scholarly journals Molecular Imaging and the PD-L1 Pathway: From Bench to Clinic

2021 ◽  
Vol 11 ◽  
Author(s):  
David Leung ◽  
Samuel Bonacorsi ◽  
Ralph Adam Smith ◽  
Wolfgang Weber ◽  
Wendy Hayes
Keyword(s):  
Clinical Studies ◽  
Diagnostic Tests ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Clinical Implementation ◽  
Pet Tracers ◽  
Multiple Tumor ◽  
Positron Emission ◽  
Programmed Death ◽  
Preclinical And Clinical Studies

Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors target the important molecular interplay between PD-1 and PD-L1, a key pathway contributing to immune evasion in the tumor microenvironment (TME). Long-term clinical benefit has been observed in patients receiving PD-(L)1 inhibitors, alone and in combination with other treatments, across multiple tumor types. PD-L1 expression has been associated with response to immune checkpoint inhibitors, and treatment strategies are often guided by immunohistochemistry-based diagnostic tests assessing expression of PD-L1. However, challenges related to the implementation, interpretation, and clinical utility of PD-L1 diagnostic tests have led to an increasing number of preclinical and clinical studies exploring interrogation of the TME by real-time imaging of PD-(L)1 expression by positron emission tomography (PET). PET imaging utilizes radiolabeled molecules to non-invasively assess PD-(L)1 expression spatially and temporally. Several PD-(L)1 PET tracers have been tested in preclinical and clinical studies, with clinical trials in progress to assess their use in a number of cancer types. This review will showcase the development of PD-(L)1 PET tracers from preclinical studies through to clinical use, and will explore the opportunities in drug development and possible future clinical implementation.

scholarly journals Towards Curative Cancer Immunotherapy: Overcoming Posttherapy Tumor Escape

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Gang Zhou ◽  
Hyam Levitsky
Keyword(s):  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Clinical Studies ◽  
Cytotoxic T Lymphocyte ◽  
Treatment Strategies ◽  
Therapeutic Modality ◽  
Tumor Escape ◽  
Immune Effector ◽  
Therapeutic Outcomes ◽  
Preclinical And Clinical Studies

The past decade has witnessed the evolvement of cancer immunotherapy as an increasingly effective therapeutic modality, evidenced by the approval of two immune-based products by the FDA, that is, the cancer vaccine Provenge (sipuleucel-T) for prostate cancer and the antagonist antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for advanced melanoma. In addition, the clinical evaluations of a variety of promising immunotherapy drugs are well under way. Benefiting from more efficacious immunotherapeutic agents and treatment strategies, a number of recent clinical studies have achieved unprecedented therapeutic outcomes in some patients with certain types of cancers. Despite these advances, however, the efficacy of most cancer immunotherapies currently under clinical development has been modest. A recurring scenario is that therapeutic maneuvers initially led to measurable antitumor immune responses in cancer patients but ultimately failed to improve patient outcomes. It is increasingly recognized that tumor cells can antagonize therapy-induced immune attacks through a variety of counterregulation mechanisms, which represent a fundamental barrier to the success of cancer immunotherapy. Herein we summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction.

scholarly journals Checkpoint Inhibition: Will Combination with Radiotherapy and Nanoparticle-Mediated Delivery Improve Efficacy?

Medicines ◽  
2018 ◽  
Vol 5 (4) ◽  
pp. 114 ◽  
Author(s):  
Purushottam Lamichhane ◽  
Neha Amin ◽  
Manuj Agarwal ◽  
Narottam Lamichhane
Keyword(s):  
Clinical Studies ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Checkpoint Inhibition ◽  
Success Story ◽  
Cancer Treatments ◽  
Clinical Investigations ◽  
Liposomal Delivery ◽  
Preclinical And Clinical Studies ◽  
Infiltrating Lymphocytes

Checkpoint inhibition (CPI) has been a rare success story in the field of cancer immunotherapy. Knowledge gleaned from preclinical studies and patients that do not respond to these therapies suggest that the presence of tumor-infiltrating lymphocytes and establishment of immunostimulatory conditions, prior to CPI treatment, are required for efficacy of CPI. To this end, radiation therapy (RT) has been shown to promote immunogenic cell-death-mediated tumor-antigen release, increase infiltration and cross-priming of T cells, and decreasing immunosuppressive milieu in the tumor microenvironment, hence allowing CPI to take effect. Preclinical and clinical studies evaluating the combination of RT with CPI have been shown to overcome the resistance to either therapy alone. Additionally, nanoparticle and liposome-mediated delivery of checkpoint inhibitors has been shown to overcome toxicities and improve therapeutic efficacy, providing a rationale for clinical investigations of nanoparticle, microparticle, and liposomal delivery of checkpoint inhibitors. In this review, we summarize the preclinical and clinical studies of combined RT and CPI therapies in various cancers, and review findings from studies that evaluated nanoparticle and liposomal delivery of checkpoint inhibitors for cancer treatments.

scholarly journals Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2249
Author(s):  
Sandra van Wilpe ◽  
Sofie H. Tolmeijer ◽  
Rutger H. T. Koornstra ◽  
I. Jolanda M. de Vries ◽  
Winald R. Gerritsen ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Multiple Tumor ◽  
Repair Deficiency ◽  
Recombination Repair ◽  
Tumor Immunogenicity

Homologous recombination repair deficiency (HRD) can be observed in virtually all cancer types. Although HRD sensitizes tumors to DNA-damaging chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors, all patients ultimately develop resistance to these therapies. Therefore, it is necessary to identify therapeutic regimens with a more durable efficacy. HRD tumors have been suggested to be more immunogenic and, therefore, more susceptible to treatment with checkpoint inhibitors. In this review, we describe how HRD might mechanistically affect antitumor immunity and summarize the available translational evidence for an association between HRD and antitumor immunity across multiple tumor types. In addition, we give an overview of all available clinical data on the efficacy of checkpoint inhibitors in HRD tumors and describe the evidence for using treatment strategies that combine checkpoint inhibitors with PARP inhibitors.

scholarly journals New emerging targets in cancer immunotherapy: the role of TIM3

ESMO Open ◽  
2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. e000497 ◽  
Author(s):  
Alex Friedlaender ◽  
Alfredo Addeo ◽  
Giuseppe Banna
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Lung Cancer Patients ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Cancer Types ◽  
Domain 3

Currently, the programmed death-1/programmed death ligand-1 and the cytotoxic T-lymphocyte-associated protein 4 are the two commonly targeted immune-checkpoint inhibition pathways. These drugs have significantly improved the prognosis of many cancer types. While immune-checkpoint inhibitors have revolutionised the treatment of many cancer types, the majority of patients still progress. Several treatment strategies have been pursued to improve current results. One approach is to combine two checkpoint inhibitors, currently with promising results in melanoma, renal cell carcinoma and a subset of non-small-cell lung cancer patients. The identification of new checkpoint targets could allow the field of immuno-oncology to evolve further. We will discuss one of the most promising immune-checkpoint targets currently under investigation, the T-cell immunoglobulin and mucin domain-3.

scholarly journals Immunotherapeutic Strategies for Gastric Carcinoma: A Review of Preclinical and Clinical Recent Development

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Mohamed Abozeid ◽  
Antonio Rosato ◽  
Roberta Sommaggio
Keyword(s):  
Gastric Carcinoma ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Adoptive T Cell Therapy ◽  
Poor Survival ◽  
T Cell Therapy ◽  
Surgical Interventions ◽  
Programmed Death ◽  
Preclinical And Clinical Studies ◽  
Cell Death Protein

Gastric carcinoma (GC) is the 2nd most common cause of cancer-related death. Despite advances in conventional treatment and surgical interventions, a high percentage of GC patients still have poor survival. Recently, immunotherapy has become a promising approach to treat GC. Here, we present preclinical and clinical studies encouraging the use of vaccination, adoptive T-cell therapy (ACT), and immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The ongoing immunotherapy clinical trials have shown promising results in safety and tolerability even in late-stage GC patients. Moreover, we highlight that the combination of ACT with chemotherapy could be the best choice to treat GC.

scholarly journals How we treat neurological toxicity from immune checkpoint inhibitors

ESMO Open ◽  
2019 ◽  
Vol 4 (Suppl 4) ◽  
pp. e000540 ◽  
Author(s):  
Lavinia Spain ◽  
Zayd Tippu ◽  
James M Larkin ◽  
Aisling Carr ◽  
Samra Turajlic
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Treatment Strategies ◽  
Presenting Symptoms ◽  
Programmed Death ◽  
Symptoms And Signs ◽  
Substantial Morbidity

Neurological adverse events from immune checkpoint inhibition are increasingly recognised, especially with combination anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) and anti-programmed death receptor 1 (anti-PD-1) therapies. Their presenting symptoms and signs are often subacute and highly variable, reflecting the numerous components of the nervous system. Given the risk of substantial morbidity and mortality, it is important to inform patients of symptoms that may be of concern, and to assess any suspected toxicity promptly. As with other immune-related adverse events, the cornerstone of management is administration of corticosteroids. Specialist neurology input is vital in this group of patients to guide appropriate investigations and tailor treatment strategies.

scholarly journals Biomarkers in Immunotherapy-Based Precision Treatments of Digestive System Tumors

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhu Zeng ◽  
Biao Yang ◽  
Zhengyin Liao
Keyword(s):  
Digestive System ◽  
Checkpoint Inhibitors ◽  
Circulating Tumor Dna ◽  
Gastrointestinal Malignancies ◽  
Programmed Death Ligand 1 ◽  
Multiple Tumor ◽  
Programmed Death ◽  
Potential Biomarker ◽  
Tumor Mutational Burden ◽  
Programmed Death 1

Immunotherapy, represented by immune checkpoint inhibitors (mainly referring to programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockades), derives durable remission and survival benefits for multiple tumor types including digestive system tumors [gastric cancer (GC), colorectal cancer (CRC), and hepatocellular carcinoma (HCC)], particularly those with metastatic or recurrent lesions. Even so, not all patients would respond well to anti-programmed death-1/programmed death-ligand 1 agents (anti-PD-1/PD-L1) in gastrointestinal malignancies, suggesting the need for biomarkers to identify the responders and non-responders, as well as to predict the clinical outcomes. PD-L1expression has increasingly emerged as a potential biomarker when predicting the immunotherapy-based efficacy; but regrettably, PD-L1 alone is not sufficient to differentiate patients. Other molecules, such as tumor mutational burden (TMB), microsatellite instability (MSI), and circulating tumor DNA (ctDNA) as well, are involved in further explorations. Overall, there are not still no perfect or well-established biomarkers in immunotherapy for digestive system tumors at present as a result of the inherent limitations, especially for HCC. Standardizing and harmonizing the assessments of existing biomarkers, and meanwhile, switching to other novel biomarkers are presumably wise and feasible.

scholarly journals Clinical significance of checkpoint regulator “Programmed death ligand-1 (PD-L1)” expression in meningioma: review of the current status

2021 ◽  
Vol 151 (3) ◽  
pp. 443-449
Author(s):  
Shirin Karimi ◽  
Sheila Mansouri ◽  
Farshad Nassiri ◽  
Severa Bunda ◽  
Olivia Singh ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Tumor Heterogeneity ◽  
Checkpoint Inhibitors ◽  
Primary Brain Tumor ◽  
Current Status ◽  
High Grade ◽  
Programmed Death Ligand 1 ◽  
Multiple Tumor ◽  
Programmed Death

Abstract Introduction Meningioma is the most common primary brain tumor. Most meningiomas are benign; however, a subset of these tumors can be aggressive, presenting with early or multiple tumor recurrences that are refractory to neurosurgical resection and radiotherapy. There is no standard systemic therapy for these patients, and post-surgical management of these patients is usually complicated due to lack of accurate prediction for tumor progression. Methods In this review, we summarise the crucial immunosuppressive role of checkpoint regulators, including PD-1 and PD-L1 interacting in the tumor microenvironment, which has led to efforts aimed at targeting this axis. Results Since their discovery, checkpoint inhibitors have significantly improved the outcome in many types of cancers. Currently, targeted therapy for PD-1 and PD-L1 proteins are being tested in several ongoing clinical trials for brain tumors such as glioblastoma. More recently, there have been some reports implicating increased PD-L1 expression in high-grade (WHO grades II and III) meningiomas. Several clinical trials are underway to assess the efficacy of checkpoint inhibitors in the therapeutic management of patients with aggressive meningiomas. Here, we review the immune suppressive microenvironment in meningiomas, and then focus on clinical and pathological characterization and tumor heterogeneity with respect to PD-L1 expression as well as challenges associated with the assessment of PD-L1 expression in meningioma. Conclusion We conclude with a brief review of ongoing clinical trials using checkpoint inhibitors for the treatment of high-grade and refractory meningiomas.

scholarly journals The Latest Findings of PD-1/PD-L1 Inhibitor Application in Gynecologic Cancers

2020 ◽  
Vol 21 (14) ◽  
pp. 5034 ◽  
Author(s):  
Omid Kooshkaki ◽  
Afshin Derakhshani ◽  
Hossein Safarpour ◽  
Souzan Najafi ◽  
Parviz Vahedi ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Checkpoint Inhibitors ◽  
Cell Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Oncological Outcome ◽  
The United States ◽  
Gynecologic Cancers ◽  
Programmed Death ◽  
The Us ◽  
Infiltrating Lymphocytes

Gynecologic cancers account for approximately 11% of the newly diagnosed cancers in women in the United States and for 18% globally. The presence of tumor-infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICIs), including anti programmed cell death protein-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), and anticytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), which have been approved for treating different types of malignancies. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host–tumor interaction. There are several the US food and drug administration (FDA)-approved ICIs targeting PD-1, including pembrolizumab and nivolumab, as well as those targeting PD-L1, including avelumab, atezolizumab, and durvalumab for melanoma, renal cell cancer, colorectal cancer, head and neck cancer, cervix cancer, urothelial cancer, and lung cancer. Current pre-clinical and clinical studies assessing PD-1/PD-L1 inhibitors in several gynecologic cancers have reported significant antitumor activity. In this review, we investigate pre-clinical and clinical studies that describe the safety and efficacy of anti-PD-1/PD-L1 antibodies, with a particular focus on ongoing clinical trials, analyzing the oncological outcome and adverse effects of ICIs in gynecologic cancers.

To do or not to do: A concise update of current clinical controversies in immune checkpoint blockade

2018 ◽  
Vol 25 (3) ◽  
pp. 663-673 ◽  
Author(s):  
Clement Chung
Keyword(s):  
Immune Response ◽  
Cancer Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Cellular Interactions ◽  
Programmed Death Ligand 1 ◽  
Multiple Tumor ◽  
First Line Therapy ◽  
Programmed Death ◽  
Starting Point

Although programmed death-ligand 1 is currently the best available biomarker for first-line therapy with pembrolizumab for patients with non-small cell lung cancer and is a required companion test approved by the US Food and Drug Administration, programmed death-ligand 1 testing is an option (as a complementary test) for patients treated with nivolumab, atezolizumab, and durvalumab. Programmed death-ligand 1 expression is continuously variable and dynamic in the tumor microenvironment. Due to the complex molecular and cellular interactions involved in immune response, a single biomarker may not be sufficient to predict response to cancer immunotherapy. Integration of multiple tumor, immune response, and genomic parameters is likely to influence the future interpretation of biomarker-based treatment outcomes. This article, in a case-based format, concisely summarizes most up-to-date evidence in answering some commonly seen clinical controversies of cancer immunotherapy, in terms of (i) the predictive value of programmed death-ligand 1 as a biomarker; (ii) whether the use of steroids with checkpoint inhibitors will decrease efficacy of the latter; (iii) selection of patients for cancer immunotherapy based on immune-based response criteria, and (iv) whether the use of influenza vaccine with checkpoint inhibitors is considered safe. Until more robust, long-term prospective clinical data are available, these discussions may serve as a starting point for pharmacists to gain timely and effective management of these realistic issues.

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