Beyond PD-1/PD-L1 Axis Blockade: New Combination Strategies in Metastatic Melanoma Treatment

2019 ◽  
Vol 15 (2) ◽  
pp. 110-119
Author(s):  
Emilio Francesco Giunta ◽  
Giuseppe Argenziano ◽  
Gabriella Brancaccio ◽  
Erika Martinelli ◽  
Fortunato Ciardiello ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Immune Escape ◽  
New Combination ◽  
Inhibitory Receptor ◽  
Combination Therapies ◽  
Tumor Immune Escape ◽  
Combination Strategies ◽  
Cell Energy ◽  
Melanoma Treatment ◽  
Reduced Activity

: Metastatic melanoma treatment has dramatically changed in the last few years, having a breakthrough with the introduction of targeted agents and immunotherapy. PD-1/PD-L1 pathway is one of the physiologic mechanisms of peripheral immune tolerance, but it also represents a mechanism of tumor immune escape. PD-1/PD-L1 inhibitors represent new immune-checkpoint drugs currently used in metastatic melanoma treatment. : Resistance to PD-1/PD-L1 axis blockade, which is the main cause of therapeutic failure during therapeutic use of these drugs, could be linked to several mechanism of immune escape. In fact, other inhibitory receptor such as CTLA-4, LAG-3, TIM-3 and TIGIT might be co-expressed on T cells, deleting the effect of anti-PD-1/PD-L1; overexpression of the enzyme IDO could cause immunosuppression through the depletion of tryptophan in the tumor microenvironment; defective c ostimulation (through reduced activity of 4-1BB and OX40 receptors) could result in T-cell energy. : Combination of anti-PD-1/PD-L1 with drugs targeting inhibitory or costimulatory receptors, intracellular pathways, enzymes or neoangiogenesis could be a possible strategy to overcome resistance to single PD-1/PD-L1 blockade. Clinical trials evaluating combination therapies have already showed interesting results, although most of them are still on going.

scholarly journals Current Advancements and Novel Strategies in the Treatment of Metastatic Melanoma

2021 ◽  
Vol 20 ◽  
pp. 153473542199007
Author(s):  
Siddhartha Sood ◽  
Rahul Jayachandiran ◽  
Siyaram Pandey
Keyword(s):  
Metastatic Melanoma ◽  
Complementary Therapy ◽  
Natural Health Products ◽  
Combination Therapies ◽  
Natural Health ◽  
The Past ◽  
Health Products ◽  
Melanoma Treatment ◽  
New Research

Melanoma is the deadliest form of skin cancer in the world with a growing incidence in North America. Contemporary treatments for melanoma include surgical resection, chemotherapy, and radiotherapy. However, apart from resection in early melanoma, the prognosis of patients using these treatments is typically poor. In the past decade, there have been significant advancements in melanoma therapies. Immunotherapies such as ipilimumab and targeted therapies such as vemurafenib have emerged as a promising option for patients as seen in both scientific and clinical research. Furthermore, combination therapies are starting to be administered in the form of polychemotherapy, polyimmunotherapy, and biochemotherapy, of which some have shown promising outcomes in relative efficacy and safety due to their multiple targets. Alongside these treatments, new research has been conducted into the evidence-based use of natural health products (NHPs) and natural compounds (NCs) on melanoma which may provide a long-term and non-toxic form of complementary therapy. Nevertheless, there is a limited consolidation of the research conducted in emerging melanoma treatments which may be useful for researchers and clinicians. Thus, this review attempts to evaluate the therapeutic efficacy of current advancements in metastatic melanoma treatment by surveying new research into the molecular and cellular basis of treatments along with their clinical efficacy. In addition, this review aims to elucidate novel strategies that are currently being used and have the potential to be used in the future.

scholarly journals Adoptive NK Cell Therapy: A Promising Treatment Prospect for Metastatic Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4722
Author(s):  
Amanda A. van Vliet ◽  
Anna-Maria Georgoudaki ◽  
Monica Raimo ◽  
Tanja D. de Gruijl ◽  
Jan Spanholtz
Keyword(s):  
Cell Therapy ◽  
Nk Cells ◽  
Metastatic Melanoma ◽  
Immune Escape ◽  
Nk Cell ◽  
Tumor Immune Escape ◽  
Promising Alternative ◽  
Promising Treatment ◽  
Melanoma Patients ◽  
Nk Cell Therapy

Adoptive cell therapy (ACT) represents a promising alternative approach for patients with treatment-resistant metastatic melanoma. Lately, tumor infiltrating lymphocyte (TIL) therapy and chimeric antigen receptor (CAR)-T cell therapy have shown improved clinical outcome, compared to conventional chemotherapy or immunotherapy. Nevertheless, they are limited by immune escape of the tumor, cytokine release syndrome, and manufacturing challenges of autologous therapies. Conversely, the clinical use of Natural Killer (NK) cells has demonstrated a favorable clinical safety profile with minimal toxicities, providing an encouraging treatment alternative. Unlike T cells, NK cells are activated, amongst other mechanisms, by the downregulation of HLA class I molecules, thereby overcoming the hurdle of tumor immune escape. However, impairment of NK cell function has been observed in melanoma patients, resulting in deteriorated natural defense. To overcome this limitation, “activated” autologous or allogeneic NK cells have been infused into melanoma patients in early clinical trials, showing encouraging clinical benefit. Furthermore, as several NK cell-based therapeutics are being developed for different cancers, an emerging variety of approaches to increase migration and infiltration of adoptively transferred NK cells towards solid tumors is under preclinical investigation. These developments point to adoptive NK cell therapy as a highly promising treatment for metastatic melanoma in the future.

scholarly journals HDAC Inhibition to Prime Immune Checkpoint Inhibitors

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 66
Author(s):  
Edith Borcoman ◽  
Maud Kamal ◽  
Grégoire Marret ◽  
Celia Dupain ◽  
Zahra Castel-Ajgal ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Hdac Inhibitors ◽  
Advanced Cancer Patients ◽  
Tumor Immune Escape ◽  
Durable Response ◽  
Combination Strategies ◽  
Epigenetic Regulations

Immunotherapy has made a breakthrough in medical oncology with the approval of several immune checkpoint inhibitors in clinical routine, improving overall survival of advanced cancer patients with refractory disease. However only a minority of patients experience a durable response with these agents, which has led to the development of combination strategies and novel immunotherapy drugs to further counteract tumor immune escape. Epigenetic regulations can be altered in oncogenesis, favoring tumor progression. The development of epidrugs has allowed targeting successfully these altered epigenetic patterns in lymphoma and leukemia patients. It has been recently shown that epigenetic alterations can also play a key role in tumor immune escape. Epidrugs, like HDAC inhibitors, can prime the anti-tumor immune response, therefore constituting interesting partners to develop combination strategies with immunotherapy agents. In this review, we will discuss epigenetic regulations involved in oncogenesis and immune escape and describe the clinical development of combining HDAC inhibitors with immunotherapies.

scholarly journals Current Approaches for Combination Therapy of Cancer: The Role of Immunogenic Cell Death

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1047 ◽  
Author(s):  
Zahra Asadzadeh ◽  
Elham Safarzadeh ◽  
Sahar Safaei ◽  
Ali Baradaran ◽  
Ali Mohammadi ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Immune Escape ◽  
Immunogenic Cell Death ◽  
Combination Therapies ◽  
Tumor Immune Escape ◽  
Different Types ◽  
Molecular Patterns

Cell death resistance is a key feature of tumor cells. One of the main anticancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells.

scholarly journals Leveraging NKG2D Ligands in Immuno-Oncology

2021 ◽  
Vol 12 ◽  
Author(s):  
Mercedes Beatriz Fuertes ◽  
Carolina Inés Domaica ◽  
Norberto Walter Zwirner
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Immune Escape ◽  
Nk Cell ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Combination Therapies ◽  
Tumor Immune Escape ◽  
Effector Functions ◽  
Immune Escape Mechanisms

Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.

New combination therapies for castration-resistant prostate cancer

2019 ◽  
Author(s):  
Mitchell G Lawrence ◽  
Laura H Porter ◽  
Daisuke Obinata ◽  
Shahneen Sandhu ◽  
Luke A Selth ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
New Combination ◽  
Combination Therapies ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Polarization of M2 Macrophages to Promote Tumor Immune Escape via Il-10 in SCLC but Not NSCLC Patients

2019 ◽  
Author(s):  
Xintong Hu ◽  
Yue Gu ◽  
Songchen Zhao ◽  
Shucheng Hua ◽  
Yanfang Jiang
Keyword(s):  
Immune Escape ◽  
M2 Macrophages ◽  
Tumor Immune Escape ◽  
Nsclc Patients

scholarly journals Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma

2021 ◽  
Vol 22 (6) ◽  
pp. 3228
Author(s):  
Alexander C. Chacon ◽  
Alexa D. Melucci ◽  
Shuyang S. Qin ◽  
Peter A. Prieto
Keyword(s):  
Skin Cancer ◽  
Small Molecules ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Treatment Resistance ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Specific Effector ◽  
Melanoma Treatment ◽  
Therapeutic Responses

Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific effector targets now affords a plethora of opportunities to increase therapeutic responses, even in resistant melanoma. In this review, we will discuss the multitude of SM classes currently under investigation, current and prospective clinical combinations of ICI and SM therapies, and their potential for synergism in melanoma eradication based on established mechanisms of immunotherapy resistance.

Sign in / Sign up

Export Citation Format

Share Document