scholarly journals Fundamental and Essential Knowledge for Pathologists Engaged in the Research and Practice of Immune Checkpoint Inhibitor-Based Cancer Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Terufumi Kubo ◽  
Tomoyo Shinkawa ◽  
Yasuhiro Kikuchi ◽  
Kenji Murata ◽  
Takayuki Kanaseki ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Predictive Biomarkers ◽  
Daily Practice ◽  
Basic Knowledge ◽  
Histopathological Analysis ◽  
Essential Knowledge

Extensive research over 100 years has demonstrated that tumors can be eliminated by the autologous immune system. Without doubt, immunotherapy is now a standard treatment along with surgery, chemotherapy, and radiotherapy; however, the field of cancer immunotherapy is continuing to develop. The current challenges for the use of immunotherapy are to enhance its clinical efficacy, reduce side effects, and develop predictive biomarkers. Given that histopathological analysis provides molecular and morphological information on humans in vivo, its importance will continue to grow. This review article outlines the basic knowledge that is essential for the research and daily practice of immune checkpoint inhibitor-based cancer immunotherapy from the perspective of histopathology.

Biomarkers of hyperprogression and pseudoprogression with immune checkpoint inhibitor therapy

2019 ◽  
Vol 15 (22) ◽  
pp. 2645-2656 ◽  
Author(s):  
Jarrett J Failing ◽  
Olivia A Dudek ◽  
Julian A Marin Acevedo ◽  
Razvan M Chirila ◽  
Haidong Dong ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Small Sample ◽  
Inhibitor Therapy ◽  
Laboratory Findings ◽  
Therapeutic Decisions ◽  
Checkpoint Inhibitor Therapy

Hyperprogression and pseudoprogression are two atypical responses to immune checkpoint inhibitor therapy that affect therapeutic decisions and prognosis. Identification of predictive biomarkers for atypical responses either before or during treatment remains a huge unmet need in cancer immunotherapy. Many studies have looked at potential biomarkers, including clinical factors and laboratory findings (e.g., peripheral blood counts, circulating tumor DNA, cytokine levels). The results of these studies have been inconsistent, possibly due to small sample sizes, different tumor types and heterogeneity of the definition of these atypical responses.

Panel-derived TMB and immune-related GEP are associated with the response to immune checkpoint inhibitors (ICIs) in urothelial cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17047-e17047
Author(s):  
Kien Thiam Tan ◽  
Shu-Jen Chen ◽  
Yi-Lin Hsieh ◽  
Yu-Li Su ◽  
Yi-hua Jan ◽  
...  
Keyword(s):  
Internal Control ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Group Analysis ◽  
Predictive Biomarkers ◽  
Cell Types ◽  
Gene Signature ◽  
Chang Gung Memorial Hospital

e17047 Background: Tumor mutational burden (TMB) and gene expression profile (GEP) have emerged as potential biomarkers for the prediction of response to the immune checkpoint inhibitor (ICI) treatment. An interferon-g gene signature was shown recently to predict ICI response in a pan-cancer setting. For TMB, not only did TMB-high patients experience better clinical outcome with ICI, but panel-derived TMB was also shown to be comparable to the gold standard, TMB derived from whole exome sequencing. Here, we evaluate possible correlations between panel-derived TMB, as well as immune-related GEP, with ICI response in urothelial cancers. Methods: FFPE tumor tissues from 30 patients with urothelial cancers who had previously received ICI as monotherapies or combination with chemotherapies at Kaohsiung Chang Gung Memorial Hospital were retrospectively tested for targeted next-generation sequencing (ACTOnco) and quantitative PCR-based GEP (ACTTME), for the identification of nonsynonymous variants across 440 cancer-associated genes and expression levels of > 90 immune-related genes, respectively. TMB was calculated by using the sequenced regions of ACTOnco to estimate the number of somatic nonsynonymous mutations per megabase of all protein-coding genes. For ACTTME, Cq values were normalized to internal control before group analysis. RECIST criteria were used to categorize tumor response to the treatment. Results: Patients were defined as responders (CR/PR) and non-responders (SD/PD) according to the RECIST criteria. In the ICI monotherapy cohort, the responders (n = 8) had significantly higher TMB than non-responders (n = 15) (Median 16.2 muts/Mb vs. 6.5 muts/Mb, p= 0.0035). In contrast, for the cohort receiving ICI combination therapy, several genes implicated in hypoxia (HIF1A), suppressive cell types (Treg & MDSC) and immune checkpoint (PD-L2) were significantly elevated ( p< 0.05) in the non-responder group by 2 to 8 folds. Conclusions: Despite the fact that the cohort size is small, this study showed panel-derived TMB, as well as immune-related GEP, can potentially serve as predictive biomarkers to identify urothelial cancer patients for immune checkpoint inhibitor therapy.

scholarly journals Paraneoplastic Neurological Syndromes and Beyond Emerging With the Introduction of Immune Checkpoint Inhibitor Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Cristina Valencia-Sanchez ◽  
Anastasia Zekeridou
Keyword(s):  
Nervous System ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Neurological Complications ◽  
High Dose ◽  
Paraneoplastic Neurological Syndromes ◽  
Clinical Presentations

Paraneoplastic neurological syndromes are more commonly seen with malignancies such as small cell lung cancer, thymoma, gynecological malignancies, and breast cancer as well as seminoma. With the introduction of immune checkpoint inhibitor (ICI) cancer immunotherapy we see an increase of autoimmune neurological complications in patients with malignancies not traditionally associated with paraneoplastic neurological syndromes, such as melanoma and renal cell carcinoma. Immune checkpoint inhibitors enhance antitumor immune responses resulting often in immune-related adverse effects that can affect any organ, including the central and peripheral nervous system, neuromuscular junction and muscle. Neurological complications are rare; neuromuscular complications are more common than central nervous system ones but multifocal neurological presentations are often encountered. The vast majority of neurological complications appear within 3 months of ICI initiation, but have been described even after ICI cessation. Neural autoantibody testing reveals autoantibodies in approximately half of the patients with CNS complications. Early suspicion and diagnosis is critical to avoid worsening and improve outcomes. Therapeutic strategies depend on the severity of the symptoms and initially typically involve discontinuation of ICI and high dose steroids. Further immunosuppression might be necessary. Outcomes are dependent on patient's characteristics and clinical presentations.

scholarly journals Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics

2020 ◽  
Vol 117 (24) ◽  
pp. 13428-13436 ◽  
Author(s):  
Colin G. Buss ◽  
Sangeeta N. Bhatia
Keyword(s):  
Animal Models ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Engineered Nanoparticles ◽  
Therapeutic Effects

The recent advent of immune checkpoint inhibitor (CPI) antibodies has revolutionized many aspects of cancer therapy, but the efficacy of these breakthrough therapeutics remains limited, as many patients fail to respond for reasons that still largely evade understanding. An array of studies in human patients and animal models has demonstrated that local signaling can generate strongly immunosuppressive microenvironments within tumors, and emerging evidence suggests that delivery of immunostimulatory molecules into tumors can have therapeutic effects. Nanoparticle formulations of these cargoes offer a promising way to maximize their delivery and to enhance the efficacy of checkpoint inhibitors. We developed a modular nanoparticle system capable of encapsulating an array of immunostimulatory oligonucleotides that, in some cases, greatly increase their potency to activate inflammatory signaling within immune cells in vitro. We hypothesized that these immunostimulatory nanoparticles could suppress tumor growth by activating similar signaling in vivo, and thereby also improve responsiveness to immune checkpoint inhibitor antibody therapies. We found that our engineered nanoparticles carrying a CpG DNA ligand of TLR9 can suppress tumor growth in several animal models of various cancers, resulting in an abscopal effect on distant tumors, and improving responsiveness to anti-CTLA4 treatment with combinatorial effects after intratumoral administration. Moreover, by incorporating tumor-homing peptides, immunostimulatory nucleotide-bearing nanoparticles facilitate antitumor efficacy after systemic intravenous (i.v.) administration.

scholarly journals NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020

2020 ◽  
Vol 18 (3) ◽  
pp. 230-241 ◽  
Author(s):  
John A. Thompson ◽  
Bryan J. Schneider ◽  
Julie Brahmer ◽  
Stephanie Andrews ◽  
Philippe Armand ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Nccn Guidelines

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor–related diarrhea/colitis and cardiovascular irAEs.

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