Cancers

2024

Jump to: 2023, 2022, 2021

15 pages, 1325 KiB

Open AccessReview

Unlocking Intracellular Oncology Targets: The Unique Role of Antibody-Based T-Cell Receptor Mimic (TCRm) Therapeutics in T-Cell Engagers (TCEs) and Antibody-Drug Conjugates (ADCs)

by Jeffrey Molldrem and Dongxing Zha

Cancers 2024, 16(22), 3776; https://doi.org/10.3390/cancers16223776 - 8 Nov 2024

Viewed by 1102

Abstract

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This [...] Read more.

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This review focuses on the innovative use of T-cell receptor mimic (TCRm) antibodies within the therapeutic frameworks of T-cell engagers (TCE) and antibody-drug conjugates (ADCs). TCRm antibodies, designed to recognize peptide-MHC complexes rather than cell surface proteins, integrate the capacity of T-cells to reach intracellular targets with the unique strengths of antibodies. When incorporated into T-cell engaging therapeutics, TCRms redirect T cells to cancer cells, facilitating direct cytotoxicity. In ADCs, TCRm antibodies deliver cytotoxic agents with highly specific targeting to cancer cells, sparing healthy tissues. Together, these antibody-based strategies represent a significant leap forward in oncology, opening new avenues for the treatment of cancers previously deemed untreatable, with other potential applications in autoimmune diseases. This review discusses the mechanisms, clinical advancements, and future prospects of these cutting-edge therapies, highlighting their potential to transform the landscape of cancer treatment. Full article

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22 pages, 1548 KiB

Open AccessReview

Chondroitin Sulfate Proteoglycan 4 (CSPG4) as an Emerging Target for Immunotherapy to Treat Melanoma

by Xinyi Chen, Shabana Habib, Madalina Alexandru, Jitesh Chauhan, Theodore Evan, Joanna M. Troka, Avigail Rahimi, Benjamina Esapa, Thomas J. Tull, Wen Zhe Ng, Amanda Fitzpatrick, Yin Wu, Jenny L. C. Geh, Hawys Lloyd-Hughes, Lais C. G. F. Palhares, Rebecca Adams, Heather J. Bax, Sean Whittaker, Joanna Jacków-Malinowska and Sophia N. Karagiannis

Cancers 2024, 16(19), 3260; https://doi.org/10.3390/cancers16193260 - 25 Sep 2024

Viewed by 1538

Abstract

Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of [...] Read more.

Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody–drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape. Full article

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25 pages, 1513 KiB

Open AccessReview

Targets in the Tumour Matrisome to Promote Cancer Therapy Response

by Siti Munira Abd Jalil, Jack C. Henry and Angus J. M. Cameron

Cancers 2024, 16(10), 1847; https://doi.org/10.3390/cancers16101847 - 11 May 2024

Cited by 1 | Viewed by 1829

Abstract

The extracellular matrix (ECM) is composed of complex fibrillar proteins, proteoglycans, and macromolecules, generated by stromal, immune, and cancer cells. The components and organisation of the matrix evolves as tumours progress to invasive disease and metastasis. In many solid tumours, dense fibrotic ECM [...] Read more.

The extracellular matrix (ECM) is composed of complex fibrillar proteins, proteoglycans, and macromolecules, generated by stromal, immune, and cancer cells. The components and organisation of the matrix evolves as tumours progress to invasive disease and metastasis. In many solid tumours, dense fibrotic ECM has been hypothesised to impede therapy response by limiting drug and immune cell access. Interventions to target individual components of the ECM, collectively termed the matrisome, have, however, revealed complex tumour-suppressor, tumour-promoter, and immune-modulatory functions, which have complicated clinical translation. The degree to which distinct components of the matrisome can dictate tumour phenotypes and response to therapy is the subject of intense study. A primary aim is to identify therapeutic opportunities within the matrisome, which might support a better response to existing therapies. Many matrix signatures have been developed which can predict prognosis, immune cell content, and immunotherapy responses. In this review, we will examine key components of the matrisome which have been associated with advanced tumours and therapy resistance. We have primarily focussed here on targeting matrisome components, rather than specific cell types, although several examples are described where cells of origin can dramatically affect tumour roles for matrix components. As we unravel the complex biochemical, biophysical, and intracellular transduction mechanisms associated with the ECM, numerous therapeutic opportunities will be identified to modify tumour progression and therapy response. Full article

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11 pages, 4574 KiB

Open AccessArticle

New N-Adducts of Thiadiazole and Thiazoline with Levoglucosenone and Evaluation of Their Significant Cytotoxic (Anti-Cancer) Activity

by Tomasz Poplawski, Grzegorz Galita, Joanna Sarnik, Anna Macieja, Roman Bielski, Donald E. Mencer and Zbigniew J. Witczak

Cancers 2024, 16(1), 216; https://doi.org/10.3390/cancers16010216 - 2 Jan 2024

Cited by 2 | Viewed by 1793

Abstract

The conjugate N-adducts of thio-1,3,4-diazole and 2-thiazoline with levoglucosenone were synthesized via a stereoselective, base-catalyzed conjugate N-Michael addition to levoglucosenone at C-4. Structural assignments were established using 1H and 13C NMR analysis, and X-ray single-crystal analysis for one of the compounds. The biological [...] Read more.

The conjugate N-adducts of thio-1,3,4-diazole and 2-thiazoline with levoglucosenone were synthesized via a stereoselective, base-catalyzed conjugate N-Michael addition to levoglucosenone at C-4. Structural assignments were established using 1H and 13C NMR analysis, and X-ray single-crystal analysis for one of the compounds. The biological properties of the novel compounds were tested on a cell model. Cytotoxicity was analyzed via colorimetric assay. Two distinct types of cell death, apoptosis and necrosis, were analyzed by determining the phosphatidylserine levels from the outer leaflet of the plasma membrane, caspase activation, and lactate dehydrogenase release. We also evaluated DNA damage using an alkaline comet assay. The level of oxidative stress was measured with a modified comet assay and an H2DCFDA probe. The thio-1,3,4-diazole adduct (FCP23) and the 2-thiazoline adduct (FCP26) exhibit similar cytotoxicity values for cancer cells (ovarian (A2780), breast (MCF-7), cervix (HeLa), colon (LoVo), and brain (MO59J and MO59K)), but their mechanism of action is drastically different. While FCP23 induces oxidative stress, DNA damage, and necrosis, FCP26 induces apoptosis through caspase activation. Full article

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2023

Jump to: 2024, 2022, 2021

12 pages, 1879 KiB

Open AccessArticle

Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases

by Polina Rusina, Erik Gandalipov, Yana Abdusheva, Maria Panova, Alexandra Burdenkova, Vasiliy Chaliy, Maria Brachs, Oleg Stroganov, Ksenia Guzeeva, Igor Svitanko, Alexander Shtil and Fedor Novikov

Cancers 2023, 15(15), 3766; https://doi.org/10.3390/cancers15153766 - 25 Jul 2023

Cited by 4 | Viewed by 1946

Abstract

The rational design of cyclin-dependent protein kinase (CDK) inhibitors presumes the development of approaches for accurate prediction of selectivity and the activity of small molecular weight anticancer drug candidates. Aiming at attenuation of general toxicity of low selectivity compounds, we herein explored the [...] Read more.

The rational design of cyclin-dependent protein kinase (CDK) inhibitors presumes the development of approaches for accurate prediction of selectivity and the activity of small molecular weight anticancer drug candidates. Aiming at attenuation of general toxicity of low selectivity compounds, we herein explored the new chemotype of imidazole-4-N-acetamide substituted derivatives of the pan-CDK inhibitor PHA-793887. Newly synthesized compounds 1–4 containing an aliphatic methyl group or aromatic radicals at the periphery of the scaffold were analyzed for the prediction of relative free energies of binding to CDK1, -2, -5, and -9 using a protocol based on non-equilibrium (NEQ) thermodynamics. This methodology allows for the demonstration of a good correlation between the calculated parameters of interaction of 1–4 with individual targets and the values of inhibitory potencies in in vitro kinase assays. We provide evidence in support of NEQ thermodynamics as a time sparing, precise, and productive approach for generating chemical inhibitors of clinically relevant anticancer targets. Full article

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19 pages, 3332 KiB

Open AccessArticle

Gold Nanobipyramids for Near-Infrared Fluorescence-Enhanced Imaging and Treatment of Triple-Negative Breast Cancer

by Ioannis G. Theodorou, Fotios Mpekris, Paris Papagiorgis, Myrofora Panagi, Maria Kalli, Louiza Potamiti, Kyriacos Kyriacou, Grigorios Itskos and Triantafyllos Stylianopoulos

Cancers 2023, 15(14), 3693; https://doi.org/10.3390/cancers15143693 - 20 Jul 2023

Cited by 2 | Viewed by 2448

Abstract

There is an imminent need for novel strategies for the diagnosis and treatment of aggressive triple-negative breast cancer (TNBC). Cell-targeted multifunctional nanomaterials hold great potential, as they can combine precise early-stage diagnosis with local therapeutic delivery to specific cell types. In this study, [...] Read more.

There is an imminent need for novel strategies for the diagnosis and treatment of aggressive triple-negative breast cancer (TNBC). Cell-targeted multifunctional nanomaterials hold great potential, as they can combine precise early-stage diagnosis with local therapeutic delivery to specific cell types. In this study, we used mesoporous silica (MS)-coated gold nanobipyramids (MS-AuNBPs) for fluorescence imaging in the near-infrared (NIR) biological window, along with targeted TNBC treatment. Our MS-AuNBPs, acting partly as light amplification components, allow considerable metal-enhanced fluorescence for a NIR dye conjugated to their surfaces compared to the free dye. Fluorescence analysis confirms a significant increase in the dye’s modified quantum yield, indicating that MS-AuNBPs can considerably increase the brightness of low-quantum-yield NIR dyes. Meanwhile, we tested the chemotherapeutic efficacy of MS-AuNBPs in TNBC following the loading of doxorubicin within the MS pores and functionalization to target folate receptor alpha (FRα)-positive cells. We show that functionalized particles target FRα-positive cells with significant specificity and have a higher potency than free doxorubicin. Finally, we demonstrate that FRα-targeted particles induce stronger antitumor effects and prolong overall survival compared to the clinically applied non-targeted nanotherapy, Doxil. Together with their excellent biocompatibility measured in vitro, this study shows that MS-AuNBPs are promising tools to detect and treat TNBCs. Full article

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2022

Jump to: 2024, 2023, 2021

15 pages, 2632 KiB

Open AccessReview

Development and Characterization of an Anti-Cancer Monoclonal Antibody for Treatment of Human Carcinomas

by Kwong yok Tsang, Massimo Fantini, Sharon A. Mavroukakis, Anjum Zaki, Christina M. Annunziata and Philip M. Arlen

Cancers 2022, 14(13), 3037; https://doi.org/10.3390/cancers14133037 - 21 Jun 2022

Cited by 9 | Viewed by 4589

Abstract

NEO-201 is an IgG1 humanized monoclonal antibody (mAb) that binds to tumor-associated variants of carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-5 and CEACAM-6. NEO-201 reacts to colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers, but is not reactive [...] Read more.

NEO-201 is an IgG1 humanized monoclonal antibody (mAb) that binds to tumor-associated variants of carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-5 and CEACAM-6. NEO-201 reacts to colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers, but is not reactive against most normal tissues. NEO-201 can kill tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) to directly kill tumor cells expressing its target. We explored indirect mechanisms of its action that may enhance immune tumor killing. NEO-201 can block the interaction between CEACAM-5 expressed on tumor cells and CEACAM-1 expressed on natural killer (NK) cells to reverse CEACAM-1-dependent inhibition of NK cytotoxicity. Previous studies have demonstrated safety/tolerability in non-human primates, and in a first in human phase 1 clinical trial at the National Cancer Institute (NCI). In addition, preclinical studies have demonstrated that NEO-201 can bind to human regulatory T (Treg) cells. The specificity of NEO-201 in recognizing suppressive Treg cells provides the basis for combination cancer immunotherapy with checkpoint inhibitors targeting the PD-1/PD-L1 pathway. Full article

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14 pages, 1164 KiB

Open AccessReview

State of the Art and Future Implications of SH003: Acting as a Therapeutic Anticancer Agent

by Kangwook Lee, Bo-Young Youn, Yu-Jeong Choi, Seunghwan Moon, Jungkwun Im, Kyongha Cho, Seong-Gyu Ko and Chunhoo Cheon

Cancers 2022, 14(4), 1089; https://doi.org/10.3390/cancers14041089 - 21 Feb 2022

Cited by 10 | Viewed by 2649

Abstract

Cancer ranks as the first leading cause of death globally. Despite the various types of cancer treatments, negative aspects of the treatments, such as side effects and drug resistance, have been a continuous dilemma for patients. Thus, natural compounds and herbal medicines have [...] Read more.

Cancer ranks as the first leading cause of death globally. Despite the various types of cancer treatments, negative aspects of the treatments, such as side effects and drug resistance, have been a continuous dilemma for patients. Thus, natural compounds and herbal medicines have earned profound interest as chemopreventive agents for reducing burden for patients. SH003, a novel herbal medicine containing Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii, showed the potential to act as an anticancer agent in previous research studies. A narrative review was conducted to present the significant highlights of the total 15 SH003 studies from the past nine years. SH003 has shown positive results in both in vivo and vitro studies against various types of cancer cells; furthermore, the first clinical trial was performed to identify the maximum tolerated dose among solid cancer patients. So far, the potential of SH003 as a chemotherapeutic agent has been well-documented in research studies; continuous work on SH003’s efficacy and safety is required to facilitate better cancer patient care but is part of the knowledge needed to understand whether SH003 has the potential to become a pharmaceutical. Full article

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22 pages, 1831 KiB

Open AccessReview

Plant-Derived Terpenoids: A Promising Tool in the Fight against Melanoma

by Patrycja Kłos and Dariusz Chlubek

Cancers 2022, 14(3), 502; https://doi.org/10.3390/cancers14030502 - 20 Jan 2022

Cited by 16 | Viewed by 4967

Abstract

Melanoma is responsible for the highest number of skin cancer-caused deaths worldwide. Despite the numerous melanoma-treating options, the fight against it remains challenging, mainly due to its great heterogeneity and plasticity, as well as the high toxicity of standard drugs. Plant-derived terpenoids are [...] Read more.

Melanoma is responsible for the highest number of skin cancer-caused deaths worldwide. Despite the numerous melanoma-treating options, the fight against it remains challenging, mainly due to its great heterogeneity and plasticity, as well as the high toxicity of standard drugs. Plant-derived terpenoids are a group of plant defense molecules that have been proven effective in killing many different types of cancer cells, both in in vitro experiments and in vivo models. In this review, we focus on recent results in the search for plant terpenoids with anti-melanoma activity. We also report on the synergistic action of combining terpenoids with other plant-derived substances, MAP kinase inhibitors, or radiation. Additionally, we present examples of terpenoid-loaded nanoparticle carriers as anti-melanoma agents that have increased permeation through the cancer tissue. Full article

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2021

Jump to: 2024, 2023, 2022

17 pages, 688 KiB

Open AccessReview

Therapeutic Targeting of Exportin-1 in Childhood Cancer

by Basia Galinski, Thomas B. Alexander, Daniel A. Mitchell, Hannah V. Chatwin, Chidiebere Awah, Adam L. Green and Daniel A. Weiser

Cancers 2021, 13(24), 6161; https://doi.org/10.3390/cancers13246161 - 7 Dec 2021

Cited by 2 | Viewed by 3751

Abstract

Overexpression of Exportin-1 (XPO1), a key regulator of nuclear-to-cytoplasmic transport, is associated with inferior patient outcomes across a range of adult malignancies. Targeting XPO1 with selinexor has demonstrated promising results in clinical trials, leading to FDA approval of its use for [...] Read more.

Overexpression of Exportin-1 (XPO1), a key regulator of nuclear-to-cytoplasmic transport, is associated with inferior patient outcomes across a range of adult malignancies. Targeting XPO1 with selinexor has demonstrated promising results in clinical trials, leading to FDA approval of its use for multiple relapsed/refractory cancers. However, XPO1 biology and selinexor sensitivity in childhood cancer is only recently being explored. In this review, we will focus on the differential biology of childhood and adult cancers as it relates to XPO1 and key cargo proteins. We will further explore the current state of pre-clinical and clinical development of XPO1 inhibitors in childhood cancers. Finally, we will outline potentially promising future therapeutic strategies for, as well as potential challenges to, integrating XPO1 inhibition to improve outcomes for children with cancer. Full article

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27 pages, 24024 KiB

Open AccessReview

Biological Significance and Targeting of the FGFR Axis in Cancer

by Athina-Myrto Chioni and Richard P. Grose

Cancers 2021, 13(22), 5681; https://doi.org/10.3390/cancers13225681 - 13 Nov 2021

Cited by 31 | Viewed by 4791

Abstract

The pleiotropic effects of fibroblast growth factors (FGFs), the widespread expression of all seven signalling FGF receptors (FGFRs) throughout the body, and the dramatic phenotypes shown by many FGF/R knockout mice, highlight the diversity, complexity and functional importance of FGFR signalling. The FGF/R [...] Read more.

The pleiotropic effects of fibroblast growth factors (FGFs), the widespread expression of all seven signalling FGF receptors (FGFRs) throughout the body, and the dramatic phenotypes shown by many FGF/R knockout mice, highlight the diversity, complexity and functional importance of FGFR signalling. The FGF/R axis is critical during normal tissue development, homeostasis and repair. Therefore, it is not surprising that substantial evidence also pinpoints the involvement of aberrant FGFR signalling in disease, including tumourigenesis. FGFR aberrations in cancer include mutations, gene fusions, and amplifications as well as corrupted autocrine/paracrine loops. Indeed, many clinical trials on cancer are focusing on targeting the FGF/FGFR axis, using selective FGFR inhibitors, nonselective FGFR tyrosine kinase inhibitors, ligand traps, and monoclonal antibodies and some have already been approved for the treatment of cancer patients. The heterogeneous tumour microenvironment and complexity of FGFR signalling may be some of the factors responsible for the resistance or poor response to therapy with FGFR axis-directed therapeutic agents. In the present review we will focus on the structure and function of FGF(R)s, their common irregularities in cancer and the therapeutic value of targeting their function in cancer. Full article

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13 pages, 1404 KiB

Open AccessReview

OB-Folds and Genome Maintenance: Targeting Protein–DNA Interactions for Cancer Therapy

by Sui Par, Sofia Vaides, Pamela S. VanderVere-Carozza, Katherine S. Pawelczak, Jason Stewart and John J. Turchi

Cancers 2021, 13(13), 3346; https://doi.org/10.3390/cancers13133346 - 3 Jul 2021

Cited by 7 | Viewed by 3332

Abstract

Genome stability and maintenance pathways along with their requisite proteins are critical for the accurate duplication of genetic material, mutation avoidance, and suppression of human diseases including cancer. Many of these proteins participate in these pathways by binding directly to DNA, and a [...] Read more.

Genome stability and maintenance pathways along with their requisite proteins are critical for the accurate duplication of genetic material, mutation avoidance, and suppression of human diseases including cancer. Many of these proteins participate in these pathways by binding directly to DNA, and a subset employ oligonucleotide/oligosaccharide binding folds (OB-fold) to facilitate the protein–DNA interactions. OB-fold motifs allow for sequence independent binding to single-stranded DNA (ssDNA) and can serve to position specific proteins at specific DNA structures and then, via protein–protein interaction motifs, assemble the machinery to catalyze the replication, repair, or recombination of DNA. This review provides an overview of the OB-fold structural organization of some of the most relevant OB-fold containing proteins for oncology and drug discovery. We discuss their individual roles in DNA metabolism, progress toward drugging these motifs and their utility as potential cancer therapeutics. While protein–DNA interactions were initially thought to be undruggable, recent reports of success with molecules targeting OB-fold containing proteins suggest otherwise. The potential for the development of agents targeting OB-folds is in its infancy, but if successful, would expand the opportunities to impinge on genome stability and maintenance pathways for more effective cancer treatment. Full article

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10 pages, 465 KiB

Open AccessReview

Drug Development in Tissue-Agnostic Indications

by Pauline du Rusquec and Christophe Le Tourneau

Cancers 2021, 13(11), 2758; https://doi.org/10.3390/cancers13112758 - 2 Jun 2021

Cited by 11 | Viewed by 2961

Abstract

A better understanding of cancer biology has led to the development of targeted therapies specifically designed to modulate an altered molecular pathway in the cancer cells or their microenvironment. Despite the identification of molecular targets across cancer types, most of targeted therapies were [...] Read more.

A better understanding of cancer biology has led to the development of targeted therapies specifically designed to modulate an altered molecular pathway in the cancer cells or their microenvironment. Despite the identification of molecular targets across cancer types, most of targeted therapies were developed per cancer type. In this ancestral paradigm, randomization was the gold-standard approach for market access. Randomization of large patient populations was feasible for drugs developed in common cancer types but more challenging in rare cancer types. The traditional paradigm of drug development in oncology was further challenged by the ever-expanding molecular segmentation of cancer with ever-smaller subgroups of patients who might benefit from specific targeted therapies or immunotherapies and the identification of molecular alterations against which drugs may be effective across cancer types. In this novel drug development paradigm, novel ways of evaluating the efficacy of drugs are highly needed in these small patient populations. One approach is to use each patient as his/her own control by comparing the efficacy of a drug to the efficacy of prior treatments received. This approach allows to overcome patient heterogeneity, especially in a tissue-agnostic drug development paradigm. Full article

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16 pages, 543 KiB

Open AccessReview

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

by Kenji Hashimoto

Cancers 2021, 13(10), 2288; https://doi.org/10.3390/cancers13102288 - 11 May 2021

Cited by 41 | Viewed by 9347

Abstract

Immune checkpoint inhibitors have altered the treatment landscape significantly in several cancers, yet not enough for many cancer patients. T cell costimulatory receptors have been pursued as targets for the next generation of cancer immunotherapies, however, sufficient clinical efficacy has not yet been [...] Read more.

Immune checkpoint inhibitors have altered the treatment landscape significantly in several cancers, yet not enough for many cancer patients. T cell costimulatory receptors have been pursued as targets for the next generation of cancer immunotherapies, however, sufficient clinical efficacy has not yet been achieved. CD137 (TNFRSF9, 4-1BB) provides co-stimulatory signals and activates cytotoxic effects of CD8⁺ T cells and helps to form memory T cells. In addition, CD137 signalling can activate NK cells and dendritic cells which further supports cytotoxic T cell activation. An agonistic monoclonal antibody to CD137, urelumab, provided promising clinical efficacy signals but the responses were achieved above the maximum tolerated dose. Utomilumab is another CD137 monoclonal antibody to CD137 but is not as potent as urelumab. Recent advances in antibody engineering technologies have enabled mitigation of the hepato-toxicity that hampered clinical application of urelumab and have enabled to maintain similar potency to urelumab. Next generation CD137 targeting molecules currently in clinical trials support T cell and NK cell expansion in patient samples. CD137 targeting molecules in combination with checkpoint inhibitors or ADCC-enhancing monoclonal antibodies have been sought to improve both clinical safety and efficacy. Further investigation on patient samples will be required to provide insights to understand compensating pathways for future combination strategies involving CD137 targeting agents to optimize and maintain the T cell activation status in tumors. Full article

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38 pages, 1923 KiB

Open AccessReview

Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities

by Gustavo A. Arias-Pinilla and Helmout Modjtahedi

Cancers 2021, 13(8), 1781; https://doi.org/10.3390/cancers13081781 - 8 Apr 2021

Cited by 18 | Viewed by 7256

Abstract

Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world [...] Read more.

Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world in the next decade. Therefore, it is essential to discover novel therapeutic targets and to develop more effective and pancreatic cancer-specific therapeutic agents. To date, 45 monoclonal antibodies (mAbs) have been approved for the treatment of patients with a wide range of cancers; however, none has yet been approved for pancreatic cancer. In this comprehensive review, we discuss the FDA approved anticancer mAb-based drugs, the results of preclinical studies and clinical trials with mAbs in pancreatic cancer and the factors contributing to the poor response to antibody therapy (e.g. tumour heterogeneity, desmoplastic stroma). MAb technology is an excellent tool for studying the complex biology of pancreatic cancer, to discover novel therapeutic targets and to develop various forms of antibody-based therapeutic agents and companion diagnostic tests for the selection of patients who are more likely to benefit from such therapy. These should result in the approval and routine use of antibody-based agents for the treatment of pancreatic cancer patients in the future. Full article

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