 ± 2f: 55.7 ± 19.2 vs.80.94 ± 44.9, P = 0.005). However, there was no significantly difference between during RT (15 ± 2f) and RT end (30 ± 2f). We performed the CD8+ T cells suppression analysis using mice plasma in vitro. The plasma from mice after anti-PD-L1 treatment (the concentration of sPD-L1 could not be detected) didn't show any suppression activity. Instead, the plasma from the mice without anti-PDL1 treatment exhibited the remarkable CD8+ T cell suppression capacity. These results indicated that the sPD-L1 can play an important role in T cell suppression. Furthermore, the glioma murine model indicated that the combination of irradiate (IR) and anti-PD-L1 significantly reduced tumor growth than either IR or anti-PD-L1 antibody monotherapy (anti-PD-L1 vs. IR plus anti-PD-L1: 789.67 ± 55.86 mm3vs. 292.16 ± 102.98 mm3 on day 31, P < 0.001; IR vs. IR plus anti-PD-L1: 697.02 ± 12.98 mm3vs. 292.16 ± 102.98 mm3 on day 31, P < 0.001).Conclusion: This study reported that sPD-L1 might be a potential biomarker in glioma patients receiving RT. This finding means that compensation for the potential sequestration of antibodies needs to be considered in the optimization of PD-L1 blockade therapies. Because not all administered anti-PD-L1 immunotherapeutic antibodies may reach the surface of tumor cells, with a potentially appreciable proportion being sequestered by sPD-L1 within the circulation. The elevated level of sPD-L1 after RT suggested that the strategy of a combination of immune checkpoint inhibitors and RT might be promising for glioma patients.Author Disclosure: X. Ding: None. Z. Zhou: None. Z. Ge: None. Y. Guo: None. Y. Chen: None. S. Nie: None. J. Yu: None. M. Hu: None. [ABSTRACT FROM AUTHOR]- Published
- 2021
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31. Detection of MR Imaging Differences of Metastatic Intracranial Lesions in Patients Treated With or Without Immunotherapy Following Stereotactic Radiosurgery Using Radiomics and Machine Learning.
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Morris, B.A., Premkumar, H., Enright, T., Yadav, P., Burr, A., McMillan, A., and Baschnagel, A.M.
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STEREOTACTIC radiosurgery , *MAGNETIC resonance imaging , *MACHINE learning , *FEATURE extraction , *PROGRAMMED death-ligand 1 - Abstract
Purpose/objective(s): Immune checkpoint inhibitors (ICIs), targeting programmed death-ligand 1 (PD-L1) and programmed death protein 1 (PD-1) receptor, are now routinely used for treatment of metastatic non-small cell lung cancer (NSCLC). Brain MRI changes in response to ICI and stereotactic radiosurgery (SRS) can sometimes be challenging to interpret. Using radiomic analysis, we sought to objectively characterize the differences between NSCLC brain metastases treated with and without immunotherapy, before and after SRS. A machine learning model was applied on post-SRS treatment radiomic features to distinguish between ICI treated versus non-treated patients.Materials/methods: Patients with NSCLC brain metastases treated with SRS were retrospectively identified. Patients were stratified based on immunotherapy treatment at time of SRS and at 3 month follow up MRI imaging. Using open-source software, 120 different radiomic features were extracted from metastases from T1-weighted post contrast axial MRIs before SRS and 3 months post SRS treatment. Differences between cohorts were compared by univariate and multivariate analysis. Post SRS radiomic features were further analyzed with a machine learning model using extreme gradient boosting (XGBoost) algorithms to predict presence of post-SRS immunotherapy treatment from MR imaging features.Results: A total of 40 patients with NSCLC with a total of 89 brain metastases were identified. 24 patients with 57 individual lesions were treated with SRS alone without ICI. 16 patients with 32 individual lesions were treated with SRS and ICI. No significant differences were noted in the two groups prior to SRS treatment. Analysis of follow up imaging in patients on ICI after SRS versus those not on ICI revealed 30 radiomic metrics that were significantly different on univariate analysis (P < 0.05 for all). Following multivariate analysis, three radiomic metrics, flatness, sphericity, and kurtosis were significantly predictive of ICI status (P < 0.05). Machine learning analysis yielded a receiver operator curve AUC of 0.84 ± 0.12. Using this model, we observed that the same three radiomic features (flatness, sphericity, and kurtosis) were the top 3 prominent radiomic differences.Conclusion: In this observational study, we identified a set of MRI-based radiomic metrics that accurately distinguished NSCLC brain metastases treated with or without ICI after SRS. This was validated using a machine learning model that identified the same 3 radiomic features most predictive of ICI status. Future studies will investigate whether this signature can help in classifying tumor recurrence from treatment effect and predict outcomes in this patient population.Author Disclosure: B.A. Morris: Employee; Epic Systems. H. Premkumar: None. T. Enright: None. P. Yadav: None. A. Burr: None. A. McMillan: None. A.M. Baschnagel: Consultant; HealthMyne, Inc. [ABSTRACT FROM AUTHOR]- Published
- 2021
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32. PD-L1 Expression Level of Primary Tumor as a Predictor of Local Control and Symptomatic Radiation Necrosis in Patients With Brain Metastases Undergoing SRS/fSRT With Concurrent Immunotherapy.
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Alexander, G.S., Savla, B., Berg, L.J., Sun, K., Remick, J.S., Kowalski, E.S., Chen, S., Lamichhane, N., Regine, W.F., Mishra, M.V., and Regine, W F Jr
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BRAIN metastasis , *PROGRAMMED death-ligand 1 , *BRAIN damage , *NECROSIS , *RADIATION - Abstract
Purpose/objective(s): PD-L1 is often overexpressed in the tumor microenvironment to dampen host immune response and allow tumor proliferation. Radiation works partially through the immune system, but the correlation between PD-L1 expression in primary tumors and oncologic outcomes for metastatic lesions treated with SRS with concurrent immunotherapy (ICI) is unknown. We seek to evaluate the association of PD-L1 expression level of the primary tumor in patients undergoing SRS/fSRT with local control and symptomatic radiation necrosis.Materials/methods: A total of 282 patients with 616 metastatic brain lesions which were treated with SRS or fSRT from 2014-2020 were retrospectively reviewed at a single institution. PD-L1 expression level in the primary tumor was available for 43 patients with 147 metastatic brain lesions, of whom 33 patients with 103 lesions received concurrent ICI. Concurrent ICI was defined as having received ICI within 3 months before, during, or after SRS. PD-L1 expression was categorized as negative (PDn) (< 1%), or positive (PDp) (≥1% - 100%). Patients were excluded if a one month post-treatment MRI was not available or if > 15 lesions were treated. The lesion level endpoint of local failure (LF) and symptomatic radiation necrosis (RN) were analyzed using Kaplan Meyer method with salvage WBRT used as a censoring event. Univariate and multivariate analysis were performed with competing risk adjustment.Results: One-hundred and four lesions (range 1-10) from 33 unique patients were included in the analysis. Ten patients with PDn primary tumors with 31 lesions and 23 patients with PDp primary tumors with 73 lesions were analyzed. After competing risk adjustment, the LF rate at 12 months were rare for both patient cohorts: PDn vs PDp was 3.5% and 1.5% (P = 0.99), respectively. For RN, the event rate at 12 months for PDn vs PDp was 4% vs 14% (HR 0.648; 95% CI 0.05-9.03; P = 0.747). On MVA for local control, factors such as metastasis size (< 2cm vs ≥2 cm; P = 0.181), histology (NSCLC vs other; P = 0.997), or lesion location (supratentorial vs other; P = 0.392) were not found to have a statistically significant association. On MVA for RN, only metastasis size reached statistical significance (HR 32.8; 95% CI 3.56-301.81; P < 0.002).Conclusion: Patients receiving concurrent ICI and SRS for management of brain metastases have an excellent local control, irrespective of PD-L1 status. PD-L1 positive patients may be at an increased risk for RN. These findings require further evaluation in a larger patient cohort.Author Disclosure: G.S. Alexander: None. B.Savla: None. L.J. Berg: None. K. Sun: None. J.S.Remick: None. E.S. Kowalski: None. S. Chen: None. N.Lamichhane: None. W.F. Regine: None. M.V. Mishra: Employee; Orthofix. Research Grant; ASTRO, Keep Punching. Advisory Board; Patient Centers Outcomes Research Institute (PCORI. Travel Expenses; Patient Centers Outcomes Research Institute (PCORI. [ABSTRACT FROM AUTHOR]- Published
- 2021
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33. Sequential Monitoring of PD-L1 on Circulating Tumor Stromal Cells Predicts Survival Outcomes for Unresectable Stage 3 NSCLC Treated With Immunotherapies After Definitive Chemoradiation.
- Author
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Lin, S.H., Augustyn, A., He, J., Qiao, Y., Xu, T., Liao, Z., Gardner, K.P., Moran, J.A., Tang, C.M., and Adams, D.L.
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SURVIVAL rate , *CELL survival , *STROMAL cells , *PROGRAMMED death-ligand 1 , *PROGRESSION-free survival - Abstract
Purpose/objective(s): Cancer Associated Macrophage-Like cells (CAMLs) are a type of circulating stromal cell found in the blood of cancer patients (pts), described as of myeloid origin that represent the inflammatory state of the tumor microenvironment. We have previously reported that in non-small cell lung carcinoma (NSCLC), CAML PD-L1 expression is dynamic and trackable throughout chemoradiation (CRT). However, it is unknown if PD-L1 on CAMLs has clinical utility, particularly in immunotherapy (IMT) efficacy after CRT. We studied stage 3 unresectable NSCLC pts treated with (n = 80) or without (n = 55) IMT agents after CRT to evaluate CAML PD-L1 expression on progression free survival (PFS) & overall survival (OS).Materials/methods: We used 2 sets of IMT treated pts: first set from a single arm phase 2 trial treated with CRT and atezolizumab (atezo) (n = 34) and a second from a multi-year prospective study treated with standard of care CRT with consolidation durvalumab (durva) (n = 46). A control group of CRT alone pts (n = 55) were evaluated during the same period (majority before 2018). In all, 135 pts with pathologically confirmed unresectable stage 3 NSCLC were included. 15mL blood samples were taken at Baseline (BL) & ∼1 month after completion of CRT. Blood was filtered & CAMLs quantified for PD-L1 expression using a binary score (0/1 = low & 2/3 = high), to evaluate PFS & OS hazard ratios (HRs) by censored univariate & multivariate analysis at 24 months.Results: CAMLs were found in 92% of all samples, on average 5.2 CAMLs/15mL. From the available tumor biopsies, > 1% PD-L1 expression using DAKO 22c3 did not predict CRT+IMT (atezo/durva) response (PFS HR 1.4 P = 0.642 & OS HR 1.9 P = 0.293). At BL, high CAML PD-L1 was not associated with PFS in CRT alone (HR 1.5 P = 0.435), CRT+atezo (HR 1.0 P = 0.843), or CRT+durva (HR 1.6 P = 0.6180). After CRT, while high CAML PD-L1 did not predict PFS in CRT alone (HR 1.0 P = 0.925), it was associated with superior PFS in CRT+atezo (HR 2.8 P = 0.046), & CRT+durva (HR 5.2 P = 0.036). For OS, high CAML PD-L1 was not predictive of outcomes in CRT alone (HR 0.8 P = 0.929), but strongly predictive of superior OS for CRT+atezo (HR 4.3 P = 0.036) & CRT+durva (HR 5.9 P = 0.033) groups. Combined (atezo or durva, n = 80), 57% of pts had either maintained high PD-L1 before and after CRT (N = 25) or increased from BL (N = 21). Pts with high PD-L1 post CRT had better outcomes than pts with low expression, PFS HR = 4.1 P < 0.001 and OS HR = 4.7 P < 0.001. This pattern was not seen in pts treated with CRT alone (PFS HR = 1.2 P = 0.763 and OS HR = 0.9 P = 0.977).Conclusion: Our data suggests that in unresectable stage 3 NSCLC, high PD-L1 expression on CAMLs after CRT completion is predictive of superior clinical outcomes in pts treated with IMT, but not in those treated with CRT alone. Prospective validation is needed to confirm these findings. [ABSTRACT FROM AUTHOR]- Published
- 2021
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34. Regulation of DNA Damage Signal-dependent PD-L1 Upregulation In Cancer Cells After Ionizing Irradiation.
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Sato, H., Permata, T.B.M., Gu, W., Kakoti, S., Oike, T., Yasuhara, T., Nakano, T., Ohno, T., and Shibata, A.
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PROGRAMMED death-ligand 1 , *DNA damage , *CANCER cells , *IRRADIATION , *DOUBLE-strand DNA breaks , *PROGRAMMED cell death 1 receptors - Published
- 2020
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35. Impact of Programmed Death-Ligand 1 (PD-L1) Expression on The Efficacy of First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKI) in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC).
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Lee, C.C., Soon, Y.Y., Leong, C.N., Koh, W.Y., and Tey, J.
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PROGRAMMED death-ligand 1 , *EPIDERMAL growth factor receptors , *NON-small-cell lung carcinoma , *PROTEIN-tyrosine kinases , *KINASE inhibitors - Published
- 2020
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36. Superior Prognostic Performance of an Immunohistochemistry Trained DNA-Methylation Based PD-L1 Score in Patients with HNSCC Treated with Radiochemotherapy: A Multicenter Study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
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Knoll, M., Balermpas, P., von der Grün, J., Tawk, B., Adeberg, S., Tinhofer, I., Budach, V., Linge, A., Krause, M., Stuschke, M., Grosu, A.L., Zips, D., Combs, S.E., Belka, C., Kriegsmann, M., Weichert, W., Baumann, M., Roedel, C., Debus, J., and Abdollahi, A.
- Subjects
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PROGRAMMED death-ligand 1 , *PROGRAMMED cell death 1 receptors , *CHEMORADIOTHERAPY , *IMMUNOHISTOCHEMISTRY , *CONSORTIA , *ONCOLOGY - Published
- 2020
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37. Trimodal Therapy Consisting of DNA-PK Inhibition, PD-L1 Immune Checkpoint Blockade and Radiotherapy with Carbon Ions.
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Klein, C.D., Schlegel, J., Knoll, M., Dokic, I., Moustafa, M., Mairani, A., Brons, S., Zimmermann, A., Zenke, F.T., Blaukat, A., Debus, J., and Abdollahi, A.
- Subjects
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PROGRAMMED death-ligand 1 , *IONS , *ONCOLOGY , *RADIOTHERAPY , *CYTOTOXIC T lymphocyte-associated molecule-4 - Published
- 2020
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