scholarly journals Failure of Immunotherapy—The Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer

2021 ◽  
Vol 22 (16) ◽  
pp. 9030
Author(s):  
Justyna Błach ◽  
Kamila Wojas-Krawczyk ◽  
Marcin Nicoś ◽  
Paweł Krawczyk
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Treatment Resistance ◽  
Immune Checkpoints ◽  
Cytotoxic T Cell ◽  
Number Of Patients ◽  
Cell Death Protein

Immune checkpoint inhibitors (ICIs) have a huge impact on clinical treatment results in non-small cell lung cancer (NSCLC). Blocking antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death protein ligand 1 (PD-L1) or CTLA-4 (cytotoxic T cell antigen 4) have been developed and approved for the treatment of NSCLC patients. However, a large number of patients develop resistance to this type of treatment. Primary and secondary immunotherapy resistance are distinguished. No solid biomarkers are available that are appropriate to predict the unique sensitivity to immunotherapy. Knowledge of predictive markers involved in treatment resistance is fundamental for planning of new treatment combinations. Scientists focused research on the use of immunotherapy as an essential treatment in combination with other therapy strategies, which could increase cancer immunogenicity by generating tumor cells death and new antigen release as well as by targeting other immune checkpoints and tumor microenvironment. In the present review, we summarize the current knowledge of molecular bases underlying immunotherapy resistance and discuss the capabilities and the reason of different therapeutic combinations.

scholarly journals Immune Thrombocytopenia Induced by Immune Checkpoint Inhibitrs in Lung Cancer: Case Report and Literature Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Wang Xie ◽  
NaNa Hu ◽  
LeJie Cao
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Clinical Presentation ◽  
Checkpoint Inhibitors ◽  
Immune Dysregulation ◽  
Cancer Case ◽  
Severe Thrombocytopenia ◽  
Cell Death Protein

Immune checkpoint inhibitors (ICIs), including antibodies targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1), are being extensively used on advanced human malignancies therapy. The treatment with ICIs have acquired durable tumor inhibition and changed the treatment landscape in lung cancer. Immune-related adverse events including pneumonitis and thyroiditis have been well described, but less frequent events, such as ICIs-induced thrombocytopenia, are now emerging and may sometimes be severe or fatal. Since early detection and prompt intervention are crucial to prevent fatal consequences, it is of outmost importance that medical staff is aware of these potential toxicities and learn to recognize and treat them adequately. This review focuses on the epidemiology, clinical presentation, mechanisms, and clinical management of ICIs-induced thrombocytopenia in patients with lung cancer. We also present a patient with advanced lung adenocarcinoma who received the PD-L1 inhibitor atezolizumab and eventually developed severe thrombocytopenia. The case indirectly suggests that cytokine changes might contribute to immune dysregulation in ICIs-induced thrombocytopenia.

Pointed Progress in Second-Line Advanced Non–Small-Cell Lung Cancer: The Rapidly Evolving Field of Checkpoint Inhibition

2016 ◽  
Vol 34 (14) ◽  
pp. 1676-1688 ◽  
Author(s):  
Barbara Melosky ◽  
Quincy Chu ◽  
Rosalyn Juergens ◽  
Natasha Leighl ◽  
Deanna McLeod ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Randomized Trials ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Second Line ◽  
Small Cell Lung ◽  
Cell Death Protein

Purpose Non–small-cell lung cancer (NSCLC) is globally prevalent and associated with high rates of mortality. Immune checkpoint pathways are often exploited by tumors to evade immunity-mediated destruction, and checkpoint inhibitors can reactivate tumor-related immune responses. This review considers available clinical evidence for the use of checkpoint inhibitors in the treatment of second-line advanced NSCLC. Methods Our systematic search revealed 20 clinical trials evaluating checkpoint inhibitors in the second-line setting, three of which were randomized trials comparing programmed cell death protein 1 and programmed death ligand 1 (PD-L1) inhibitors to docetaxel, the current standard of care in this setting. Results A randomized phase II trial comparing the PD-L1 inhibitor atezolizumab to docetaxel did not demonstrate improved survival for atezolizumab in patients overall, although a trend toward improved survival with increased PD-L1 expression was apparent. Twin phase III trials showed significantly improved survival for the programmed cell death protein 1 inhibitor nivolumab compared with docetaxel in patients with both squamous and nonsquamous disease. PD-L1 expression correlated with improved survival in patients with nonsquamous disease, and patients with low levels of PD-L1 expression (< 10%) and those with EGFR mutations are unlikely to benefit. Checkpoint inhibitor therapy is generally well tolerated and associated with low rates of grade 3 or 4 adverse events compared with standard care. Conclusion Level 1 evidence exists to support the use of nivolumab as second-line treatment of patients with squamous advanced NSCLC, as well as in select patients with nonsquamous disease. Benefits remain unknown in patients with targetable driver mutations, and use of PD-L1 expression to guide therapy remains controversial. Results from ongoing randomized trials evaluating biomarkers and other checkpoint inhibitors will further our understanding of this rapidly evolving area of oncology.

scholarly journals Immunotherapy in Bladder Cancer: Current Methods and Future Perspectives

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1181 ◽  
Author(s):  
Mikołaj Wołącewicz ◽  
Rafał Hrynkiewicz ◽  
Ewelina Grywalska ◽  
Tomasz Suchojad ◽  
Tomasz Leksowski ◽  
...  
Keyword(s):  
Immune Response ◽  
Bladder Cancer ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Cytotoxic T Cell ◽  
Interleukin 12 ◽  
High Morbidity ◽  
Number Of Patients ◽  
Cell Death Protein

Bladder cancer is one of the most significant genitourinary cancer, causing high morbidity and mortality in a great number of patients. Over the years, various treatment methods for this type of cancer have been developed. The most common is the highly efficient method using Bacillus Calmette-Guerin, giving a successful effect in a high percentage of patients. However, due to the genetic instability of bladder cancer, together with individual needs of patients, the search for different therapy methods is ongoing. Immune checkpoints are cell surface molecules influencing the immune response and decreasing the strength of the immune response. Among those checkpoints, the PD-1 (programmed cell death protein-1)/PD-L1 (programmed cell death protein ligand 1) inhibitors aim at blocking those molecules, which results in T cell activation, and in bladder cancer the use of Atezolizumab, Avelumab, Durvalumab, Nivolumab, and Pembrolizumab has been described. The inhibition of another pivotal immune checkpoint, CTLA-4 (cytotoxic T cell antigen), may result in the mobilization of the immune system against bladder cancer and, among anti-CTLA-4 antibodies, the use of Ipilimumab and Tremelimumab has been discussed. Moreover, several different approaches to successful bladder cancer treatment exists, such as the use of ganciclovir and mTOR (mammalian target of rapamycin) kinase inhibitors, IL-12 (interleukin-12) and COX-2 (cyclooxygenase-2). The use of gene therapies and the disruption of different signaling pathways are currently being investigated. Research suggests that the combination of several methods increases treatment efficiency and the positive outcome in individual.

IMMUNE CHECKPOINT BLOCKADE IN BREAST CANCER THERAPY

2020 ◽  
pp. 33-38
Author(s):  
I. A. Hromakova ◽  
P. P. Sorochan ◽  
N. E. Prokhach ◽  
I. N. Ponamarov ◽  
I. S. Hromakova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Cell Function ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Immune Checkpoints ◽  
Cancer Information ◽  
Cell Death Protein

Despite advances in early detection and treatment, breast cancer remains the deadliest oncopathology for women worldwide. Today there is an urgent need for new approaches to this disease treatment. Recently, immune therapy, especially inhibitors of immune checkpoints, has taken the lead when fighting against cancer. Blocking immune checkpoints is an effective approach to enhance the effector T cell function. Immune checkpoint blockers, namely inhibitors of cytotoxic T−lymphocyte−associated antigen 4 (CTLA−4), programmed cell death protein 1 (PD−1) and ligand 1 of programmed cell death protein 1 (PD−L1) are approved by the US Food and Drug Association (FDA) to be used in various solid tumors, refractory cancers with microsatellite instability, classical Hodgkin's lymphoma. In March 2019, the first inhibitor for the treatment of breast cancer was approved, i.e. atezolizumab (anti−PD−L1) in combination with nab−paclitaxel in the patients with metastatic triple−negative breast cancer, which aroused the interest of experts in the study of immunotherapeutic agents for the treatment of these patients. The review presents the results of using the inhibitors of immune control points in monotherapy and in combination with standard methods of antitumor treatment (chemotherapy and radiotherapy, targeted therapy) in patients with breast cancer. Information on potential biomarkers of response to immunotherapy in breast cancer is presented. Key words: breast cancer, checkpoint inhibitors, biomarkers of response.

scholarly journals Immunotherapy in Patients with Advanced Non-Small Cell Lung Cancer Lacking Driver Mutations and Future Perspectives

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 122
Author(s):  
Ramon Andrade Bezerra De Mello ◽  
Rafael Voscaboinik ◽  
João Vittor Pires Luciano ◽  
Rafaela Vilela Cremonese ◽  
Giovanna Araujo Amaral ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Cell Death Protein

From a complete literature review, we were able to present in this paper what is most current in the treatment with immunotherapy for advanced non-small cell lung cancer (NSCLC). Especially the use of immunotherapy, particularly inhibitors of PD-1 (programmed cell death protein 1), PDL-1 (programmed cell death protein ligand 1), and CTLA-4 (cytotoxic T-lymphocyte antigen 4). Since 2015, these drugs have transformed the treatment of advanced NSCLC lacking driver mutations, evolving from second-line therapy to first-line, with excellent results. The arrival of new checkpoint inhibitors such as cemiplimab and the use of checkpoint inhibitors earlier in the therapy of advanced and metastatic cancers has been making the future prospects for treating NSCLC lacking driver mutations more favorable and optimistic. In addition, for those patients who have low PDL-1 positivity tumors, the combination of cytotoxic chemotherapy, VEGF inhibitor, and immunotherapy have shown an important improvement in global survival and progression free survival regardless the PDL-1 status. We also explored the effectiveness of adding radiotherapy to immunotherapy and the most current results about this combination. One concern that cannot be overlooked is the safety profile of immune checkpoint inhibitors (ICI) and the most common toxicities are described throughout this paper as well as tumor resistance to ICI.

scholarly journals Research Progresses in Immunological Checkpoint Inhibitors for Breast Cancer Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Wenxiang Zhang ◽  
Xiangyi Kong ◽  
Bolun Ai ◽  
Zhongzhao Wang ◽  
Xiangyu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Tumor Immune Escape ◽  
Cell Death Protein

Tumor immune escape refers to the phenomenon in which tumor cells escape the recognition and attack of the body’s immune system through various mechanisms so that they can survive and proliferate in vivo. The imbalance of immune checkpoint protein expression is the primary mechanism for breast cancer to achieve immune escape. Cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1)/programmed cell death protein-ligand 1 (PD-L1) are critical immune checkpoints for breast cancer. Immune checkpoint inhibitors block the checkpoint and relieve its inhibition effect on immune cells, reactivate T-cells and destroy cancer cells and restore the body’s ability to resist tumors. At present, immunological checkpoint inhibitors have made significant progress in breast cancer immunotherapy, and it is expected to become a new treatment for breast cancer.

scholarly journals Clinical Applications of Immunotherapy Combination Methods and New Opportunities for the Future

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Ece Esin
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Checkpoint Inhibitors ◽  
Innate Immune ◽  
Small Subset ◽  
New Class ◽  
Combination Strategies ◽  
Combination Methods ◽  
Immune Editing ◽  
Cell Death Protein

In the last decade, we have gained a deeper understanding of innate immune system. The mechanism of the continuous guarding of progressive mutations happening in a single cell was discovered and the production and the recognition of tumor associated antigens by the T-cells and elimination of numerous tumors by immune-editing were further understood. The new discoveries on immune mechanisms and its relation with carcinogenesis have led to development of a new class of drugs called immunotherapeutics. T lymphocyte-associated antigen 4, programmed cell death protein 1, and programmed cell death protein ligand 1 are the classes drugs based on immunologic manipulation and are collectively known as the “checkpoint inhibitors.” Checkpoint inhibitors have shown remarkable antitumor efficacy in a broad spectrum of malignancies; however, the strongest and most durable immune responses do not last long and the more durable responses only occur in a small subset of patients. One of the solutions which have been put forth to overcome these challenges is combination strategies. Among the dual use of methods, a backbone with either PD-1 or PD-L1 antagonist drugs alongside with certain cytotoxic chemotherapies, radiation, targeted drugs, and novel checkpoint stimulators is the most promising approach and will be on stage in forthcoming years.

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