Frequency and prognostic role of tumor infiltrating lymphocytes and MMR status in advanced non-colorectal GI malignancies.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 89-89
Author(s):  
Uqba Khan ◽  
Ameer Hamza ◽  
Renny Abraham ◽  
Muhammad S Khurram ◽  
Tarik H. Hadid ◽  
...  

89 Background: Tumor infiltrating lymphocytes (TILs) and mismatch repair gene mutation (MMR) status are emerging biomarkers in immunotherapy. MMR status and TILs have significant clinical implications with respect to treatment with checkpoint inhibitors. We designed a study to determine the frequency and prognostic utility of TILs and MMR in advanced unresectable non-colorectal GI (NCGI) cancers. Methods: This is a retrospective cohort study of patients who were diagnosed with metastatic or unresectable NCGI cancers between 2009 and 2015 at St. John Hospital and Medical Center. Immunohistochemistry panels were performed on representative tissue sections for MMR testing. TILs were assessed on the hematoxylin and eosin stained slide of the same tissue section. MMR was interpreted as deficient (d) or proficient and TILs were categorized as ≤5 or > 5 per high power field. Descriptive statistics were generated using frequency distributions, medians and means. Kaplan-Meier analysis was performed to determine the impact of TILS and MMR on survival; differences by factor were assessed with the Log_Rank test. Results: We analyzed 132 patients; the mean age at diagnosis was 66.7 years, 62.1% were male. All samples had proficient MMR status. The percentage of patients with TILs ≤ 5 was 46.2. There was no statistically significant difference in median overall survival (OS) by TILs when stratified by stage of tumor. When stratified by type of tumor, median OS by TILs level was significantly different only for hepatocellular cancers (HCC) (≤ 5 TILs, 86 days vs. > 5 TILs 312 days, p = 0.031), table 1. Conclusions: Our study suggests that MMR-d tumors are quite rare in advanced NCGI malignancies. TILs can be present in tumor microenvironment of NCGI malignancies. Though the number of patients in our study was small, there was a statistically significant difference in median OS of patients with HCC when stratified by TILs status.[Table: see text]

2018 ◽  
Vol 27 (3) ◽  
pp. 263-267 ◽  
Author(s):  
Ameer Hamza ◽  
Uqba Khan ◽  
Muhammad Siddique Khurram ◽  
Renny Abraham ◽  
Paul Mazzara ◽  
...  

Background. Tumor-infiltrating lymphocytes (TILs) and mismatch repair gene mutation (MMR) status are emerging biomarkers in immunotherapy. MMR status and TILs have significant clinical implications with regard to treatment with checkpoint inhibitors. We designed a study to determine the frequency and prognostic utility of TILs and MMR in advanced unresectable noncolorectal gastrointestinal (NCGI) malignancies. Methods. This is a retrospective cohort study of patients who were diagnosed with advanced noncolorectal gastrointestinal tumors. Biopsy specimens were tested for MMR status by immunohistochemistry along with evaluation of TILs. Kaplan-Meier analysis was performed to determine the impact of TILS and MMR on survival. Results. We analyzed 146 patients; the mean age at diagnosis was 66.4 ± 11.2 years. 65.8% patients were male, and 62.3% patients had stage 4 disease. All cases had proficient MMR status. The percentage of patients with TILs >5 was 50.7%. There was no statistically significant difference in median overall survival (OS) by TILs when stratified by stage of tumor. When stratified by type of tumor, median OS by TILs level was significantly different for hepatocellular cancers (⩽5 TILs, 86 days versus >5 TILs 312 days, P = .031). Conclusions. Our study suggests that MMR-deficient tumors are quite rare in advanced NCGI malignancies. More than 5 TILs per high power field, evaluated simply on a routine hematoxylin and eosin–stained glass slide confer a better prognosis to most noncolorectal gastrointestinal malignancies, especially hepatocellular carcinoma. This has immense clinical utility with regard to eligibility for immunotherapy.


2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 313-313
Author(s):  
Uqba Khan ◽  
Ameer Hamza ◽  
Muhammad S Khurram ◽  
Renny Abraham ◽  
Paul Mazzara ◽  
...  

313 Background: Mismatch repair gene mutation status not only has a role in pathogenesis but also has significant clinical implications with respect to treatment with checkpoint inhibitors. Additionally tumor infiltrating lymphocytes (TILs) are also emerging prognostic biomarker and are utilized in adoptive T-cell therapy as well. Methods: This is a retrospective cohort study of patients who were diagnosed with advanced unresectable non-colorectal GI (NCGI) cancers. Biopsy specimens of patients diagnosed between 2009 and 2015 at St. John Hospital and Medical Center were analyzed. Immunohistochemistry panels were performed on a representative tissue sections for microsatellite instability (MSI) testing. TILs were assessed on the hematoxylin and Eosin stained slide of the same tissue section. MSI was interpreted as stable or high and TILs were categorized as ≤5 and > 5 per high power field. Descriptive statistics were generated using frequency distributions, medians and means. Kaplan-Meier analysis was performed to determine the impact of TILs and MSI on survival; differences by factor were assessed with the Log_Rank test. Results: We analyzed 114 patients; the mean age at diagnosis was 66.8 ± 10.7 years, 61.4% were male. All samples were MSI stable. The percentage of patients with TILs ≤ 5 was 46.5. When stratified by tumor stage, overall median survival by TILs level did not differ significantly. When stratified by type of tumor, overall median survival by TILs level was significantly different only for hepatocellular cancers (HCC) (≤ 5 TILs, 86 days vs. > 5 TILs 312 days, p = 0.031) only, (see table). Conclusions: Our study shows that MSI-H tumors are very rare in advanced NCGI malignancies. TILs are definitely present in tumor microenvironment of NCGI malignancies. Though the number of patients of our study was small, there was a statistically significant difference in median overall survival of patients with HCC when stratified by TILs status.[Table: see text]


2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 190-190
Author(s):  
Mary Nesline ◽  
Igor Puzanov ◽  
Marc S. Ernstoff ◽  
Sarabjot Pabla ◽  
Jeffrey M. Conroy ◽  
...  

190 Background: CD8 positive tumor infiltrating lymphocytes (TILS) are highly associated with immune response and prognosis, and are also under investigation as a marker of response to checkpoint inhibitors. Given lack of predictive biomarkers for ipilimumab, growing number of trials for new indications for combination ipilimumab + nivolumab, and evidence to support therapeutic target overexpression as markers of response, we examined the role of CTLA-4 expression and TILS in response to ipilimumab and combination ipilimumab + nivolumab in melanoma. Methods: Formalin-fixed paraffin embedded melanoma samples taken prior to treatment by ipilimumab (n = 36) or combination ipilimumab + nivolumab (n = 10) were evaluated by a comprehensive immune gene expression profile to establish the relationship between CTLA-4 and CD8 and therapeutic response (RECIST v1.1). Results: Increased CTLA-4 expression was moderately associated with increased TILS (r2= .41, p = .004). This was observed in the monotherapy group (r2= .38, p = .02), and was higher in the smaller combination therapy group, though not statistically significant (r2= .59, p = .06). Higher levels of TILS were observed in responders who achieved clinical benefit from either regimen within 6 months (n = 20). No significant difference was observed between responders (M = 57.1, SD = 30.2) and nonresponders (M = 48.6, SD = 32.9); t(44) = -.895, p = .376. Lower levels of CTLA-4 were observed in responders who achieved clinical benefit from either regimen within 6 months. No significant difference was observed between responders (M = 54, SD = 35) and nonresponders (M = 38.7, SD = 26.8); t(44) = 1.70, p = .09. The ratio of TILS to CTLA-4 expression was higher in responders who achieved clinical benefit within 6 months (n = 20).No significant difference was observed between responders (M = 5.2, SD = 14.0) and nonresponders (M = 1.4, SD = 2.7); t(41) = -1.2, p = .212. Conclusions: While not statistically significant, CTLA-4 expression in melanoma patients treated with either ipilimumab or combination ipilimumab + nivolumab was lower in responders compared to nonresponders. This analysis does not support the concept that over-expression of CTLA-4 is a biomarker of response to anti-CTLA-4 therapy.


2021 ◽  
Vol 164 (4) ◽  
pp. 781-787
Author(s):  
Samuel Rubin ◽  
Jacqueline A. Wulu ◽  
Heather A. Edwards ◽  
Robert W. Dolan ◽  
David M. Brams ◽  
...  

Objective Determine whether opioid prescriber patterns have changed for tonsillectomy, parotidectomy, and thyroidectomy after implementation of the Massachusetts Prescription Awareness Tool (MassPAT). Study Design Retrospective cohort study. Setting Single-center tertiary care hospital. Methods Patients were included if they received tonsillectomy, parotidectomy, or thyroid surgery at Lahey Hospital and Medical Center (Burlington, Massachusetts) between October 1, 2015, and October 1, 2019. Prescribing patterns were compared prior to implementation of MassPAT, October 1, 2015, to October 14, 2016, to postimplementation of MassPAT, October 15, 2016, to October 1, 2019. Quantity of opioids prescribed was described using total morphine milligram equivalents (MME). Data were analyzed using univariate analysis, multivariate analysis, and trend line using line of best fit. Results A total of 737 subjects were included in the study. There was a downward trend in the quantity of opioids prescribed for all 3 surgeries during the study period. There was a significant difference in the quantity of opioids prescribed pre- and postimplementation of MassPAT for tonsillectomy (647.70 ± 218.50 MME vs 474.60 ± 185.90 MME, P < .001), parotidectomy (241.20 ± 57.66 MME vs 156.70 ± 72.99 MME, P < .001), and thyroidectomy (171.20 ± 93.77 MME vs 108.50 ± 63.84 MME, P < .001). There was also a decrease in the number of patients who did not receive opioids for thyroidectomy pre- and post-MassPAT (7.56% vs 24.14%). Conclusion We have demonstrated that there is an association with state drug monitoring programs and decrease in the amount of opioids prescribed for acute postoperative pain control for common otolaryngology surgeries.


2019 ◽  
Vol 34 (2) ◽  
pp. 132-138 ◽  
Author(s):  
Young San Ko ◽  
Jung-Soo Pyo

Purpose: This study aimed to elucidate the clinicopathological significance and prognostic role of tumor-infiltrating lymphocytes in colorectal cancer. Methods: The immunohistochemistry of CD3 and CD8 was performed on 265 human colorectal cancer tissues to investigate the tumor-infiltrating lymphocytes using Immunoscore. The correlation between Immunoscore and clinicopathological characteristics, including survival rates, was elucidated. In addition, the impact of tumor-infiltrating lymphocytes on programmed death-ligand 1 (PD-L1) protein expression was evaluated through immunohistochemistry. Results: Of the 265 colorectal cancer tissues, 40.8% had high Immunoscore, while 59.2% had low Immunoscore. A high Immunoscore was significantly correlated with favorable tumor behaviors, including lower rates of vascular, lymphatic, and perineural invasion; lymph node metastasis; and distant metastasis. PD-L1 expressions of tumor and immune cells were significantly higher in patients with high Immunoscore than in those with low Immunoscore. In addition, colorectal cancer tissues with high CD8-positive lymphocytes showed higher PD-L1 expressions of tumor and immune cells than colorectal cancer tissues with low CD8-positive lymphocytes. There was a significant correlation between high Immunoscore and better overall survival. However, there was no significant difference in survival rate according to PD-L1 expressions of tumor and immune cells in high and low Immunoscore subgroups. Conclusions: Taken together, our results showed that high tumor-infiltrating lymphocytes were significantly correlated with favorable tumor behaviors and better survival. In addition, there was a significant correlation between PD-L1 expression and tumor-infiltrating lymphocytes.


2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 48-48
Author(s):  
Satoshi Muto ◽  
Hayato Mine ◽  
Hironori Takagi ◽  
Masayuki Watanabe ◽  
Yuki Ozaki ◽  
...  

48 Background: Depending on the number of tumor infiltrating lymphocytes, immunological cold to hot conditions vary. There are several clinical trials of administering immune checkpoint inhibitors as perioperative adjuvant therapy. Immune checkpoint inhibitors are generally effective in immunologically hot conditions. However, biopsy specimens are not enough to determine the amount of tumor infiltrating lymphocytes. Therefore, we focused on effector T lymphocytes in peripheral blood, and tried to understand the tumor microenvironment by looking at peripheral blood. Methods: Twenty-four patients with lung cancer who underwent surgery at Fukushima Medical University Hospital from December 2018 to June 2019 were able to separate and collect tumor infiltrating lymphocytes by magnetic cell sorting. Flow cytometry was used to analyze infiltrating lymphocytes and preoperative peripheral blood lymphocytes. Those not expressing CD62L, a marker of Naïve T lymphocytes, were designated as effector T lymphocytes. Results: In the group with a high proportion of cytotoxic T lymphocytes in tumor infiltrating lymphocytes, the proportion of CD62L-negative effector CD4 T lymphocytes in peripheral blood was high (p < 0.05). The percentage of lymphocytes in peripheral blood was also high (p < 0.05). Furthermore, tumor infiltrating lymphocytes had a high proportion of effector CD4 T lymphocytes (p < 0.05). There was a similar trend in the proportion of CD8 T lymphocytes, but there was no statistically significant difference. Conclusions: These results showed that immunologically hot cases could be identified by measuring effector CD4 T lymphocytes in peripheral blood. In the future, we will continue to verify the results and examine antigen specificity of these T lymphocytes.


2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A378-A378
Author(s):  
Antonio Jimeno ◽  
Sophie Papa ◽  
Missak Haigentz ◽  
Juan Rodríguez-Moreno ◽  
Julian Schardt ◽  
...  

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.


2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S144-S144
Author(s):  
Azza Elamin ◽  
Faisal Khan ◽  
Ali Abunayla ◽  
Rajasekhar Jagarlamudi ◽  
aditee Dash

Abstract Background As opposed to Staphylococcus. aureus bacteremia, there are no guidelines to recommend repeating blood cultures in Gram-negative bacilli bacteremia (GNB). Several studies have questioned the utility of follow-up blood cultures (FUBCs) in GNB, but the impact of this practice on clinical outcomes is not fully understood. Our aim was to study the practice of obtaining FUBCs in GNB at our institution and to assess it’s impact on clinical outcomes. Methods We conducted a retrospective, single-center study of adult patients, ≥ 18 years of age admitted with GNB between January 2017 and December 2018. We aimed to compare clinical outcomes in those with and without FUBCs. Data collected included demographics, comorbidities, presumed source of bacteremia and need for intensive care unit (ICU) admission. Presence of fever, hypotension /shock and white blood cell (WBC) count on the day of FUBC was recorded. The primary objective was to compare 30-day mortality between the two groups. Secondary objectives were to compare differences in 30-day readmission rate, hospital length of stay (LOS) and duration of antibiotic treatment. Mean and standard deviation were used for continuous variables, frequency and proportion were used for categorical variables. P-value &lt; 0.05 was defined as statistically significant. Results 482 patients were included, and of these, 321 (67%) had FUBCs. 96% of FUBCs were negative and 2.8% had persistent bacteremia. There was no significant difference in 30-day mortality between those with and without FUBCs (2.9% and 2.7% respectively), or in 30-day readmission rate (21.4% and 23.4% respectively). In patients with FUBCs compared to those without FUBCs, hospital LOS was longer (7 days vs 5 days, P &lt; 0.001), and mean duration of antibiotic treatment was longer (14 days vs 11 days, P &lt; 0.001). A higher number of patients with FUBCs needed ICU care compared to those without FUBCs (41.4% and 25.5% respectively, P &lt; 0.001) Microbiology of index blood culture in those with and without FUBCs Outcomes in those with and without FUBCs FUBCs characteristics Conclusion Obtaining FUBCs in GNB had no impact on 30-day mortality or 30-day readmission rate. It was associated with longer LOS and antibiotic duration. Our findings suggest that FUBCs in GNB are low yield and may not be recommended in all patients. Prospective studies are needed to further examine the utility of this practice in GNB. Disclosures All Authors: No reported disclosures


Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2689
Author(s):  
Felix Popp ◽  
Ingracia Capino ◽  
Joana Bartels ◽  
Alexander Damanakis ◽  
Jiahui Li ◽  
...  

Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, LAG3, IDO, and TIM3 on tumor-infiltrating lymphocytes (TILs) and its impact on patient survival. We analyzed 153 pancreatic cancer patients from the prospectively managed database of the multicentered PANCALYZE study. Immunohistochemistry on a tissue microarray assessed VISTA, LAG3, IDO, and TIM3 expression of TILs from the patients undergoing primary resection. Complementarily, we analyzed publicly available transcriptomic data (n = 903). Successful completion of chemotherapy, and lymph node status were independent predictors of survival in the multivariate analysis of the clinicopathologic parameters. Fifteen tumors were exclusively VISTA-positive, thirteen tumors expressed VISTA together with TIM3, and ten tumors expressed VISTA together with IDO. Patients featuring tumors with high numbers of IDO-positive TILs had better patient survival (p = 0.037). VISTA, LAG3, and TIM3 expression did not correlate with survival. The analysis of publicly available data did not show survival differences. Tumors rarely co-express more than two immune molecules at the same time, and VISTA is most frequently co-expressed. Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.


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