Assessment of tumor infiltrating lymphocytes (TILs) in histopathological specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting ...response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible and reliable immuno-oncology biomarkers is clear. In Part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on H&E sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in Part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.
Abstract
Background: A high quality PD-L1 companion diagnostic may help predict which patients are more likely to respond to PD-1/PD-L1 antibody-based therapy. Here we describe a PD-L1 ...immunohistochemical (IHC) diagnostic test developed by Ventana Medical Systems for use with durvalumab.
Methods: An anti-human PD-L1 rabbit monoclonal antibody (SP263) was optimized for use with Ventana OptiView DAB IHC Detection Kit on the automated BenchMark ULTRA platform. The PD-L1 IHC assay was validated for use in formalin-fixed, paraffin-embedded samples of NSCLC in a series of studies addressing sensitivity, specificity, robustness, and precision. Durvalumab is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity. A subset of clinical trial samples from a Phase 1/2 study of durvalumab (NCT01693562) was analyzed to determine optimal cut-off for enriching response to durvalumab. Inter-reader precision was established by 3 pathologists who evaluated 81 NSCLC samples across the range of expression levels.
Results: The Ventana PD-L1 IHC (SP263) assay met all pre-defined acceptance criteria. The scoring algorithm was defined using statistical analysis of clinical response data and PD-L1 staining parameters observed in a set of NCT01693562 clinical trial samples. Samples of both cancer types are considered test positive when the membrane of ≥ 25% of tumor cells stain for PD-L1 at any intensity. Inter-reader precision in determining PD-L1 status resulted in an overall percentage agreement of 97% for NSCLC. PD-L1+ patients identified by the scoring algorithm had a higher response rate than PD-L1- patients. Interlaboratory testing was performed at 3 external laboratories and demonstrated an overall agreement rate of 86.4%.
Conclusions: These results highlight the robustness and reproducibility of the PD-L1 IHC (SP263) assay in a clinical setting. In NSCLC patients treated with durvalumab, PD-L1+ patients identified by the scoring algorithm had a higher response rate than PD-L1- patients. The clinical utility of the PD-L1 diagnostic assay will be further validated in a prospective manner using additional patients in this study and in other durvalumab studies.
Citation Format: Marlon C. Rebelatto, Amita Mistry, Constantine Sabalos, Nicole Schechter, Jill Walker, Anita Midha, Keith E. Steele, Paul B. Robbins, Xia Li, Li Shi, John A. Blake-Haskins, Ramy A. Ibrahim, Laura Richman. An immunohistochemical PD-L1 companion diagnostic assay for treatment with durvalumab (MEDI4736) in NSCLC patients. abstract. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B005.
Spontaneous amyloidosis was diagnosed in 11 male and 1 female chimpanzees and confirmed histologically and immunohistochemically. The chimpanzees were ≥15 years of age when first diagnosed and ...averaged 22.4 years of age. The average survival time after diagnosis of systemic amyloidosis was 1.86 years with a standard deviation of 4.06 years (n=7). The chimpanzees with amyloidosis were asymptomatic except for hepatomegaly, which became more detectable with age. Significant increases in clinical chemistry values, as compared with referenced normals and established normals, of blood urea nitrogen (BUN), asparate aminotransferase (AST), gamma‐glutamyltransferase (GGT), globulin, total protein, creatinine phosphokinase (CPK), sedimentation rate, and triglycerides were found in animals 7 years of age or older with amyloidosis. These serum chemistry values, while increased in chimpanzees with amyloidosis, were generally within normal limits. Immunohistochemistry for both amyloid A protein and amyloid P component‐labeled extracellular amyloid in all chimpanzees with amyloidosis was determined. Amyloid was deposited primarily in the liver. Amyloidosis in the chimpanzee is a chronic, intractable, progressive, fatal disease, and appears to be similar to secondary amyloidosis in other species.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
BackgroundAs single agents, durvalumab (MEDI4736), a human IgG1 anti-PD-L1 antibody, and tremelimumab, a human IgG2 anti-CTLA-4 antibody, have shown acceptable safety profiles and antitumor activity. ...Similar to other anti-PD-L1/anti-PD-1 monotherapies, durvalumab has shown greater objective tumor response rates in PD-L1-positive patients compared with PD-L1-negative patients. Anti-CTLA4 therapies activate T-cells and may increase immune infiltrate and PD-L1 expression in tumor cells and tumor infiltrating immune cells. Thus, combination therapy with durvalumab and tremelimumab could be active in NSCLC regardless of baseline PD-L1 expression.MethodsThis is a phase 1, open-label, dose-escalation/expansion study (NCT02000947) of D+T in patients with Stage III/IV NSCLC (any number of prior lines of therapy; immunotherapy-naïve). The primary endpoint is safety and tolerability; secondary endpoints include investigator-reported RECIST v1.1 response. PD-L1 expression was tested retrospectively using an immunohistochemical assay (Ventana).ResultsAs of 1 June 2015, 102 patients received treatment in the dose escalation phase; combinations of durvalumab 3 mg/kg (D3) to 20 mg/kg (D20) every 2 (q2w) or 4 weeks (q4w) and tremelimumab 1 mg/kg (T1) to 3 mg/kg (T3) q4w, plus a D15 + T10 combination, were explored. Across all cohorts, 80% and 42% of patients had ≥1 treatment-related AE (any Grade and Grade 3/4, respectively); 28% discontinued treatment due to a related AE. A greater frequency of AEs, without a corresponding increase in tumor response, was seen with increasing T dose. In the combined T1 cohort (D10–D20), 73% and 30% of patients had ≥1 related AE (any Grade and Grade 3/4, respectively); 16% discontinued treatment due to a related AE. There were 3 treatment-related deaths (myasthenia gravis, T1; pericardial effusion, T1; neuromuscular disorder, T3).84 patients (73 EGFR/ALK wild-type; 77 non-squamous; 48 with ≥2 prior lines of therapy) were evaluable for response (Table 1). The overall response rate (confirmed+unconfirmed) was 25%. Higher response rates were observed in those with 1 vs ≥2 prior therapies. Response rates do not appear dependent on PD-L1 status: 35% (PD-L1-positive), 22% (PD-L1-negative, <25% tumor cell staining) and 33% (PD-L1-negative, 0% tumor cell staining). Similar findings were observed for the combined T1 cohort. D+T also showed good durability of response similar to that seen for monotherapy.Response rates (Confirmed/unconfirmed with ≥16 weeks follow-up)Overall populationEGFR/ALK wild-type populationAll cohortsCombined cohort: D10–20 q4w or q2w + T1All cohortsCombined cohort: D10–20 q4w or q2w + T1n/N (%)95% CIn/N (%)95% CIn/N (%)95% CIn/N (%)95% CIAll patients21/84 (25)16–3611/39 (28)15–4521/73 (29)19–4111/34 (32)17–51PD-L1+ (≥25%)7/20 (35)15–593/9 (33)8–707/17 (41)18–673/9 (33)8–70PD-L1- (<25%)11/49 (22)12–376/23 (26)10–4811/45 (24)13–406/19 (32)13–57PD-L1- (0%)9/27 (33)17–546/12 (50)21–799/26 (35)17–566/11 (55)23–83All 2L patients15/32 (47)29–657/16 (44)20–7015/31 (48)30–677/15 (47)21–73PD-L1+ (≥25%)6/8 (75)35–972/3 (67)9–996/8 (75)35–972/3 (67)9–99PD-L1- (<25%)7/18 (39)17–644/11 (36)11–697/17 (41)18–674/10 (40)12–74PD-L1- (0%)6/8 (75)35–974/5 (80)28–1006/8 (75)35–974/5 (80)28–1002L, second line: 1 prior line of therapy, receiving D+T in second lineConclusionsD+T at selected phase 3 dose (D20, T1) has a manageable tolerability profile and anti-tumor activity in NSCLC. Unlike anti- PD-1/PD-L1 monotherapies, the combination of D+T appears to be active regardless of PD-L1 status, including even in patients with no tumor cell membrane PD-L1 staining, a setting where patients would not be expected to derive significant benefit from anti-PD-1/PD-L1 monotherapy over current standard of care 1, 2.
BackgroundThe immune system is able to control the growth of many types of cancers. Most tumors show infiltration by tumor infiltrating lymphocytes, but tumors modulate the local microenvironment by ...expressing immune-inhibitory molecules. Blockade of immune checkpoints such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1) has shown clinical activity in immune-responsive tumors as well as those historically deemed unresponsive to treatment. Durvalumab (MEDI4736) is a selective, high affinity human IgG1 monoclonal antibody (mAb) that blocks PD-L1 binding to PD-1 (IC50 0.1 nM) and CD80 (IC50 0.04 nM). Tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4 which promotes T-cell activity through CTLA-4 inhibition. Both durvalumab and tremelimumab have demonstrated acceptable safety profiles and promising clinical activity as single agents in multiple tumor types. Recent data suggest that combined checkpoint inhibition may generate superior antitumor activity versus monotherapy, resulting in higher, deeper, and more durable response rates, which suggests that dual inhibition may overcome barriers to immune response in historically non-immune responsive tumors. We describe an ongoing study assessing the safety and antitumor activity of durvalumab in combination with tremelimumab in patients with advanced solid tumors.MethodsThis is a Phase I, multicenter, open-label, dose-exploration and dose-expansion study in patients with select advanced solid tumors (NCT02261220). Eligible patients (≥18 years) will have recurrent or metastatic (R/M) disease and may have been previously treated in the R/M setting. The primary objective of this study is to assess the safety and tolerability, and maximum tolerated dose of durvalumab in combination with tremelimumab. The secondary objectives are to assess antitumor activity (including overall response rate, disease control rate, duration of response, progression-free survival, and overall survival), pharmacokinetics, pharmacodynamics, and immunogenicity of the combination. Exploratory objectives will include an assessment of biomarkers that may correlate with clinical activity of durvalumab in combination with tremelimumab. Recruitment is ongoing, with an estimated enrollment of 225–240 patients.Trial registrationClinicalTrials.gov identifier NCT02261220.
BackgroundDespite improvements in diagnosis, surgical techniques, and multidisciplinary approaches to patient care, the median survival of patients with metastatic gastroesophageal adenocarcinoma is ...less than one year. Chemotherapy is the mainstay of treatment in patients with metastatic disease, but is associated with significant toxicity. There is still, therefore, a significant unmet clinical need in this patient population. Blockade of immune checkpoints is one of the most promising novel approaches in cancer treatment. Blocking programmed cell death ligand-1 (PD-L1) or cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) immune checkpoints with anti-PD-L1 or anti-CTLA-4 antibodies has shown clinical promise in other solid tumors. Durvalumab (MEDI4736) is a selective, high affinity human IgG1 monoclonal antibody (mAb) that blocks PD-L1 binding to programmed cell death-1 (PD-1) (IC50 0.1 nM) and CD80 (IC50 0.04 nM). Tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4, which promotes T-cell activity through CTLA-4 inhibition. Preclinical data suggest that combining immunotherapies may result in superior antitumor activity versus monotherapy, leading to higher and more durable response rates and improved overall and progression-free survival (PFS).MethodsThis is a randomized, multicenter, open-label Phase Ib/II study to investigate the safety and antitumor activity of durvalumab and tremelimumab, given as monotherapy or in combination, in patients with histologically- or cytologically-confirmed recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma who have progressed on, or are refractory to standard regimens (NCT02340975). The Phase Ib part of the study will identify the doses and schedules to be used in Phase II. In Phase II, patients will be enrolled in one of four treatment arms. The objectives for Phase Ib are to assess the safety and tolerability (primary objective) and the antitumor activity (objective response rate ORR, and PFS at six months PFS-6; secondary objectives) of durvalumab in combination with tremelimumab. The primary objectives for Phase II are to assess the antitumor activity (ORR and PFS-6) of the monotherapies and combination therapy; the secondary objectives are to further assess safety, tolerability, and antitumor activity (disease control rate, duration of response, overall survival), and to investigate correlations between PD-L1 expression and clinical activity. Exploratory objectives include evaluation of pharmacokinetics, pharmacodynamics, and immunogenicity. Recruitment is ongoing, with an estimated enrollment of 174 patients.Trial registrationClinicalTrials.gov identifier NCT02340975.
Abstract
Background: Durvalumab (D) is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1 binding to programmed cell death-1 (PD-1) and CD80 with high affinity and selectivity. PD-L1 is ...expressed in NSCLC tumors and may be associated with response to anti-PD-L1 treatment. This ongoing Phase 1/2, multicenter, open-label study (NCT01693562) evaluates the safety and clinical activity of D in patients (pts) with multiple solid tumor types including NSCLC.
Methods: D is administered at 10 mg/kg IV every 2 weeks (wks) (q2w) until unacceptable toxicity, disease progression, or for up to 12 months. Safety evaluations occur prior to each dose (toxicities graded by CTCAE v4.0). Response is based on investigator assessment (RECIST v1.1; includes confirmed/unconfirmed responses) at 6, 12, and 16 wks, then every 8 wks. Retreatment is permitted upon disease progression after 12 months of therapy. PD-L1 expression within the pre-treatment tumor is assessed using Ventana PD-L1 immunohistochemistry (IHC) (SP263).
Results: As of February 27, 2015, 228 pts (126 non-squamous and 102 squamous histology; mean age 64 range 26 – 87; Eastern Cooperative Oncology Group Performance Status 0 25% or 1 74%; 83% current/prior smokers; 0 12%, 1 29%, or ≥2 56% prior lines of therapy) have been treated with D 10 mg/kg q2w (median 6 doses; range 1 – 27). Drug-related adverse events (AEs) were reported in 50% of pts; most frequently fatigue (15%), decreased appetite (9%), and nausea (8%). Grade ≥3 drug-related AEs were reported in 8% of pts. Drug-related AEs led to study discontinuation in 5% of pts with no treatment-related deaths. Pneumonitis occurred in 3 (1%) pts; none were Grade ≥3. In all, 200 pts were evaluable for response with ≥12 wks of follow-up; objective response rate (ORR) was 16% (27% in PD-L1+), and disease control rate at 12 wks was 42%. ORR was higher in squamous (21%) than non-squamous pts (13%). Responses were durable with 66% ongoing (duration of response range 0.1+ – 54.4+ wks). Data from translational studies will be presented.
Conclusions: With longer follow-up, the safety profile of D in NSCLC is manageable and consistent with our previous reports. Responses are durable; ORR appears to be higher in squamous NSCLC and PD-L1+ pts. A broad development program of D alone and in combination with other treatments in NSCLC is underway.
Citation Format: Scott Antonia, Naiyer Rizvi, Julie Brahmer, Sai-Hong Ou, Samir N. Khleif, Wen-Jen Hwu, Martin Gutierrez, Patrick Schoffski, Omid Hamid, Jared Weiss, Jose Lutzky, Michele Maio, John Nemunaitis, Dirk Jaeger, Ani Balmanoukian, Marlon C. Rebelatto, Keith E. Steele, Xiaoping Jin, Paul B. Robbins, John A. Blake-Haskins, Neil H. Segal. Safety and clinical activity of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). abstract. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A047.
Chikungunya in a North American traveler PILE, J. C; HENCHAL, E. A; CHRISTOPHER, G. W ...
Journal of travel medicine,
06/1999, Volume:
6, Issue:
2
Journal Article
Peer reviewed
Open access
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BFBNIB, FZAB, GIS, IJS, KILJ, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK