Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?

2019 ◽  
pp. 147-164 ◽  
Author(s):  
Charlene M. Fares ◽  
Eliezer M. Van Allen ◽  
Charles G. Drake ◽  
James P. Allison ◽  
Siwen Hu-Lieskovan
Keyword(s):  
Immune Checkpoint ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mechanisms Of Resistance ◽  
Primary Resistance ◽  
Wide Range ◽  
Clinical Responses ◽  
Tumor Types

The emergence of immune checkpoint blockade therapies over the last decade has transformed cancer treatment in a wide range of tumor types. Unprecedented and durable clinical responses in difficult-to-treat cancer histologies have been observed. However, despite these promising long-term responses, the majority of patients fail to respond to immune checkpoint blockade, demonstrating primary resistance. Additionally, many of those who initially respond to treatment eventually experience relapse secondary to acquired resistance. Both primary and acquired resistance are a result of complex and constantly evolving interactions between cancer cells and the immune system. Many mechanisms of resistance have been characterized to date, and more continue to be uncovered. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve clinical outcomes. This review will discuss the landscape of immune checkpoint blockade response data, different resistance mechanisms, and potential therapeutic strategies to overcome resistance.

scholarly journals Resistance to Immune Checkpoint Blockade in Uterine Leiomyosarcoma: What Can We Learn from Other Cancer Types?

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2040
Author(s):  
Wout De Wispelaere ◽  
Daniela Annibali ◽  
Sandra Tuyaerts ◽  
Diether Lambrechts ◽  
Frédéric Amant
Keyword(s):  
Immune Checkpoint ◽  
Gynecological Cancer ◽  
Single Agent ◽  
Acquired Resistance ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Clinical Activity ◽  
Uterine Leiomyosarcoma ◽  
Mechanisms Of Resistance ◽  
Cancer Types

The onset of immune checkpoint blockade (ICB) therapy over the last decade has transformed the therapeutic landscape in oncology. ICB has shown unprecedented clinical activity and durable responses in a variety of difficult-to-treat cancers. However, despite these promising long-term responses, a majority of patients fail to respond to single-agent therapy, demonstrating primary or acquired resistance. Uterine leiomyosarcoma (uLMS) is a rare high-risk gynecological cancer with very limited treatment options. Despite research indicating a strong potential for ICB in uLMS, a clinical trial assessing the response to immunotherapy with single-agent nivolumab in advanced-stage uLMS showed no clinical benefit. Many mechanisms of resistance to ICB have been characterized in a variety of tumor types, and many more continue to be uncovered. However, the mechanisms of resistance to ICB in uLMS remain largely unexplored. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve clinical outcomes. Therefore, in this review we will explore what is known about the immunosuppressive microenvironment of uLMS, link these data to possible resistance mechanisms extrapolated from other cancer types, and discuss potential therapeutic strategies to overcome resistance.

scholarly journals Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

2021 ◽  
Vol 12 ◽  
Author(s):  
Binghan Zhou ◽  
Yuan Gao ◽  
Peng Zhang ◽  
Qian Chu
Keyword(s):  
Immune Checkpoint ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Treatment Modalities ◽  
Immune Checkpoints ◽  
Number Of Patients ◽  
Clinical Responses ◽  
Underlying Mechanisms ◽  
Definition Of

The immune checkpoint blockade therapy has completely transformed cancer treatment modalities because of its unprecedented and durable clinical responses in various cancers. With the increasing use of immune checkpoint blockades in clinical practice, a large number of patients develop acquired resistance. However, the knowledge about acquired resistance to immune checkpoint blockades is limited and poorly summarized. In this review, we clarify the principal elements of acquired resistance to immune checkpoint blockades. The definition of acquired resistance is heterogeneous among groups or societies, but the expert consensus of The Society for Immunotherapy of Cancer can be referred. Oligo-progression is the main pattern of acquired resistance. Acquired resistance can be derived from the selection of resistant cancer cell clones that exist in the tumor mass before therapeutic intervention or gradual acquisition in the sensitive cancer cells. Specifically, tumor intrinsic mechanisms include neoantigen depletion, defects in antigen presentation machinery, aberrations of interferon signaling, tumor-induced exclusion/immunosuppression, and tumor cell plasticity. Tumor extrinsic mechanisms include upregulation of other immune checkpoints. Presently, a set of treatment modalities is applied to patients with similar clinical characteristics or resistance mechanisms for overcoming acquired resistance, and hence, further research is required.

scholarly journals Tumor Genotype Is Shaping Immunophenotype and Responses to Immune Checkpoint Inhibitors in Solid Tumors

2020 ◽  
Vol 3 (3) ◽  
pp. 121-127
Author(s):  
Kathrina L. Marcelo-Lewis ◽  
Shhyam Moorthy ◽  
Ecaterina Ileana-Dumbrava
Keyword(s):  
Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mechanisms Of Resistance ◽  
Oncogenic Pathways ◽  
Immune Editing ◽  
Tumor Types

ABSTRACT A major breakthrough in cancer treatment was ushered in by the development of immune checkpoint blockade therapy such as anti-CTLA4 antibody and anti-PD-1 and anti-programmed cell death-ligand 1 antibodies that are now approved for use in an increasing number of malignancies. Despite the relative success of immune checkpoint inhibitors with certain tumor types, many patients still fail to respond to such therapies, and the field is actively trying to understand the mechanisms of resistance, intrinsic or acquired, to immune checkpoint blockade. Herein, we discuss the roles that somatic genomic mutations in oncogenic pathways play in immune editing, as well as some of the current approaches toward improving response to immunotherapy.

scholarly journals 284 Integrated molecular characterization of primary resistance mechanisms to immune checkpoint blockade in advanced non-small cell lung carcinoma (a-NSCLC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A308-A308
Author(s):  
Benjamin Besse ◽  
DIB Colette ◽  
Eladio Marquez ◽  
Joon Sang Lee ◽  
Shu Yan ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Integrated Analysis ◽  
Rna Seq ◽  
Primary Resistance ◽  
Immune Infiltration ◽  
Ifn Γ ◽  
High Infiltration

BackgroundReinvigoration of anti-tumor immunity via immune checkpoint blockade (ICB) has transformed outcomes in a-NSCLC. However, a majority of patients are innately resistant to ICB, and a better understanding of the resistance mechanisms may guide the development of new treatment strategies and therapies for patients.MethodsBiopsies performed immediately before treatment with single agent ICB in patients with a-NSCLC (MATCH-R trial [NCT02517892]) were analyzed. The stromal microenvironment and immune context were characterized via an integrated analysis of whole transcriptome (RNA-seq), whole exome sequencing (WES), and immunohistochemistry (IHC) of CD3, CD8, FOXP3 and PDL1. Specifically, the immune context and the relative abundance of 10 immune and stromal cell types were assessed with integrated IHC and Cell Populations-counter (MCP-counter) [1] analysis of the RNA-seq. Somatic mutations and Tumor Mutation Burden (TMB) were evaluated. The transcriptional state of the tumor and its microenvironment were assessed by GSVA analysis [2] of the MSigDB collection [3]. Patient‘s outcome was associated to molecular data. Primary resistance to ICB was defined as PD (progressive disease) in the first radiological examination, or a median PFS inferior to 3 months.ResultsFifty-two patients with NSCLC were enrolled (43 adeno, 6 squamous, and 3 other carcinoma): Median age was 61 (34–93), 18 were female, 46 were smokers, 22 were responders, and 30 were non-responders. Median tumor cellularity was 60% (30%–90%).Patients may be divided into two groups (HIGH and LOW) at baseline based on their degree of immune infiltration as assessed by RNAseq or IHC. A hallmark of the HIGH infiltration group is an increase in Interferon Gamma (IFN-γ) pathway signature [4]. In contrast, patients in the LOW infiltration group (relative to the HIGH infiltration group) exhibit a decrease in IFN-γ pathway signaling and concomitantly an increase in hypoxia and gluconeogenic pathway signatures. Response rates to ICB were not associated to immune infiltration groups at baseline, but an analysis within each infiltration group revealed that high TMB is only associated to response in the HIGH infiltration group. Furthermore, only in the LOW infiltration group was increased the transforming growth factor (TGF-β) pathway signature associated to ICB response.ConclusionsThis study suggests that the tumor and its microenvironment influence baseline immune infiltration. Tumors with LOW baseline infiltration show altered metabolism such as gluconeogenic activation and hypoxia activation. In contrast, factors such as TMB are not associated with baseline infiltration

scholarly journals Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

2020 ◽  
Vol 21 (17) ◽  
pp. 6176 ◽  
Author(s):  
Yolla Haibe ◽  
Ziad El Husseini ◽  
Rola El Sayed ◽  
Ali Shamseddine
Keyword(s):  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Immune Checkpoints ◽  
Therapeutic Approaches ◽  
Standard Chemotherapy ◽  
Primary Resistance ◽  
In The Beginning ◽  
Tumor Types

The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

Managing Resistance to Immune Checkpoint Inhibitors in Lung Cancer: Treatment and Novel Strategies

2022 ◽  
Author(s):  
Antonio Passaro ◽  
Julie Brahmer ◽  
Scott Antonia ◽  
Tony Mok ◽  
Solange Peters
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Primary Resistance ◽  
Previous Response ◽  
Immune Resistance ◽  
Clinical Resistance

A proportion of patients with lung cancer experience long-term clinical benefit with immune checkpoint inhibitors (ICIs). However, most patients develop disease progression during treatment or after treatment discontinuation. Definitions of immune resistance are heterogeneous according to different clinical and biologic features. Primary resistance and acquired resistance, related to tumor-intrinsic and tumor-extrinsic mechanisms, are identified according to previous response patterns and timing of occurrence. The clinical resistance patterns determine differential clinical approaches. To date, several combination therapies are under development to delay or prevent the occurrence of resistance to ICIs, including the blockade of immune coinhibitory signals, the activation of those with costimulatory functions, the modulation of the tumor microenvironment, and the targeting T-cell priming. Tailoring the specific treatments with distinctive biologic resistance mechanisms would be ideal to improve the design and results of clinical trial. In this review, we reviewed the available evidence on immune resistance mechanisms, clinical definitions, and management of resistance to ICIs in lung cancer. We also reviewed data on novel strategies under investigation in this setting.

scholarly journals Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors

Immunity ◽  
2016 ◽  
Vol 44 (6) ◽  
pp. 1255-1269 ◽  
Author(s):  
Jonathan M. Pitt ◽  
Marie Vétizou ◽  
Romain Daillère ◽  
María Paula Roberti ◽  
Takahiro Yamazaki ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Extrinsic Factors ◽  
Cancer Tumor ◽  
Intrinsic And Extrinsic Factors
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