Development and clinical applications of cancer immunotherapy against PD-1 signaling pathway

AbstractDramatic advances in immune therapy have emerged as a promising strategy in cancer therapeutics. In addition to chemotherapy and radiotherapy, inhibitors targeting immune-checkpoint molecules such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death receptor-1 (PD-1) and its ligand (PD-L1) demonstrate impressive clinical benefits in clinical trials. In this review, we present background information about therapies involving PD-1/PD-L1 blockade and provide an overview of current clinical trials. Furthermore, we present recent advances involving predictive biomarkers associated with positive therapeutic outcomes in cancer immunotherapy.

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Immune-Related Pancytopenia Induced by Anti-PD-1 Therapy – Interrupt or Continue Treatment – The Role of Immunohistochemical Examination

Case Reports in Oncology ◽

10.1159/000504130 ◽

2019 ◽

Vol 12 (3) ◽

pp. 820-828 ◽

Cited By ~ 1

Author(s):

Bożena Cybulska-Stopa ◽

Andrzej Gruchała ◽

Maciej Niemiec

Keyword(s):

Bone Marrow ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Positive Outcomes ◽

Hematological Disorders ◽

Therapeutic Outcomes ◽

Appropriate Treatment ◽

Programmed Death

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed death receptor-1/ligand-1 (anti-PD-1/anti-PD-L1) caused a breakthrough in oncology and significantly improved therapeutic outcomes in cancer patients. ICIs generate a specific reaction in T cells, directed against antigens on cancer cells, leading to their damage and death. Through similar or the same antigens, activated lymphocytes may also have a cytotoxic effect on healthy cells, causing development of specific adverse effects – so-called immune-related adverse events (irAEs). We present the case report of a 56 year old patient with disseminated melanoma. During treatment with immunotherapy (anti PD-1), neutropenic fever and pancytopenia occurred. Trepanobiopsy of the bone marrow was performed to determine the cause of pancytopenia. Histopathological assessment of bone marrow combined with immunophenotype investigations may explain the cause of hematological disorders occurring in the course of treatment with ICIs, and support the choice of an appropriate treatment, directly translated into positive outcomes.

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Cancer Immunotherapy: A Review

The Indonesian Biomedical Journal ◽

10.18585/inabj.v8i1.189 ◽

2016 ◽

Vol 8 (1) ◽

pp. 1 ◽

Cited By ~ 5

Author(s):

Anna Meiliana ◽

Nurrani Mustika Dewi ◽

Andi Wijaya

Keyword(s):

T Cell ◽

Cancer Immunotherapy ◽

Immune Cells ◽

Tumor Antigens ◽

Cytotoxic T Lymphocyte ◽

Immune Surveillance ◽

Cancer Therapeutics ◽

Adoptive Cell Transfer ◽

Cell Transfer ◽

Genetically Engineer

BACKGROUND: The goals of treating patients with cancer are to cure the disease, prolong survival, and improve quality of life. Immune cells in the tumor microenvironment have an important role in regulating tumor progression. Therefore, stimulating immune reactions to tumors can be an attractive therapeutic and prevention strategy.CONTENT: During immune surveillance, the host provides defense against foreign antigens, while ensuring it limits activation against self antigens. By targeting surface antigens expressed on tumor cells, monoclonal antibodies have demonstrated efficacy as cancer therapeutics. Recent successful antibody-based strategies have focused on enhancing antitumor immune responses by targeting immune cells, irrespective of tumor antigens. The use of antibodies to block pathways inhibiting the endogenous immune response to cancer, known as checkpoint blockade therapy, has stirred up a great deal of excitement among scientists, physicians, and patients alike. Clinical trials evaluating the safety and efficacy of antibodies that block the T cell inhibitory molecules cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) have reported success in treating subsets of patients. Adoptive cell transfer (ACT) is a highly personalized cancer therapy that involve administration to the cancer-bearing host of immune cells with direct anticancer activity. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment.SUMMARY: For cancer treatment, 2011 marked the beginning of a new era. The underlying basis of cancer immunotherapy is to activate a patient’s own T cells so that they can kill their tumors. Reports of amazing recoveries abound, where patients remain cancer-free many years after receiving the therapy. The idea of harnessing immune cells to fight cancer is not new, but only recently have scientists amassed enough clinical data to demonstrate what a game-changer cancer immunotherapy can be. This field is no stranger to obstacles, so the future looks very promising indeed.KEYWORDS: immune checkpoint, adoptive cell transfer, neoantigen, monoclonal antibody

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Towards Curative Cancer Immunotherapy: Overcoming Posttherapy Tumor Escape

Clinical and Developmental Immunology ◽

10.1155/2012/124187 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 26

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.

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Nano-Enhanced Cancer Immunotherapy: Immunology Encounters Nanotechnology

Cells ◽

10.3390/cells9092102 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2102

Author(s):

Ernesto Bockamp ◽

Sebastian Rosigkeit ◽

Dominik Siegl ◽

Detlef Schuppan

Keyword(s):

Cancer Immunotherapy ◽

Immune Therapy ◽

Therapy Resistance ◽

Therapeutic Outcomes ◽

Life Threatening ◽

Cancer Types ◽

Cancer Immunotherapeutic ◽

Cancer Immunotherapies ◽

Fine Tune ◽

Insight Into

Cancer immunotherapy utilizes the immune system to fight cancer and has already moved from the laboratory to clinical application. However, and despite excellent therapeutic outcomes in some hematological and solid cancers, the regular clinical use of cancer immunotherapies reveals major limitations. These include the lack of effective immune therapy options for some cancer types, unresponsiveness to treatment by many patients, evolving therapy resistance, the inaccessible and immunosuppressive nature of the tumor microenvironment (TME), and the risk of potentially life-threatening immune toxicities. Given the potential of nanotechnology to deliver, enhance, and fine-tune cancer immunotherapeutic agents, the combination of cancer immunotherapy with nanotechnology can overcome some of these limitations. In this review, we summarize innovative reports and novel strategies that successfully combine nanotechnology and cancer immunotherapy. We also provide insight into how nanoparticular combination therapies can be used to improve therapy responsiveness, to reduce unwanted toxicity, and to overcome adverse effects of the TME.

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Imperfect Predictors for Lung Cancer Immunotherapy—A Field for Further Research

Frontiers in Oncology ◽

10.3389/fonc.2020.568174 ◽

2020 ◽

Vol 10 ◽

Author(s):

Kamila Wojas-Krawczyk ◽

Tomasz Kubiatowski

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Cancer Cells ◽

Cancer Immunotherapy ◽

Cancer Patients ◽

Tumor Cells ◽

Predictive Factor ◽

Specific Antigen ◽

Clinical Benefits ◽

Potential Factors

The armamentarium for lung cancer immunotherapy has been strengthened using two groups of monoclonal antibodies: 1) anti-PD-1 antibodies, including pembrolizumab and nivolumab, which block the programmed death 1 receptor on the lymphocyte surface, resulting in increasing activity of these cells, and 2) anti-PD-L1 antibodies, including atezolizumab, durvalumab, and avelumab, which block the ligand for the PD-1 molecule on tumor cells and on tumor-infiltrating immune cells. The effectiveness of both groups of antibodies has been proven in many clinical trials, which translates into positive immunotherapeutic registrations for cancer patients. Regarding the predictive factor, PD-L1 expression on cancer cells is the only biomarker validated in prospective clinical trials used for qualification to immunotherapy in advanced non-small cell lung cancer (NSCLC) patients. However, it is not an ideal one. Unfortunately, no clinical benefits could be noted in patients with high PD-L1 expression on tumor cells against the effectiveness of immunotherapy that may be observed in patients without PD-L1 expression. Furthermore, the mechanism of antitumor immune response is extremely complex, multistage, and depends on many factors. Cancer cells could be recognized by the immune system, provided tumor-specific antigen presentation, and these arise as a result of somatic mutations in tumor cells. Based on novel immunotherapy registration, high tumor mutation burden (TMB) has become an important predictive factor. The intensity of lymphocyte infiltration in tumor tissue may be another predictive factor. The effectiveness of anti-PD-L1 immunotherapy is observed in patients with high expression of genes associated with the effector function of T lymphocytes (i.e., their ability to produce IFN-gamma). This does not end the list of potential factors that become useful in qualification of cancer patients for immunotherapy. There remains a need to search for new and perfect predictive factors for immunotherapy.

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New Trends in Anti-Cancer Therapy: Combining Conventional Chemotherapeutics with Novel Immunomodulators

Current Medicinal Chemistry ◽

10.2174/0929867324666170830094922 ◽

2018 ◽

Vol 25 (36) ◽

pp. 4758-4784 ◽

Cited By ~ 8

Author(s):

Amy L. Wilson ◽

Magdalena Plebanski ◽

Andrew N. Stephens

Keyword(s):

Clinical Trials ◽

Cell Death ◽

Immune System ◽

Cancer Therapy ◽

Immune Cell ◽

Cytotoxic T Lymphocyte ◽

Tumour Microenvironment ◽

Immune Checkpoints ◽

Tumour Regression ◽

Cell Trafficking

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

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BIOM-60. BIOMARKER EVALUATION FOR IMIPRIDONE ONC206 REVEALS ClpP, ATF4, MYC, EGFR and HIF1 AS KEY PREDICTORS OF ANTI-CANCER EFFICACY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.057 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii14-ii15

Author(s):

Sara Morrow ◽

Mathew Garnett ◽

Ultan McDermott ◽

Cyril Benes ◽

Joshua Allen ◽

...

Keyword(s):

Clinical Trials ◽

Strong Predictor ◽

Predictive Biomarkers ◽

Receptor Expression ◽

Tumor Type ◽

Anticancer Efficacy ◽

Type Selection ◽

Egfr Expression ◽

Transport Chain ◽

Biomarker Evaluation

Abstract ONC206 is a DRD2 antagonist and ClpP agonist that is a chemical derivative of ONC201, which is in Phase II clinical trials for H3 K27M-mutant glioma. We have previously reported that dopamine receptor expression correlates with ONC201 and ONC206 efficacy. Here, we evaluated additional predictive biomarkers for both agents in the GDSC panel using RNA-seq expression data. ClpP emerged as a strong predictor of efficacy for ONC206 (IC50: p = 1.83E-4, AUC: 9.92E-13). ClpP activation enhances degradation of its substrates, including electron transport chain members responsible for oxidative phosphorylation (OXPHOS). Imipridones activate the integrated stress response involving ATF4 and cause proteasomal degradation of c-myc, which also reduces OXPHOS. Accordingly, high ATF4 (IC50: p = 4.92E-5, AUC: p=2.84E-9) and elevated c-myc correlated with ONC206 efficacy (IC50: p = 6.42E-6, AUC: 3.31E-12). EGFR expression is inversely correlate with DRD2 expression in glioma and its activation is associated with glycolysis. Low EGFR expression correlated with increased ONC206 efficacy (IC50: p = 4.32E-7, AUC: p = 6.44E-20). Loss of HIF1 shunts cellular metabolism toward OXPHOS. Low HIF1 expression correlated with increased anticancer efficacy for ONC206 (IC50: p = 1.96E-3, AUC: p = 1.56E-11). Expression of each of the five markers was significantly different in cell lines that achieved an IC90 with ONC206 (~10%) versus those that did not. A similar analysis for ONC201 revealed that ClpP, MYC and EGFR are more predictive of efficacy relative to ATF4 and HIF1. Combinatorial biomarker analyses revealed MYC/EGFR as the most significant predictor of IC50 for both agents. ClpP/MYC and ClpP/HIF1 were the most significant predictors of AUC for ONC201 and ONC206, respectively. Ongoing studies are further investigating tumor type enrichment of biomarkers. Prediction of innate imipridone sensitivity using biomarkers identified in this study may guide patient and tumor type selection in clinical trials.

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Recent Advances to Augment NK Cell Cancer Immunotherapy Using Nanoparticles

Pharmaceutics ◽

10.3390/pharmaceutics13040525 ◽

2021 ◽

Vol 13 (4) ◽

pp. 525

Author(s):

Kwang-Soo Kim ◽

Dong-Hwan Kim ◽

Dong-Hyun Kim

Keyword(s):

Clinical Trials ◽

Nk Cells ◽

Cancer Immunotherapy ◽

Tumor Cells ◽

Therapeutic Efficacy ◽

Nk Cell ◽

Cell Cancer ◽

Immune Surveillance ◽

Cytolytic Activity ◽

Contact Frequency

Among various immunotherapies, natural killer (NK) cell cancer immunotherapy using adoptive transfer of NK cells takes a unique position by targeting tumor cells that evade the host immune surveillance. As the first-line innate effector cell, it has been revealed that NK cells have distinct mechanisms to both eliminate cancer cells directly and amplify the anticancer immune system. Over the last 40 years, NK cell cancer immunotherapy has shown encouraging reports in pre-clinic and clinic settings. In total, 288 clinical trials are investigating various NK cell immunotherapies to treat hematologic and solid malignancies in 2021. However, the clinical outcomes are unsatisfying, with remained challenges. The major limitation is attributed to the immune-suppressive tumor microenvironment (TME), low activity of NK cells, inadequate homing of NK cells, and limited contact frequency of NK cells with tumor cells. Innovative strategies to promote the cytolytic activity, durable persistence, activation, and tumor-infiltration of NK cells are required to advance NK cell cancer immunotherapy. As maturing nanotechnology and nanomedicine for clinical applications, there is a greater opportunity to augment NK cell therapeutic efficacy for the treatment of cancers. Active molecules/cytokine delivery, imaging, and physicochemical properties of nanoparticles are well equipped to overcome the challenges of NK cell cancer immunotherapy. Here, we discuss recent clinical trials of NK cell cancer immunotherapy, NK cell cancer immunotherapy challenges, and advances of nanoparticle-mediated NK cell therapeutic efficacy augmentation.

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Angiogenic and T-effector subgroups identified by gene expression profiling (GEP) and propensity for PBRM1 and BAP1 alterations in clear cell renal cell carcinoma (ccRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.343 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 343-343

Author(s):

Pedro C. Barata ◽

Shuchi Gulati ◽

Andrew Elliott ◽

Arpit Rao ◽

Hans J. Hammers ◽

...

Keyword(s):

Gene Expression ◽

Clinical Trials ◽

Hierarchical Clustering ◽

Immune Cell ◽

Expression Profiles ◽

Gene Expression Signature ◽

Predictive Biomarkers ◽

Primary Tumors ◽

Metastatic Sites ◽

Patient Subgroups

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

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New drug developments in metastatic gastric cancer

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284818808072 ◽

2018 ◽

Vol 11 ◽

pp. 175628481880807 ◽

Cited By ~ 6

Author(s):

Aaron C. Tan ◽

David L. Chan ◽

Wasek Faisal ◽

Nick Pavlakis

Keyword(s):

Gastric Cancer ◽

Clinical Trials ◽

Targeted Therapies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Predictive Biomarkers ◽

Metastatic Gastric Cancer ◽

New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

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