Immunmoduláló antitestek alkalmazása – az onkológia új                     fejezete

In the past decade major advances in tumor immunology, a better understanding of antigen recognition by T-cells likewise discovering the regulatory inhibitory signals resulted in the development of new immunotherapies with promising durable responses in various solid tumor types and in hematologic malignancies. This review focuses on immunomodulatory antibodies, namely immune checkpoint inhibitor therapy. The prototype of this new class of immune stimulating agents was cytotoxic T-lymphocyte antigen-4 (CTLA-4) antagonists. After demonstrating enhanced survival, ipilimumab was approved first in the United States in 2011, further on in the European Union for second-line (2011) and for first-line therapy (2013) of metastatic melanoma. Additional T-cell intrinsic pathways were identified and targeted for clinical development. Antibodies blocking the PD-1 pathway also showed promising clinical activity and objective tumor response in several types of tumors, including metastatic melanoma, non-small- cell lung cancer. On the other hand antitumor activity is frequently accompanied by significant reversible immune-related adverse events. To explore potential new immune checkpoint targets bring forth several challanges. Future clinical development will involve identifying potential biomarkers anticipating responsiveness to pathway blockade and additional tumor types likely to respond to the therapy. Furthermore, combination strategies, immune checkpoint inhibitors combined with cancer vaccines, targeted inhibitors and traditional chemotherapies are being evaluated in pre-clinical studies. Orv. Hetil., 2016, 157(Suppl. 2), 9–16.

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Clinical Development of Immune Checkpoint Inhibitors

BioMed Research International ◽

10.1155/2015/605478 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 22

Author(s):

Ayumu Ito ◽

Shunsuke Kondo ◽

Kohei Tada ◽

Shigehisa Kitano

Keyword(s):

Clinical Trials ◽

T Cells ◽

Metastatic Melanoma ◽

Tumor Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Clinical Development ◽

Phase Iii ◽

Immune Checkpoint Molecules

Recent progress in cancer immunotherapy has been remarkable. Most striking are the clinical development and approval of immunomodulators, also known as immune checkpoint inhibitors. These monoclonal antibodies (mAb) are directed to immune checkpoint molecules, which are expressed on immune cells and mediate signals to attenuate excessive immune reactions. Although mAbs targeting tumor associated antigens, such as anti-CD20 mAb and anti-Her2 mAb, directly recognize tumor cells and induce cell death, immune checkpoint inhibitors restore and augment the antitumor immune activities of cytotoxic T cells by blocking immune checkpoint molecules on T cells or their ligands on antigen presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies of immune checkpoint inhibitors in a variety of cancers. The first in class approved immune checkpoint inhibitor is ipilimumab, an anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) mAb. Two pivotal phase III randomized controlled trials demonstrated a survival benefit in patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved ipilimumab for metastatic melanoma. Several clinical trials have since investigated new agents, alone and in combination, for various cancers. In this review, we discuss the current development status of and future challenges in utilizing immune checkpoint inhibitors.

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Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?

Cancers ◽

10.3390/cancers13205065 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5065

Author(s):

Albert Jang ◽

David M. Adler ◽

Grant P. Rauterkus ◽

Mehmet A. Bilen ◽

Pedro C. Barata

Keyword(s):

Clinical Trials ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

The United States ◽

The Past ◽

United States Food ◽

States Food ◽

Genitourinary Cancers ◽

Tumor Types

For decades, limited options existed to treat metastatic genitourinary cancers, including treatment options that could be classified as immunotherapy. Historically, immunotherapy centered on systemic cytokines for the treatment of metastatic kidney cancer, which had several adverse effects, as well as the Bacillus Calmette–Guérin vaccine for non-metastatic bladder cancer. Within the past decade, advances in immunotherapy have led to several approvals from the United States Food and Drug Administration, particularly in the field of immune checkpoint inhibition. Immune checkpoint inhibitors (ICIs) are now being used extensively to treat multiple solid tumors, including kidney and bladder cancers, and they are also being tested in many other cancers. Despite encouraging data from phase 2/3 clinical trials, less is known about biomarkers that may predict better response to ICIs. The effect of ICIs in genitourinary cancers is heterogeneous, with some tumor types having little clinical data available, or ICIs having limited activity in other tumors. In this review, we briefly discuss approved immunotherapy agents prior to the time of ICIs. Then, given the emergence of this class of agents, we summarize the several important ICIs and the clinical trials that led to their approval. Finally, we mention ongoing and future clinical trials.

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Structure and Optimization of Checkpoint Inhibitors

Cancers ◽

10.3390/cancers12010038 ◽

2019 ◽

Vol 12 (1) ◽

pp. 38 ◽

Cited By ~ 11

Author(s):

Sarah L. Picardo ◽

Jeffrey Doi ◽

Aaron R. Hansen

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Clinical Activity ◽

Binding Affinities ◽

Protein Targets ◽

Dosing Regimens ◽

Cancer Types ◽

Tumor Types

With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors.

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Anti-PD-1 and Novel Combinations in the Treatment of Melanoma—An Update

Journal of Clinical Medicine ◽

10.3390/jcm9010223 ◽

2020 ◽

Vol 9 (1) ◽

pp. 223 ◽

Cited By ~ 19

Author(s):

Frank Gellrich ◽

Marc Schmitz ◽

Stefan Beissert ◽

Friedegund Meier

Keyword(s):

Clinical Trials ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Tumor Burden ◽

Term Survival ◽

Combination Regimens

Until recently, distant metastatic melanoma was considered refractory to systemic therapy. A better understanding of the interactions between tumors and the immune system and the mechanisms of regulation of T-cells led to the development of immune checkpoint inhibitors. This review summarizes the current novel data on the treatment of metastatic melanoma with anti-programmed cell death protein 1 (PD-1) antibodies and anti-PD-1-based combination regimens, including clinical trials presented at major conference meetings. Immune checkpoint inhibitors, in particular anti-PD-1 antibodies such as pembrolizumab and nivolumab and the combination of nivolumab with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab can achieve long-term survival for patients with metastatic melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab were also approved for adjuvant treatment of patients with resected metastatic melanoma. Anti-PD-1 antibodies appear to be well tolerated, and toxicity is manageable. Nivolumab combined with ipilimumab achieves a 5 year survival rate of more than 50% but at a cost of high toxicity. Ongoing clinical trials investigate novel immunotherapy combinations and strategies (e.g., Talimogene laherparepvec (T-VEC), Bempegaldesleukin (BEMPEG), incorporation or sequencing of targeted therapy, incorporation or sequencing of radiotherapy), and focus on poor prognosis groups (e.g., high tumor burden/LDH levels, anti-PD-1 refractory melanoma, and brain metastases).

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Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.684098 ◽

2021 ◽

Vol 11 ◽

Author(s):

Daniel R. Principe ◽

Lauren Chiec ◽

Nisha A. Mohindra ◽

Hidayatullah G. Munshi

Keyword(s):

Lung Cancer ◽

Immune Function ◽

Immune Checkpoint ◽

Neutralizing Antibodies ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Immune Surveillance ◽

Survival Rates ◽

The United States ◽

Significant Advance

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for lung cancer in recent years. These strategies consist of neutralizing antibodies against negative regulators of immune function, most notably cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and PD-1 ligand 1 (PD-L1), thereby impeding the ability of tumor cells to escape immune surveillance. Though ICIs have proven a significant advance in lung cancer therapy, overall survival rates remain low, and lung cancer continues to be the leading cause of cancer-related death in the United States. It is therefore imperative to better understand the barriers to the efficacy of ICIs, particularly additional mechanisms of immunosuppression within the lung cancer microenvironment. Recent evidence suggests that regulatory T-lymphocytes (Tregs) serve as a central mediator of immune function in lung cancer, suppressing sterilizing immunity and contributing to the clinical failure of ICIs. Here, we provide a comprehensive summary of the roles of Tregs in lung cancer pathobiology and therapy, as well as the potential means through which these immunosuppressive mechanisms can be overcome.

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Sargramostim and immune checkpoint inhibitors: combinatorial therapeutic studies in metastatic melanoma

Immunotherapy ◽

10.2217/imt-2021-0119 ◽

2021 ◽

Author(s):

Ahmad A Tarhini ◽

Ila Joshi ◽

Fiona Garner

Keyword(s):

Immune Responses ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Unmet Needs ◽

Checkpoint Inhibitors ◽

Advanced Melanoma ◽

Clinical Activity ◽

Gm Csf ◽

Adaptive Immune

The use of immune checkpoint inhibitors in patients with metastatic melanoma generates clinical benefit, including improved survival. Yet disease resistance and immune-related adverse events persist as unmet needs. Sargramostim, a yeast-derived recombinant human GM-CSF, has shown clinical activity against diverse solid tumors, including metastatic melanoma. Here we review the use of sargramostim for treatment of advanced melanoma. Potential sargramostim applications in melanoma draw on the unique ability of GM-CSF to link innate and adaptive immune responses. We review preclinical and translational data describing the mechanism of action of sargramostim and synergy with immune checkpoint inhibitors to enhance efficacy and reduce treatment-related toxicity.

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Immune checkpoint blockade in hematologic malignancies

Blood ◽

10.1182/blood-2015-02-567453 ◽

2015 ◽

Vol 125 (22) ◽

pp. 3393-3400 ◽

Cited By ~ 145

Author(s):

Philippe Armand

Keyword(s):

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Hematologic Malignancies ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Programmed Death ◽

Programmed Death 1 ◽

Natural Target ◽

Tumor Types

Abstract Therapeutic blockade of immune checkpoint pathways, in particular cytotoxic T-lymphocyte associated protein 4 and programmed-death 1 (PD-1), has become a paradigm-shifting treatment in solid tumor oncology. Hematologic malignancies (HMs), many of which are known to have clinically exploitable immune sensitivity, are a natural target for this type of treatment. Several clinical trials of checkpoint blockade have been conducted in HM, with preliminary results suggesting the therapeutic usefulness of this approach across several tumor types. In particular, the results of PD-1 blockade in Hodgkin lymphoma (HL) are remarkable, and raise hope that it may alter the treatment landscape in this disease. However, numerous questions remain about the optimal role of checkpoint blockade both in HL and beyond. Those questions are the focus of this review, in the hope that, if we are at the dawn of a new day in HM immunotherapy, we may begin to envision its morning.

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Role of immune-checkpoint inhibitors in lung cancer

Therapeutic Advances in Respiratory Disease ◽

10.1177/1753465817750075 ◽

2018 ◽

Vol 12 ◽

pp. 175346581775007 ◽

Cited By ~ 28

Author(s):

Prantesh Jain ◽

Chhavi Jain ◽

Vamsidhar Velcheti

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Predictive Biomarkers ◽

Clinical Activity

Immune checkpoint inhibitors, mainly drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) pathways, represent a remarkable advance in lung cancer treatment. Immune checkpoint inhibitors targeting PD-1 and PD-L1 are approved for the treatment of patients with non-small-cell lung cancer, with impressive clinical activity and durable responses in some patients. This review will summarize the mechanism of action of these drugs, the clinical development of these agents and the current role of these agents in the management of patients with lung cancer. In addition, the review will discuss the role of predictive biomarkers for optimal patient selection for immunotherapy and management of autoimmune side effects of these agents.

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Sustained clinico-radiologic response to anti-cytotoxic T lymphocyte antigen 4 antibody therapy in metastatic myxoid liposarcoma

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155216664202 ◽

2016 ◽

Vol 23 (7) ◽

pp. 549-551

Author(s):

Constantin A Dasanu

Keyword(s):

Metastatic Melanoma ◽

T Lymphocyte ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Antibody Therapy ◽

Myxoid Liposarcoma ◽

Effective Control ◽

Lymphocyte Antigen

Rarity and heterogeneity of sarcomas pose significant challenges in terms of developing new therapies. Therefore, efforts towards studying immunotherapy in sarcomas may provide hope for effective control of this group of devastating cancers. A sustained clinico-radiologic response to the anti-cytotoxic T lymphocyte antigen 4 antibody ipilimumab in a patient with metastatic myxoid liposarcoma is reported. Although the patient was treated with this agent for metastatic melanoma, both his metastatic cancers – melanoma and sarcoma – meaningfully responded to this agent. Consideration of enrolling patients in immunotherapy trials using various immune checkpoint inhibitors, where available, is of paramount importance, especially when facing advanced and/or refractory sarcoma situation.

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231 A novel discovery pipeline identifies melanoma-specific antibodies in patients responding to immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0231 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A249-A249

Author(s):

Daniel Delitto ◽

Evan Lipson ◽

Laura Cappelli ◽

Klaus Busam ◽

Antony Rosen ◽

...

Keyword(s):

Metastatic Melanoma ◽

Treatment Response ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Tumor Regression ◽

Checkpoint Inhibitors ◽

Specific Antibodies ◽

Cancer Testis Antigens ◽

Circulating Antibodies ◽

Cancer Testis

BackgroundTumor-specific antibodies have been reported in patients with cancers responding to immune checkpoint inhibitors (ICI), and there is an increasing appreciation for the potential role of B cells in mediating ICI responses. However, the humoral immune response to melanoma remains incompletely defined. We hypothesized that screening sera for antibodies by immunoprecipitation with lysates of cultured melanoma cells would increase the likelihood of detecting circulating antibodies in melanoma patients receiving ICI, and potentially identify novel antibody targets associated with treatment response and/or immune-related adverse events (IRAEs).MethodsPre-and on/post-treatment sera or plasma from 12 clinically-annotated patients with advanced metastatic melanoma receiving ICI were assayed for tumor-specific antibodies with an established immunoprecipitation platform. 35S-methionine-labeled lysates from cultured 624Mel cells were used for immunoprecipitation. 624Mel expresses several shared non-mutated melanoma antigens (e.g., MAGEA3, tyrosinase, MART-1/Melan-A, gp75, and gp100). Antigen identity was determined using on-bead digests followed by mass spectrometry, and was confirmed by immunoprecipitation with in vitro transcription/translation (IVTT) products.ResultsAntibodies reactive against 624Mel proteins were detected in 4 of 12 (33%) patients (table 1). Mass spectrometric sequencing performed on proteins captured with sera from 3 of 4 patients identified several putative antigens. Immunoprecipitation with IVTT candidate proteins confirmed antibodies against melanoma-associated and cancer testis antigens NY-ESO-1, SSX2 and MAGEA10. Antibodies were observed in 1 of 1 (100%) patient with a complete response, 2 of 4 (50%) with a partial response, 1 of 1 (100%) with stable disease, and 0 of 6 (0%) with progressive disease. Antibody levels varied over the course of therapy, with previously undetectable specificities arising during treatment response in patients #1–3. Patient #1 with a complete tumor regression developed antibodies to SSX2 and MAGEA10 that were absent before treatment. Further, detection of these antibodies coincided with diagnosis of IRAEs (anti-SSX2 with pancreatitis and anti-MAGEA10 with dermatitis). In contrast, patient #3, initially with a partial tumor regression, demonstrated a loss of detectable anti-NY-ESO-1 antibodies upon disease progression, and subsequent metastasectomy demonstrated loss of NY-ESO-1 protein expression in the progressing tumor. Testing sera from all 12 patients with IVTT products for NY-ESO-1, SSX2 and MAGEA10 did not reveal additional humoral responses.Abstract 231 Table 1Antibodies detected in the serum or plasma of patients with metastatic melanoma treated with ICI therapy. Treatment response indicates best overall response according to RECIST v1.1. Post-treatment blood collections were drawn during or after ICI therapy.ConclusionsOur comprehensive screening platform detected circulating antibodies specific to multiple melanoma-associated and cancer testis antigens in patients deriving clinical benefit from ICI. Expanded investigations of the evolution of antibody production over the course of ICI therapy, associated with tumor response to treatment and development of IRAEs, are warranted.AcknowledgementsThis study was supported by the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, and NIH P30-AR070254.Ethics ApprovalThis study was approved by the Johns Hopkins Institutional Review Board, approval #NA_00090257.

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