scholarly journals PD-L1 expression in 522 selected sarcomas with subset analysis of recurrent or metastatic matched samples and association with tumour-infiltrating lymphocytes

2019 ◽  
Author(s):  
Ana Cristina Vargas ◽  
Fiona M Maclean ◽  
Loretta Sioson ◽  
Dinh Tran ◽  
Fiona Bonar ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Tissue Microarrays ◽  
Treatment Benefit ◽  
Paired Samples ◽  
Metastatic Setting ◽  
Tumour Infiltrating Lymphocytes ◽  
Myxoid Liposarcomas ◽  
Pleomorphic Liposarcomas ◽  
Infiltrating Lymphocytes ◽  
Matched Samples

AbstractWe assessed the frequency of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) in a cohort of 522 sarcomas from 457 patients, incuding a subset of 46 patients with 63 matched samples from local recurrence or metastases with primary tumours and/or metachronous metastases. We also investigated the correlation of PD-L1 with the presence and degree of tumour-infiltrating lymphocytes (TILs) in a subset of cases. IHC was performed using the PD-L1 SP263 companion kit (VENTANA) on tissue microarrays from an archival cohort. Evaluation of PD-L1 and TILs was performed on full sections for a subset of 23 cases. Fisher’s exact and Mann Whitney test were used to establish significance (P <0.05). PD-L1 positive expression (≥1%) was identified in 31% of undifferentiated pleomorphic sarcomas, 29% of angiosarcomas, 26% of rhabdomyosarcomas, 18% of myxofibrosarcomas, 11% of leiomyosarcomas and 10% of dedifferentiated liposarcomas. Negative expression was present in all atypical lipomatous tumous/well-differentiated lipoasarcomas, myxoid liposarcomas, synovial sarcomas, pleomorphic liposarcomas, and Ewing sarcomas. PD-L1 IHC was concordant in 81% (38 of 47) of matched/paired samples. PD-L1 IHC was discordant in 19% (9 of 47 matched/paired samples), displaying differences in the proportion of cells expressing PD-L1 amongst paired samples with the percentage of PD-L1-positive cells increasing in the metastatic/recurrent site compared to the primary in 6 of 9 cases (67%). Significant correlation between PD-L1 expression and the degree of TILs was exclusively identified in the general cohort of leiomyosarcomas, but not in other sarcoma subtypes or in metastatic/recurrent samples. We conclude that the prevalence of PD-L1 expression in selected sarcomas is variable and likely to be clone dependent. Importantly, we demonstrated that PD-L1 can objectively increase in a small proportion of metastases/recurrent sarcomas, offering the potential of treatment benefit to immune checkpoint inhibitors in this metastatic setting.

scholarly journals Immune Classification for the PD-L1 Expression and Tumour-Infiltrating Lymphocytes in Colorectal Adenocarcinoma

2019 ◽  
Author(s):  
Byeong-Joo Noh ◽  
Jae Young Kwak ◽  
Dae-Woon Eom
Keyword(s):  
Colorectal Adenocarcinoma ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Tumour Microenvironment ◽  
Tumour Cells ◽  
Effective Response ◽  
Recent Emergence ◽  
Tumour Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes ◽  
Colorectal Adenocarcinomas

Abstract Background Colorectal adenocarcinoma is the third most common cancer worldwide and a leading cause of cancer-related death. The recent emergence of diverse immunotherapeutic agents has made it crucial to interpret a complex tumour microenvironment intermingled with tumour-infiltrating immune cells to predict the immunotherapeutic response rate. However, in colorectal adenocarcinoma, studies are lacking that provide detailed analyses of programmed death-ligand 1 (PD-L1) and tumour-infiltrating lymphocytes (TIL) to elucidate their prognostic values and to identify immunotherapy-targetable subgroups, preferably with multiple immune-related biomarkers. In the present study, we categorize colorectal adenocarcinomas into four types of tumour immune microenvironments according to PD-L1 expression and TIL, analyse their prognostic values, and propose an immunotherapy-targetable subgroup.Methods Formalin-fixed, paraffin-embedded tissue samples of surgically resected primary colorectal adenocarcinomas (n = 489) were obtained and arrayed on tissue microarray blocks. Immunohistochemical stains for PD-L1, programmed cell death protein 1 (PD-1), cluster of differentiation 8 (CD8), and microsatellite instability (MSI) were performed and evaluated.Results Tumour microenvironment immune type (TMIT) I (PD-L1-positive tumour cells and CD8-high TIL) and type II (PD-L1-negative tumour cells and CD8-low TIL) showed the best and worst prognoses, respectively. PD-L1 overexpression was significantly associated with MSI status. PD-L1 immunoreactivity was positively correlated with TIL having CD8 or PD-1 overexpression.Conclusions TMIT I subgroup showed stronger CD8/PD-L1/PD-1 signalling interaction compared to the other TMIT. Therefore, we propose that the TMIT I subgroup is a candidate TMIT to predict effective response rate for existing immune checkpoint inhibitors and determine targetable subgroups for emerging therapies.

scholarly journals CD8+ Tumour-Infiltrating Lymphocytes and Tumour Microenvironment Immune Types as Biomarkers for Immunotherapy in Sinonasal Intestinal-Type Adenocarcinoma

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 202
Author(s):  
Rocío García-Marín ◽  
Sara Reda ◽  
Cristina Riobello ◽  
Virginia N. Cabal ◽  
Laura Suárez-Fernández ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Value ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumour Microenvironment ◽  
Intestinal Type ◽  
Rare Tumour ◽  
Intestinal Type Adenocarcinoma ◽  
Tumour Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

Background. Intestinal-type adenocarcinoma (ITAC) is a rare tumour occurring in the ethmoid sinus. Recent years have brought advances in endoscopic surgery and precision radiotherapy; however, five-year overall survival has not improved and remains at 35–80%, depending on tumour stage and histology. Therefore, there is a need for new therapeutic options. Methods. We evaluated CD8+ tumour-infiltrating lymphocytes (TILs) and tumour microenvironment immune type (TMIT, combining CD8+ TILs and PD-L1) as predictive biomarkers for immunotherapy in a series of 133 ITAC. All results were correlated to clinical and follow-up data. Results. The presence of intratumoural CD8+ TILs was low in 57% of cases and high in 8% of cases. Tumoural PD-L1 positivity was observed in 26% of cases. CD8+ TILs and TMIT correlated with the histological subtype of ITAC and with better overall survival. The presence of stromal PD-L1-positive macrophages was related to intratumoural CD8+ TILs. PD-L1 expression on tumour cells or macrophages did not show prognostic value. Conclusions. TMIT classification did not have additional prognostic value over CD8+ TILs alone. The modest percentage of CD8high/PD-L1pos cases indicates that ITAC is a lowly immunogenic tumour type. Nevertheless, a proportion of ITAC, especially the papillary and colonic subtypes, could benefit from therapy with immune checkpoint inhibitors.

scholarly journals Immune Classification for the PD-L1 Expression and Tumour-Infiltrating Lymphocytes in Colorectal Adenocarcinoma

2020 ◽  
Author(s):  
Byeong-Joo Noh ◽  
Jae Young Kwak ◽  
Dae-Woon Eom
Keyword(s):  
Colorectal Adenocarcinoma ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Tumour Microenvironment ◽  
Tumour Cells ◽  
Effective Response ◽  
Recent Emergence ◽  
Tumour Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes ◽  
Colorectal Adenocarcinomas

Abstract Background Colorectal adenocarcinoma is the third most common cancer worldwide and a leading cause of cancer-related death. The recent emergence of diverse immunotherapeutic agents has made it crucial to interpret a complex tumour microenvironment intermingled with tumour-infiltrating immune cells to predict the immunotherapeutic response rate. However, in colorectal adenocarcinoma, studies are lacking that provide detailed analyses of programmed death-ligand 1 (PD-L1) and tumour-infiltrating lymphocytes (TIL) to elucidate their prognostic values and to identify immunotherapy-targetable subgroups, preferably with multiple immune-related biomarkers. In the present study, we categorize colorectal adenocarcinomas into four types of tumour immune microenvironments according to PD-L1 expression and TIL, analyse their prognostic values, and propose an immunotherapy-targetable subgroup.Methods Formalin-fixed, paraffin-embedded tissue samples of surgically resected primary colorectal adenocarcinomas (n = 489) were obtained and arrayed on tissue microarray blocks. Immunohistochemical stains for PD-L1, programmed cell death protein 1 (PD-1), cluster of differentiation 8 (CD8), and microsatellite instability (MSI) were performed and evaluated.Results Tumour microenvironment immune type (TMIT) I (PD-L1-positive tumour cells and CD8-high TIL) and type II (PD-L1-negative tumour cells and CD8-low TIL) showed the best and worst prognoses, respectively. PD-L1 overexpression was significantly associated with MSI status. PD-L1 immunoreactivity was positively correlated with TIL having CD8 or PD-1 overexpression.Conclusions TMIT I subgroup showed stronger CD8/PD-L1/PD-1 signalling interaction compared to the other TMIT. Therefore, we propose that the TMIT I subgroup is a candidate TMIT to predict effective response rate for existing immune checkpoint inhibitors and determine targetable subgroups for emerging therapies.

Immune microenvironment in mesothelioma: Looking beyond PD-L1.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8515-8515 ◽  
Author(s):  
Bibhusal Thapa ◽  
Marzena Walkiewicz ◽  
Gareth Rivalland ◽  
Carmel Murone ◽  
Khashayar Asadi ◽  
...  
Keyword(s):  
Survival Data ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Tissue Microarrays ◽  
Tumour Microenvironment ◽  
Physiological Status ◽  
Invasive Tumour ◽  
Predictive Role ◽  
Infiltrating Lymphocytes

8515 Background: Studies using immune checkpoint inhibitors in mesothelioma (MM) have shown promise. Differences in response to PD-L1 and PD-1 inhibitors (10% vs 25%) have been reported. Also, expression of PD-L1 alone appears to be a limited predictor. As the roles of the multiple check point receptors and their ligands become defined, an understanding of their expression and interplay in the mm tumour microenvironment, which could affect suitability for checkpoint inhibition therapy, has become necessary. Methods: Tissue microarrays were constructed and stained with PD-L2, LAG3 and TIM3 antibodies. Tumour infiltrating lymphocytes (TILs) were assessed in the stroma and expressed as a % of stromal area within invasive tumour. These data were combined with PD-L1 expression, CD4+ and CD8+ infiltration in the same cohort reported previously. To quantify the immunosuppressive milieu, we combined our assessment of PD-L1, PD-L2 and TIM3 expression to derive an “Immune checkpoint score (ICS)” and explored its correlation with the tumour microenvironment and clinicopathological covariates. We are also exploring its predictive value in an independent cohort of mm patients who have received anti-PD-1 treatment. Results: Amongst 329 patients evaluated, PD-L1 was positive (+) in 41.7% and PD-L2+ in 24.5%. TIM3+ lymphocytes were found in 99.4% but LAG3+ lymphocytes in only 0.2%. 28/173 (16%) of PD-L1- patients were PD-L2+ and 31/136 (22%) PD-L1 and PD-L2 negative patients had high infiltration with TIM3+ lymphocytes. High ICS was associated with non-epithelioid histology, increased TILs and poorer survival. On multivariate analysis, high TILs, non-epithelioid histology and poor physiological status remained significantly associated with poorer survival. Data on the predictive role of ICS score will also be reported. Conclusions: While co-expression of PD-L1, PD-L2 and TIM3 can occur, their expression is mutually exclusive in a large proportion of patients. The expression of PD-L2 may explain differences in responses seen between PD-1 compared to PD-L1 inhibitors. A comprehensive assessment of these multiple immunosuppressive pathways may be necessary to truly gauge the immunosuppressive environment and tailor immunotherapy for individual cases.

scholarly journals Immune Classification for the PD-L1 Expression and Tumour-Infiltrating Lymphocytes in Colorectal Adenocarcinoma

2020 ◽  
Author(s):  
Byeong-Joo Noh ◽  
Jae Young Kwak ◽  
Dae-Woon Eom
Keyword(s):  
Colorectal Adenocarcinoma ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Tumour Microenvironment ◽  
Tumour Cells ◽  
Effective Response ◽  
Recent Emergence ◽  
Tumour Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes ◽  
Colorectal Adenocarcinomas

Abstract Background Colorectal adenocarcinoma is the third most common cancer worldwide and a leading cause of cancer-related death. The recent emergence of diverse immunotherapeutic agents has made it crucial to interpret a complex tumour microenvironment intermingled with tumour-infiltrating immune cells to predict the immunotherapeutic response rate. However, in colorectal adenocarcinoma, studies are lacking that provide detailed analyses of programmed death-ligand 1 (PD-L1) and tumour-infiltrating lymphocytes (TIL) to elucidate their prognostic values and to identify immunotherapy-targetable subgroups, preferably with multiple immune-related biomarkers. In the present study, we categorize colorectal adenocarcinomas into four types of tumour immune microenvironments according to PD-L1 expression and TIL, analyse their prognostic values, and propose an immunotherapy-targetable subgroup.Methods Formalin-fixed, paraffin-embedded tissue samples of surgically resected primary colorectal adenocarcinomas (n = 489) were obtained and arrayed on tissue microarray blocks. Immunohistochemical stains for PD-L1, programmed cell death protein 1 (PD-1), cluster of differentiation 8 (CD8), and microsatellite instability (MSI) were performed and evaluated.Results Tumour microenvironment immune type (TMIT) I (PD-L1-positive tumour cells and CD8-high TIL) and type II (PD-L1-negative tumour cells and CD8-low TIL) showed the best and worst prognoses, respectively. PD-L1 overexpression was significantly associated with MSI status. PD-L1 immunoreactivity was positively correlated with TIL having CD8 or PD-1 overexpression.Conclusions TMIT I subgroup showed stronger CD8/PD-L1/PD-1 signalling interaction compared to the other TMIT. Therefore, we propose that the TMIT I subgroup is a candidate TMIT to predict effective response rate for existing immune checkpoint inhibitors and determine targetable subgroups for emerging therapies.

Regulatory-T cells (Tregs) in tumor infiltrating lymphocytes (TILs) from patients with advanced gastric cancer (AGC) after chemotherapy containing ramucirumab.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15570-e15570
Author(s):  
Daisuke Kotani ◽  
Yosuke Togashi ◽  
Akihito Kawazoe ◽  
Toshihiko Doi ◽  
Hiroyoshi Nishikawa ◽  
...  
Keyword(s):  
T Cells ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Vascular Endothelial ◽  
Flow Cytometry Assay ◽  
Paired Samples ◽  
Programmed Cell Death 1 ◽  
Endothelial Growth Factor ◽  
Infiltrating Lymphocytes ◽  
To Receive

e15570 Background: Vascular endothelial growth factor-A (VEGF-A) and VEGF recepter-2 (VEGFR-2) axis is known to induce Tregs in tumor bearing mice. Ramucirumab (RAM), a monoclonal antibody for VEGFR-2, was recently approved for patients with AGC. However, little is known about the influence of RAM on Tregs in TILs from AGC patients. Methods: Patients with AGC who had been planned to receive chemotherapy containing RAM were prospectively enrolled for this study from January 2016 to August 2016. Paired samples were obtained from primary tumor at pre- and post-RAM therapy to analyze immune profiles of TILs using flow cytometry assay. Results: A total of 17 patients were analyzed. Median age was 68 years old (range, 46-79). All patients received one or more previous chemotherapy. RAM containing regimens included RAM+paclitaxel (n = 13), RAM monotherapy (n = 3) and RAM+irinotecan (n = 2). FOXP3highCD45RA-CD4+ T cells (effector Tregs: eTregs) in CD4+ T cells was significantly decreased after RAM therapy compared with that in baseline (mean, 19.5% vs.13.6%, P = 0.036). In contrast, no significant change of CD8+ T cells was observed (mean, 36.7% vs. 36.0%, P = 0.86). Expression of programmed cell death-1 (PD-1) on CD8+ T cells was tended to be decreased after RAM therapy. Conclusions: eTregs in TILs was suggested to be decreased after RAM-containing therapy which warrants further evaluation in a larger cohorts. This observation might be a rationale to use RAM as an immunomodulator in combination of immune checkpoint inhibitors for AGC.

scholarly journals 353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A378-A378
Author(s):  
Antonio Jimeno ◽  
Sophie Papa ◽  
Missak Haigentz ◽  
Juan Rodríguez-Moreno ◽  
Julian Schardt ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Single Agent ◽  
Objective Response ◽  
Tumor Resection ◽  
Tumor Infiltrating Lymphocytes ◽  
Open Label ◽  
Safety And Efficacy ◽  
Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

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