scholarly journals CTIM-19. MOLECULAR AND GENETIC DETERMINANTS OF RESPONSE TO PD-1 BLOCKADE IN RECURRENT GLIOBLASTOMA PATIENTS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii37-ii37
Author(s):  
Robert Prins ◽  
Mildred Galvez ◽  
Meelad Amouzgar ◽  
Katie Campbell ◽  
Daniel Wells ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Immune Checkpoint ◽  
Copy Number ◽  
Neoadjuvant Treatment ◽  
Interferon Γ ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Post Surgery ◽  
Mutational Burden ◽  
Recurrent Gbm

Abstract Despite immune checkpoint inhibitors having success in several other tumor types, many glioblastoma (GBM) patients fail to respond or maintain a sustained response. Work published by our group (Cloughesy et al, 2019) demonstrated that relative to adjuvant programmed cell death-1 (PD-1) blockade, neoadjuvant treatment doubled the median overall survival (OS) for recurrent GBM patients and resulted in an enhanced interferon-γ signature. This suggests that anti-PD-1 given in the neoadjuvant setting may improve outcomes for recurrent GBM patients. The challenge remains in identifying the molecular and genetic signatures associated with response to immune checkpoint blockade. To address this, we analyzed the tumor sample and clinical response data from the patients treated in this clinical trial (n=31). We stratified patients as stable disease (SD) versus progressive disease (PD) based on their response assessment in neuro-oncology criteria (RANO) scores from cycle 2 of treatment post-surgery. Among the SD patients, 77.8% received neoadjuvant treatment while 22.2% received adjuvant therapy. In this group, a median OS was not reached. Among the PD patients, 40.9% received neoadjuvant treatment and 59.1% received adjuvant therapy, with a median OS of 257 days. Next, we analyzed factors that impact response to immunotherapy, which includes somatic mutational burden and interferon-γ pathway induction. We calculated somatic mutational variants, copy number variants (CNVs), and differential gene expression from the bulk tumor exome and RNA-sequencing data. The total mutation counts were similar between groups and no association was identified with increased mutational burden. In addition, total CNV stability was similar between groups. However, when looking at genes involved in the JAK/STAT signaling pathway, there were notably more copy number losses of JAK2 in the PD group when compared to the SD group (85.0% versus 66.7%). These findings merit further exploration as the JAK/STAT pathway has been implicated in response to immune checkpoint blockade.

scholarly journals Immune Checkpoint Blockade in HER2-Positive Breast Cancer: What Role in Early Disease Setting?

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1655
Author(s):  
Cinzia Solinas ◽  
Debora Fumagalli ◽  
Maria Vittoria Dieci
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Neoadjuvant Treatment ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Current Evidence ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

The present commentary synthesizes the current evidence on the role of the immune response in HER2-positive breast cancer. It points out the strengths and weaknesses of the findings observed so far, particularly in the early setting, including the clinical significance of scoring tumor-infiltrating lymphocytes. A figure proposing research hypotheses for the implementation of immune checkpoint blockade use for patient candidates to neoadjuvant treatment is presented.

scholarly journals Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e000374 ◽  
Author(s):  
Zhihao Lu ◽  
Huan Chen ◽  
Shuang Li ◽  
Jifang Gong ◽  
Jian Li ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Copy Number ◽  
Validation Cohort ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Copy Number Alterations ◽  
Gi Cancer

BackgroundDespite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer.MethodsThis study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patients were randomly assigned into discovery (n=44) and validation (n=29) cohorts. Comprehensive genomic profiling was performed on all samples to determine tumor mutational burden (TMB) and copy-number alterations (CNAs). A subset of samples was collected for RNA immune oncology (IO) panel sequencing, microsatellite instability (MSI)/mismatch repair and program death ligand 1 (PD-L1) expression evaluation. In addition, 20 gastric cancer (GC) patients were recruited as the second validation cohort.ResultsIn the first cohort of 73 GI cancer patients, a lower burden of CNA was observed in patients with durable clinical benefit (DCB). In both the discovery (n=44) and validation (n=29) subsets, lower burden of CNA was associated with an improved clinical benefit and better overall survival (OS). Efficacy also correlated with a higher TMB. Of note, a combinatorial biomarker of TMB and CNA may better stratify DCB patients from ICB treatment, which was further confirmed in the second validation cohort of 20 GC patients. Finally, patients with lower burden of CNA revealed increased immune signatures in our cohort and The Cancer Genome Atlas data sets as well.ConclusionsOur results suggest that the burden of CNA may have superior predictive value compared with other signatures, including PD-L1, MSI and TMB. The joint biomarker of CNA burden and TMB may better stratify DCB patients, thereby providing a rational choice for GI patients treated with ICBs.

scholarly journals Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Cancer Cell ◽  
2020 ◽  
Author(s):  
Catherine S. Grasso ◽  
Jennifer Tsoi ◽  
Mykola Onyshchenko ◽  
Gabriel Abril-Rodriguez ◽  
Petra Ross-Macdonald ◽  
...  
Keyword(s):  
Clinical Response ◽  
Immune Checkpoint ◽  
Interferon Γ ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Cancer Cell ◽  
2020 ◽  
Vol 38 (4) ◽  
pp. 500-515.e3 ◽  
Author(s):  
Catherine S. Grasso ◽  
Jennifer Tsoi ◽  
Mykola Onyshchenko ◽  
Gabriel Abril-Rodriguez ◽  
Petra Ross-Macdonald ◽  
...  
Keyword(s):  
Clinical Response ◽  
Immune Checkpoint ◽  
Interferon Γ ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Immunogenomic profile of colorectal cancer response to immune checkpoint blockade

2020 ◽  
Author(s):  
Michele Bortolomeazzi ◽  
Mohamed Reda Keddar ◽  
Lucia Montorsi ◽  
Amelia Acha-Sagredo ◽  
Lorena Benedetti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Critical Threshold ◽  
Mutational Burden ◽  
Antigen Presenting

To dissect the determinants of the heterogeneous response of colorectal cancer (CRC) to immune checkpoint blockade, we profile tumour and immune infiltrates of 721 cancer regions from 29 patients treated with Pembrolizumab or Nivolumab. Combining multi-regional whole exome, RNA and T-cell receptor sequencing we show that anti-PD1 agents are most effective in CRCs with high mutational burden and low activation of the WNT pathway. However, above a critical threshold defining the hypermutated phenotype, response is no longer associated with mutational burden but rather with high clonality of immunogenic mutations, expanded T cells and active immune escape mechanisms. Using high-dimensional imaging mass cytometry and multiplexed immunofluorescence, we observe that responsive hypermutated CRCs are rich in cytotoxic and proliferating PD1-expressing CD8 infiltrates interacting with high-density clusters of PDL1-expressing antigen presenting macrophages. We propose that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages thus promoting their expansion in intra-tumour niches.

scholarly journals MP24-01 RESPONSE TO IMMUNE CHECKPOINT BLOCKADE IN PATIENTS WITH MICROSATELLITE INSTABLE AND HIGH TUMOR MUTATIONAL BURDEN PROSTATE CANCER

2021 ◽  
Vol 206 (Supplement 3) ◽  
Author(s):  
Andrew T. Lenis ◽  
Vignesh Ravichandran ◽  
Hong Truong ◽  
Peter Reisz ◽  
Barbara Nweji ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mutational Burden ◽  
Tumor Mutational Burden

scholarly journals A PD-L1 Negative Advanced Gastric Cancer Patient With a Long Response to PD-1 Blockade After Failure of Systematic Treatment: A Case Report

2021 ◽  
Vol 12 ◽  
Author(s):  
Fangyuan Zhang ◽  
Jieying Zhang ◽  
Lei Zhao ◽  
Menglan Zhai ◽  
Tao Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patient ◽  
Gastric Cancer Patient ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Systematic Treatment ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Gastric Cancer Patients

BackgroundIt was widely accepted that programmed death-ligand 1 (PD-L1) positive, tumor mutational burden-high (TMB-H) or microsatellite instability-high (MSI-H) tumor are prone to have better treatment response to immune checkpoint blockade. The value of immune checkpoint blockade in PD-L1 negative gastric cancer patients has been questioned due to lower objective response rate (ORR).Case PresentationWe report an unusual case of a PD-L1 negative, proficient mismatch repair (pMMR)/microsatellite stability (MSS), tumor mutational burden-low (TMB-L) gastric cancer patient who achieved good response to immune checkpoint blockade after failure of systematic treatment. Multiple lymph nodes and bone metastases are the main characteristics of this patient. The patient survived for more than 30 months after diagnosis.ConclusionsThis case suggested that PD-L1 negative gastric cancer patient may also benefit from immune checkpoint blockade. In gastric cancer, patients with lymph node metastasis may be potential beneficiaries.

scholarly journals Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade

Immunity ◽  
2019 ◽  
Vol 50 (2) ◽  
pp. 477-492.e8 ◽  
Author(s):  
Chien-Chun Steven Pai ◽  
John T. Huang ◽  
Xiaoqing Lu ◽  
Donald M. Simons ◽  
Chanhyuk Park ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Interferon Γ ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Therapeutic Resistance ◽  
Clonal Deletion

Burden of copy number alterations predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14068-e14068
Author(s):  
Zhihao Lu ◽  
Huan Chen ◽  
Shuang Li ◽  
Xi Jiao ◽  
Lihong Wu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Copy Number ◽  
Objective Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Copy Number Alterations ◽  
Sequencing Platform ◽  
Gi Cancer ◽  
Ffpe Tumor ◽  
Gi Cancers

e14068 Background: Despite the great achievements made in immune checkpoint blockade (ICB) in cancer therapy, how to identify patients who may benefit from ICB still remains one of the central questions, especially in gastrointestinal (GI) cancer. Methods: To address this, we analyzed FFPE tumor specimens from 73 patients with metastatic GI cancers who were treated with ICB. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Overall, tumor mutation burden (TMB) and copy number alterations (CNAs) were determined by using the whole-exome sequencing platform. FFPE samples of 65 patients were analyzed via a multiplex RNA immune oncology sequencing panel. Results: Here we show that lower burden of copy number alteration (CNA) was observed in responders to immunotherapy in both discovery and validation cohorts. More importantly, lower burden of CNA in GI cancers were associated with improved objective response, clinical benefit and overall survival. Efficacy also correlated with the higher TMB. Of note, a combinatorial biomarker of TMB and burden of CNA may better stratify responders from patients received immunotherapy. In addition, patients with lower burden of CNA revealed increased IFNγ and expanded immune signatures in our GI patient cohort and TCGA cohorts as well. Conclusions: Our results suggest that burden of CNA may expand the predictive and prognostic value of genomic determinants in identifying potential responders with GI cancer to immune checkpoint blockade therapy.

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