scholarly journals Emerging Trends for Radio-Immunotherapy in Rectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1374
Author(s):  
Claudia Corrò ◽  
Valérie Dutoit ◽  
Thibaud Koessler
Keyword(s):  
Rectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Infiltration ◽  
Emerging Trends ◽  
Tumor Mutational Burden ◽  
Microsatellite Stability

Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.

scholarly journals Tumor-Infiltrating Lymphocytes and Breast Cancer: Are Immune Checkpoint Inhibitors Ready for Prime Time in Breast Cancer?

2016 ◽  
Vol 33 (4) ◽  
pp. 237-246 ◽  
Author(s):  
Ana Cvetanović ◽  
Slađana Filipović ◽  
Nikola Živković ◽  
Miloš Kostić ◽  
Svetislav Vrbić ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Tumors ◽  
Prime Time ◽  
Infiltrating Lymphocytes

SummaryIn recent years, results obtained from different studies with large cohorts have revealed a bond between the presence of extensive lymphocytic infiltration and favourable prognostic associations in the early-stage of breast cancer (BC) and high response rates to neoadjuvant chemotherapy. Examiners used tumors from large cohorts of patients who took part in randomized neoadjuvant and adjuvant clinical trials. The importance of tumor infiltrating lymphocytes (TILs) appears to be subtype-specific and varies depending on the histological characteristics of the tumor. TILs have proven to be a good prognostic marker, but only in highly proliferative breast tumors such as triple negative breast tumors (TNBC) or HER 2 positive BC.In the era when standard, well-known, prognostic and predictive biomarkers are ever changing and the use of molecular profiling analyses are increasing, we are looking for techniques to improve our understanding of tumor biology and improve patient outcome. The relevance of TILs cannot be ignored but needs to be properly evaluated in larger prospective studies which must encompass the parameters set out in previous studies. The use of TILs as prognostic biomarkers in early breast cancer may represent a new dawn, and use of immunotherapy, especially immune checkpoint inhibitors, probably is the future for the breast cancer but it is not yet ready for prime time.

scholarly journals Multitumor Case Series of Germline BRCA1, BRCA2 and CHEK2-Mutated Patients Responding Favorably on Immune Checkpoint Inhibitors

2021 ◽  
Vol 28 (5) ◽  
pp. 3227-3239
Author(s):  
Lisa Kinget ◽  
Oliver Bechter ◽  
Kevin Punie ◽  
Philip R. Debruyne ◽  
Hilde Brems ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Case Series ◽  
Predictive Biomarkers ◽  
Solid Malignancies ◽  
Tumor Mutational Burden ◽  
Brca1 Brca2 ◽  
Tumor Types ◽  
Selection Of

In recent years, immune checkpoint inhibitors (ICPI) have become widely used for multiple solid malignancies. Reliable predictive biomarkers for selection of patients who would benefit most are lacking. Several tumor types with somatic or germline alterations in genes involved in the DNA damage response (DDR) pathway harbor a higher tumor mutational burden, possibly associated with an increased tumoral neoantigen load. These neoantigens are thought to lead to stronger immune activation and enhanced response to ICPIs. We present a series of seven patients with different malignancies with germline disease-associated variants in DDR genes (BRCA1, BRCA2, CHEK2) responding favorably to ICPIs.

scholarly journals Immunotherapy in Breast Cancer Patients: A Focus on the Use of the Currently Available Biomarkers in Oncology

2021 ◽  
Vol 21 ◽  
Author(s):  
Carmen Criscitiello ◽  
Elena Guerini-Rocco ◽  
Giulia Viale ◽  
Caterina Fumagalli ◽  
Elham Sajjadi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Randomized Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Optimal Timing ◽  
Breast Cancer Patients ◽  
Tumor Mutational Burden ◽  
Clinical Benefits

: Immune checkpoint inhibitors (ICIs) have remarkably modified the way solid tumors are managed, including breast cancer. Unfortunately, only a relatively small number of breast cancer patients significantly respond to these treatments. To maximize the immunotherapy benefit in breast cancer, several efforts are currently being put forward for the identification of i) the best therapeutic strategy (i.e. ICI monotherapy or in association with chemotherapy, radiotherapy, or other drugs); ii) the optimal timing for administration (e.g. early/advanced stage of disease; adjuvant/neoadjuvant setting); iii) the most effective and reliable predictive biomarkers of response (e.g. tumor-infiltrating lymphocytes, programmed death-ligand 1, microsatellite instability associated with mismatch repair deficiency, and tumor mutational burden). This article reviews the impacts and gaps in the characterization of immune-related biomarkers raised by clinical and translational research studies with immunotherapy treatments. Particular emphasis has been put on the documented evidence of significant clinical benefits of ICI in different randomized clinical trials, along with preanalytical and analytical issues in predictive biomarkers pathological assessment.

scholarly journals Case Report: A Case Study Documenting the Activity of Atezolizumab in a PD-L1-Negative Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Fara Brasó-Maristany ◽  
Miriam Sansó ◽  
Nuria Chic ◽  
Débora Martínez ◽  
Blanca González-Farré ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Genomic Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Durable Response ◽  
Tumor Mutational Burden

The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune checkpoint inhibitors in TNBC beyond PD-L1 expression and to better select patients that will benefit from immunotherapy.

scholarly journals Pancreatic Cancer Progression in a Patient With Lynch Syndrome Receiving Immunotherapy: A Cautionary Tale

2021 ◽  
Vol 19 (8) ◽  
pp. 883-887
Author(s):  
Yifan Wang ◽  
Adeline Cuggia ◽  
Alain Pacis ◽  
Jean-Christian Boileau ◽  
Victoria A. Marcus ◽  
...  
Keyword(s):  
Disease Progression ◽  
Cancer Progression ◽  
Checkpoint Inhibitors ◽  
Dna Mismatch ◽  
T Cell Infiltration ◽  
Confirmatory Assay ◽  
Tumor Mutational Burden ◽  
Treatment Naïve ◽  
Hyperprogressive Disease ◽  
Microsatellite Stability

Pancreatic ductal adenocarcinomas (PDACs) with DNA mismatch repair deficiency (MMRd) respond preferentially to immune checkpoint inhibitors (ICIs). However, a subset of MMRd PDACs does not respond to these agents. This report describes a patient with PDAC who experienced rapid disease progression suggestive of hyperprogressive disease. The case involved a 63-year-old man carrying a pathogenic germline PMS2 mutation who developed metastatic PDAC. His tumor showed isolated loss of PMS2 expression by immunohistochemistry (IHC). He was treated with pembrolizumab, but his disease rapidly progressed. Whole-genome and transcriptome sequencing of a liver metastasis biopsy, acquired at disease progression, showed a retained wild-type PMS2 allele and hallmarks of microsatellite stability, including low tumor mutational burden and low MSIsensor score. PCR-based microsatellite instability (MSI) testing of the treatment-naïve tumor showed microsatellite stability. The ICI-treated tumor had a lower density of CD8+ T-cell infiltration than the treatment-naïve tumor, which is contrary to the expected evolution with ICI responsiveness. Through this case and a review of the literature, we highlight the low penetrance of PMS2 germline mutations in PDAC and discuss pitfalls in ascertaining MMRd and MSI based on IHC testing alone. An orthogonal confirmatory assay is warranted in the presence of uncommon immunophenotypes, such as isolated PMS2 loss, to optimize selection of patients with PDAC for immunotherapy.

Effect of NKTR-214 on the number and activity of CD8+ tumor infiltrating lymphocytes in patients with advanced renal cell carcinoma.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 454-454 ◽  
Author(s):  
Michael E. Hurwitz ◽  
Adi Diab ◽  
Chantale Bernatchez ◽  
Cara L. Haymaker ◽  
Harriet M. Kluger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Poor Response ◽  
Post Treatment ◽  
Open Label

454 Background: Patients with low baseline CD8+ T-cells within the tumor microenvironment (TILs) have a poor response to immune checkpoint inhibitors. Agents designed to specifically activate and expand CD8+ T cells may improve clinical outcomes in patients with low TILs. NKTR-214 is a CD-122-biased agonist designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) and preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells. Methods: A dose escalation, open-label, trial was initiated to assess the safety of NKTR-214 and explore immune changes in the blood and tumor microenvironment in patients with advanced solid tumors. NKTR-214 was administered IV in an outpatient setting with initial dosing at 0.003 mg/kg. Pre and post treatment blood and tumor samples were analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by immunohistochemistry. Results: Among 25 patients dosed, 15 had RCC ([email protected]/kg, [email protected]/kg, and [email protected]/kg). Treatment with NKTR-214 was well tolerated and the MTD was not reached. One patient experienced DLTs (Gr3 syncope and hypotension) at 0.012 mg/kg. There were no immune-related AEs. Of 12 patients evaluable for response, 75% had SD at their first on treatment scan. Of 5 patients, who were immune checkpoint naïve with ≥ 1 prior TKI treatments, 3 experienced tumor shrinkage, 1 with PR per RECIST 1.1 (unconfirmed). Interrogation of the tumor microenvironment revealed many significant immunological changes post treatment, including increase in total and proliferating NK, CD8+, and CD4+ T cells. There was good correlation between increase in activated CD4+ and CD8+ T cells in peripheral blood with an increase in T cell infiltrates within the tumor tissue. Conclusions: NKTR-214 increased immune infiltration in the tumor and anti-tumor activity in patients who previously progressed on TKIs, with a favorable safety profile. The ability to alter the immune environment and increase PD-1 expression on effectors T cells may improve the effectiveness of anti-PD-1 blockade. A trial combining NKTR-214 and nivolumab is enrolling. Clinical trial information: 02869295.

Therapeutic checkpoint targets: Evaluation of co-expression profiles in individual tumor and immune cells in the tumor microenvironment of FFPE tissue.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 176-176
Author(s):  
Annelies Laeremans ◽  
Na Li ◽  
Jeff Kim ◽  
Xiao-Jun Ma ◽  
Emily Park
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Expression Profiles ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Durable Response

176 Background: Interactions between tumor and immune cells in the tumor microenvironment (TME) play a key role in tumor progression and treatment response with accumulating evidence indicating a crucial role for tumor infiltrating immune cells. Although infiltrating cytotoxic T lymphocytes (CTLs) have been correlated with improved clinical outcome, they are ineffective in eradicating tumors due to their inhibition by immune checkpoint molecules. Immune checkpoint inhibitors have demonstrated therapeutic efficacy and durable response for several tumor types including non-small cell lung cancer (NSCLC). However, the majority of patients are resistant or relapse after initial response. Characterizing the TME for checkpoint expression with single-cell and spatial resolution can provide critical insight into new immunotherapeutic strategies and identify new predictive biomarkers for stratifying and identifying patients most likely to benefit from immunotherapy including PD-1/PD-L1 immune checkpoint blockade. Methods: Using RNAscope in situ hybridization, we evaluated in situ co-expression profiles of therapeutic checkpoint targets at single-cell level in the TME of 56 archived NSCLC FFPE tissues. Results: Checkpoint molecules including PD1, PD-L1, PD-L2, TIM3, LAG3, CTLA-4 and GITR were visualized in a highly specific and sensitive manner in individual cells within tissue morphological context. Multiple checkpoint molecules were detected in the same immune environment, especially in highly inflamed tumors. In addition to PD-L1, tumor cell-intrinsic expression of PD1, TIM3, LAG3, and PD-L2 was observed in a subset of samples. Furthermore, co-expression of therapeutic checkpoint targets including PD1, LAG3, and TIM3 was observed in infiltrating immune cells and tumor cells. Conclusions: Single-cell co-expression profiles of checkpoint molecules could shed light on how cancer cells evade the host immune surveillance and develop resistance against checkpoint blockades. Also, they could reveal valuable insights into combinatorial therapies for checkpoint markers co-expressed by the patient’s immune cells in the TME.

scholarly journals Predictive biomarkers of response for PD-1/PD-L1 inhibitors: a cumbersome gold rush

2017 ◽  
Vol 5 (3) ◽  
pp. 14-19
Author(s):  
Andrea Vingiani ◽  
Massimo Barberis ◽  
Elena Guerini-Rocco
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Gold Rush ◽  
Repair Deficiency ◽  
Tumor Mutational Burden ◽  
Predictive Role

Programmed cell death protein 1 (PD-1) and its ligand programmed cell death-ligand 1 (PD-L1) are overexpressed in a number of human malignancies. More interestingly, their expression has been associated with patient survival in non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, esophageal, pancreatic and colorectal carcinoma, with the data commonly suggesting a negative prognostic role. In this review, we summarize the pros and cons regarding the predictive role of PD-L1 expression in candidate patients for checkpoint inhibitors. Furthermore, we discuss the potential predictive role of other biomarkers, such as tumor mutational burden, microsatellite instability, mismatch repair deficiency and tumor infiltrating lymphocytes. We conclude that PD-L1 testing probably represents simply a “snapshot” of an intricate, fluctuating and dynamic process, that in turn represents the interplay between the immune system and cancer. The PD-L1 assay can be considered more useful for response stratification than in patient selection.

scholarly journals Serological assessment of collagen fragments and tumor fibrosis may guide immune checkpoint inhibitor therapy

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Christina Jensen ◽  
Neel I. Nissen ◽  
Claus S. Von Arenstorff ◽  
Morten A. Karsdal ◽  
Nicholas Willumsen
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Common Denominator ◽  
Improve Patient Selection ◽  
Number Of Patients ◽  
Tumor Mutational Burden ◽  
Activated Fibroblasts

AbstractDespite the overall clinical success of immune checkpoint inhibitors (ICIs) for treating patients with solid tumors, a large number of patients do not benefit from this approach. Consequently, there is a need for predictive biomarkers. The most prevalent biomarkers such as PD-L1 expression and tumor mutational burden (TMB) do not reliably predict response to ICIs across different solid tumor types suggesting that a broader view of regulating factors in the tumor microenvironment is needed. Emerging evidence indicates that one central common denominator of resistance to ICIs may be fibrotic activity characterized by extracellular matrix (ECM) and collagen production by cancer-associated fibroblasts (CAFs). A fibroblast-and collagen-rich stroma attenuates immunotherapy response by contributing to inhibition and exclusion of T cells. Here we review opportunities and limitations in the utilization of the most prevalent biomarkers for ICIs and elaborate on the unique opportunities with biomarkers originating from the activated fibroblasts producing an impermeable ECM. We propose that ECM and collagen biomarkers measured non-invasively may be a novel and practical approach to optimize treatment strategies and improve patient selection for ICI therapy.

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