MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas

Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma, namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors, and targeted immunotherapies, may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combination, order, and timing of administration remains under investigation. Here, we measure how MEK inhibition alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes the peptide MHC (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1000 copies-per-cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting 4 epitopes with pMHC-specific T cell engagers and antibody drug conjugates, enhancing cell killing in tumor cells following MEK inhibition. These results highlight drug treatment as a means to enhance immunotherapy efficacy by targeting specific upregulated pMHCs and provide a methodological framework for identifying, quantifying, and therapeutically targeting additional epitopes of interest.

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Significance of BRAF Kinase Inhibitors for Melanoma Treatment: From Bench to Bedside

Cancers ◽

10.3390/cancers11091342 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1342 ◽

Cited By ~ 7

Author(s):

Taku Fujimura ◽

Yasuhiro Fujisawa ◽

Yumi Kambayashi ◽

Setsuya Aiba

Keyword(s):

Clinical Trials ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Combined Therapy ◽

Hdac Inhibitors ◽

Asian Population ◽

Phase Iii ◽

Braf Inhibitors ◽

Mek Inhibitors ◽

Braf Mutant

According to clinical trials, BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most promising chemotherapy regimens for the treatment of advanced BRAF-mutant melanoma, though the rate of BRAF mutation gene-bearing cutaneous melanoma is limited, especially in the Asian population. In addition, drug resistance sometimes abrogates the persistent efficacy of combined therapy with BRAF and MEK inhibitors. Therefore, recent pre-clinical study-based clinical trials have attempted to identify optimal drugs (e.g., immune checkpoint inhibitors or histone deacetylase (HDAC) inhibitors) that improve the anti-melanoma effects of BRAF and MEK inhibitors. In addition, the development of novel protocols to avoid resistance of BRAF inhibitors is another purpose of recent pre-clinical and early clinical trials. This review focuses on pre-clinical studies and early to phase III clinical trials to discuss the development of combined therapy based on BRAF inhibitors for BRAF-mutant advanced melanoma, as well as mechanisms of resistance to BRAF inhibitors.

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Novel Tyrosine Kinase Targets in Urothelial Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22020747 ◽

2021 ◽

Vol 22 (2) ◽

pp. 747

Author(s):

Javier Torres-Jiménez ◽

Víctor Albarrán-Fernández ◽

Javier Pozas ◽

María San Román-Gil ◽

Jorge Esteban-Villarrubia ◽

...

Keyword(s):

Tyrosine Kinase ◽

Urothelial Carcinoma ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitors ◽

Advanced Disease ◽

Checkpoint Inhibitors ◽

Genetic Alterations ◽

Drug Conjugates ◽

Therapeutic Landscape ◽

Muscle Invasive

Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.

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The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis

Cancers ◽

10.3390/cancers13102396 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2396

Author(s):

Nina Schoenwaelder ◽

Inken Salewski ◽

Nadja Engel ◽

Mareike Krause ◽

Björn Schneider ◽

...

Keyword(s):

Combination Therapy ◽

Head And Neck ◽

Kinase Inhibitors ◽

In Vivo Studies ◽

Specific Response ◽

Cyclin Dependent Kinase ◽

Systematic Analysis ◽

Mhc I ◽

Oncological Treatment

Cyclin-dependent kinase inhibitors (CDKi´s) display cytotoxic activity against different malignancies, including head and neck squamous cell carcinomas (HNSCC). By coordinating the DNA damage response, these substances may be combined with cytostatics to enhance cytotoxicity. Here, we investigated the influence of different CDKi´s (palbociclib, dinaciclib, THZ1) on two HNSCC cell lines in monotherapy and combination therapy with clinically-approved drugs (5-FU, Cisplatin, cetuximab). Apoptosis/necrosis, cell cycle, invasiveness, senescence, radiation-induced γ-H2AX DNA double-strand breaks, and effects on the actin filament were studied. Furthermore, the potential to increase tumor immunogenicity was assessed by analyzing Calreticulin translocation and immune relevant surface markers. Finally, an in vivo mouse model was used to analyze the effect of dinaciclib and Cisplatin combination therapy. Dinaciclib, palbociclib, and THZ1 displayed anti-neoplastic activity after low-dose treatment, while the two latter substances slightly enhanced radiosensitivity. Dinaciclib decelerated wound healing, decreased invasiveness, and induced MHC-I, accompanied by high amounts of surface-bound Calreticulin. Numbers of early and late apoptotic cells increased initially (24 h), while necrosis dominated afterward. Antitumoral effects of the selective CDKi palbociclib were weaker, but combinations with 5-FU potentiated effects of the monotherapy. Additionally, CDKi and CDKi/chemotherapy combinations induced MHC I, indicative of enhanced immunogenicity. The in vivo studies revealed a cell line-specific response with best tumor growth control in the combination approach. Global acting CDKi’s should be further investigated as targeting agents for HNSCC, either individually or in combination with selected drugs. The ability of dinaciclib to increase the immunogenicity of tumor cells renders this substance a particularly interesting candidate for immune-based oncological treatment regimens.

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Adjuvant Therapy in Renal Cell Carcinoma: Current Stance and Future Directions

Kidney Cancer ◽

10.3233/kca-200105 ◽

2021 ◽

pp. 1-12

Author(s):

Austin G. Kazarian ◽

Neal S. Chawla ◽

Ramya Muddasani ◽

Sumanta K. Pal

Keyword(s):

Renal Cell Carcinoma ◽

Adjuvant Therapy ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Unmet Need ◽

Disease Free Survival ◽

Adjuvant Setting ◽

Metastatic Setting

In recent years, incredible progress has been made in the treatment of metastatic renal cell carcinoma, with a paradigm shift from the use of cytokines to tyrosine kinase inhibitors, and more recently, immune checkpoint inhibitors (ICIs). Despite advances in the metastatic setting, effective therapies in the adjuvant setting are a largely unmet need. Currently, sunitinib (Sutent, Pfizer) is the only therapy for the adjuvant treatment of RCC included in the National Comprehensive Cancer Network guidelines, which was approved by the FDA based on the improvement in disease-free survival (DFS) seen in the S-TRAC trial. However, improvement in DFS has not translated into an overall survival (OS) benefit for patients at high-risk of relapse post-nephrectomy, illustrating the need for more effective therapies. This manuscript will highlight attributes of both historical and current drug trials and their implications on the landscape of adjuvant therapy. Additionally, we will outline strategies for selecting patients in whom treatment would be most beneficial, as optimal patient selection is a crucial step towards improving outcomes in the adjuvant setting. This is especially critical, given the financial cost and pharmacological toxicity of therapeutic agents. Furthermore, we will review the design of clinical trials including the value of utilizing OS as an endpoint over DFS. Finally, we will discuss how the incorporation of genomic data into predictive models, the use of more sensitive imaging modalities for more accurate staging, and more extensive surgical intervention involving lymph node dissection, may impact outcomes.

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Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

International Journal of Molecular Sciences ◽

10.3390/ijms22020493 ◽

2021 ◽

Vol 22 (2) ◽

pp. 493

Author(s):

Christos Vallilas ◽

Panagiotis Sarantis ◽

Anastasios Kyriazoglou ◽

Evangelos Koustas ◽

Stamatios Theocharis ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Gastrointestinal Stromal Tumors ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Survival Rates ◽

Cancer Therapeutics ◽

Gastrointestinal Neoplasms ◽

Mesenchymal Tumors ◽

Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

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Dendritic Cell Tumor Vaccination via Fc Gamma Receptor Targeting: Lessons Learned from Pre-Clinical and Translational Studies

Vaccines ◽

10.3390/vaccines9040409 ◽

2021 ◽

Vol 9 (4) ◽

pp. 409

Author(s):

Enrique Gómez Alcaide ◽

Sinduya Krishnarajah ◽

Fabian Junker

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Tumor Antigens ◽

Checkpoint Inhibitors ◽

Critical Role ◽

Lessons Learned ◽

Antigen Delivery ◽

Tumor Vaccination ◽

Translational Studies

Despite significant recent improvements in the field of immunotherapy, cancer remains a heavy burden on patients and healthcare systems. In recent years, immunotherapies have led to remarkable strides in treating certain cancers. However, despite the success of checkpoint inhibitors and the advent of cellular therapies, novel strategies need to be explored to (1) improve treatment in patients where these approaches fail and (2) make such treatments widely and financially accessible. Vaccines based on tumor antigens (Ag) have emerged as an innovative strategy with the potential to address these areas. Here, we review the fundamental aspects relevant for the development of cancer vaccines and the critical role of dendritic cells (DCs) in this process. We first offer a general overview of DC biology and routes of Ag presentation eliciting effective T cell-mediated immune responses. We then present new therapeutic avenues specifically targeting Fc gamma receptors (FcγR) as a means to deliver antigen selectively to DCs and its effects on T-cell activation. We present an overview of the mechanistic aspects of FcγR-mediated DC targeting, as well as potential tumor vaccination strategies based on preclinical and translational studies. In particular, we highlight recent developments in the field of recombinant immune complex-like large molecules and their potential for DC-mediated tumor vaccination in the clinic. These findings go beyond cancer research and may be of relevance for other disease areas that could benefit from FcγR-targeted antigen delivery, such as autoimmunity and infectious diseases.

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Therapeutic Cancer Vaccination with Immunopeptidomics-Discovered Antigens Confers Protective Antitumor Efficacy

Cancers ◽

10.3390/cancers13143408 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3408

Author(s):

Karita Peltonen ◽

Sara Feola ◽

Husen M. Umer ◽

Jacopo Chiaro ◽

Georgios Mermelekas ◽

...

Keyword(s):

Tumor Antigens ◽

Endogenous Retrovirus ◽

Peptide Ligands ◽

Tumor Control ◽

Preclinical Model ◽

Vaccine Platform ◽

Therapeutic Cancer Vaccine ◽

Mhc I ◽

Specific Tumor ◽

Therapeutic Cancer Vaccines

Knowledge of clinically targetable tumor antigens is becoming vital for broader design and utility of therapeutic cancer vaccines. This information is obtained reliably by directly interrogating the MHC-I presented peptide ligands, the immunopeptidome, with state-of-the-art mass spectrometry. Our manuscript describes direct identification of novel tumor antigens for an aggressive triple-negative breast cancer model. Immunopeptidome profiling revealed 2481 unique antigens, among them a novel ERV antigen originating from an endogenous retrovirus element. The clinical benefit and tumor control potential of the identified tumor antigens and ERV antigen were studied in a preclinical model using two vaccine platforms and therapeutic settings. Prominent control of established tumors was achieved using an oncolytic adenovirus platform designed for flexible and specific tumor targeting, namely PeptiCRAd. Our study presents a pipeline integrating immunopeptidome analysis-driven antigen discovery with a therapeutic cancer vaccine platform for improved personalized oncolytic immunotherapy.

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Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22126290 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6290

Author(s):

Hye-Won Lee

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Imaging Techniques ◽

Predictive Biomarkers ◽

Effective Control ◽

Extrinsic Factors ◽

Medical Needs

Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. Understanding the role of brain-specific tumor immune microenvironment (TIME) is important for developing rationale-driven ICI-based combination strategies that circumvent tumor intrinsic and extrinsic factors and complex positive feedback loops associated with resistance to ICIs in RCC-BM via combination with ICIs involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; therefore, novel combination approaches are being developed for synergistic potential against RCC-BM; however, further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain TIME.

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Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Cancers ◽

10.3390/cancers13040678 ◽

2021 ◽

Vol 13 (4) ◽

pp. 678 ◽

Cited By ~ 1

Author(s):

Adrien Procureur ◽

Audrey Simonaggio ◽

Jean-Emmanuel Bibault ◽

Stéphane Oudard ◽

Yann-Alexandre Vano

Keyword(s):

Cell Death ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Tumor Antigens ◽

Checkpoint Inhibitors ◽

Mitotic Cell ◽

Immunogenic Cell Death ◽

Dna Damages ◽

Multiple Tumor ◽

Tumor Types

The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.

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Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01961-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Revati Sharma ◽

Elif Kadife ◽

Mark Myers ◽

George Kannourakis ◽

Prashanth Prithviraj ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Resistance Mechanisms ◽

Number Of Patients ◽

Angiogenesis Pathway

AbstractVascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies.

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