CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

Molecular Therapy, Journal Year: 2020, Volume and Issue: 28(11), P. 2320 - 2339

Published: Sept. 16, 2020

Chimeric antigen receptor (CAR) T cell therapy has garnered significant excitement due to its success for hematological malignancies in clinical studies leading the US Food and Drug Administration (FDA) approval of three CD19-targeted CAR products. In contrast, experience with solid tumors brain been less encouraging, only a few patients achieving complete responses. Clinical preclinical have identified multiple "roadblocks," including (1) limited array targetable antigens heterogeneous expression, (2) fitness survival before reaching tumor sites, (3) an inability cells efficiently traffic sites penetrate physical barriers, (4) immunosuppressive microenvironment. Herein, we review these challenges discuss strategies that investigators taken improve effector function adoptive immunotherapy tumors. Adoptive therapies utilizing expressing chimeric receptors (CARs) propelled forefront experimental their targeting range antigens, CD19, CD22, CD30, kappa, B maturation (BCMA).1Porter D.L. 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Rooney Dittus al.Anti-CD30 CAR-T relapsed refractory Hodgkin lymphoma.J. Clin. Oncol. 2020; (Published online July 23, 2020. 10.1200/JCO.20.01342)Crossref 7Ramos Savoldo Torrano V. Ballard Zhang Dakhova Liu E. Carrum G. Kamble R.T. Gee A.P. al.Clinical responses lymphocytes malignancy-associated κ light chains.J. Invest. 2016; 126: 2588-2596Crossref (134) 8Raje Berdeja Lin Y. Siegel Jagannath Madduri Liedtke Rosenblatt Maus M.V. Turka al.Anti-BCMA T-cell bb2121 myeloma.N. 2019; 380: 1726-1737Crossref (249) 9Turtle C.J. Hanafi L.A. Berger Hudecek Pender Robinson Hawkins Chaney Cherian Chen X. al.Immunotherapy non-Hodgkin's lymphoma ratio CD8+ CD4+ CD19-specific cells.Sci. Transl. 8: 355ra116Crossref (421) 10Kochenderfer J.N. Somerville R.P.T. Lu Yang J.C. Sherry R.M. Feldman McIntyre L. Bot Rossi Lam Rosenberg Long-duration diffuse large after anti-CD19 therapy.Mol. 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Gilham Guest R.D. Rothwell Pillai Burt D.J. Byatte A.J. Kirillova Valle Sharma S.K. al.The efficacy first-generation carcinoembryonic (CEACAM5)-specific poor transient pre-conditioning-dependent respiratory toxicity.Cancer Immunol. 66: 1425-1436Crossref (94) 26Ahmed Bielamowicz Kalra Landi Gray T.L. Diouf Wakefield al.HER2-specific virus-specific progressive glioblastoma: 1 dose-escalation trial.JAMA 3: 1094-1101Crossref (187) This failure most likely multifactorial includes design generation, expression (aka "antigen dilemma"), fitness, inefficient homing penetration (5) hostile microenvironment (TME) (Figure 1).27Rafiq Hackett C.S. Engineering overcome current roadblocks therapy.Nat. 17: 147-167Crossref (46) 28Rodriguez-Garcia Palazon Noguera-Ortega Powell Jr., Guedan hit microenvironment: escape.Front. 11: 1109Crossref 29Schmidts Making option tumors.Front. 9: 2593Crossref 30Knochelmann H.M. Smith A.S. Dwyer Wyatt Mehrotra Paulos tumors: blueprints building effective therapies.Front. 1740Crossref design, genetic approaches aforementioned roadblocks. Since allogeneic mainly explored studies, refer interested reader recently published reviews.31Depil Duchateau Mufti Poirot "Off-the-shelf" development challenges.Nat. Discov. 19: 185-199Crossref (47) Scholar,32Qasim Allogeneic leukemia.Am. Hematol. 94: S50-S54Crossref (10) also CRS neurotoxicity since several reviews covered this topic.14Neelapu Scholar,33Frey Cytokine therapy.Biol. e123-e127Abstract CARs modular consists antigen-binding domain, commonly single-chain variable fragment (scFv) derived monoclonal antibody (mAb), hinge transmembrane intracellular domain.27Rafiq Scholar,34Kuwana Asakura Utsunomiya Nakanishi Arata Itoh Nagase F. Kurosawa Expression composed immunoglobulin-derived V regions receptor-derived C regions.Biochem. Biophys. 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Oncolytics. 1-9PubMed approach allows molecules, it renders recognition dependent particular HLA type, restricting application subset patients. addition, become sensitive decreased defects processing pathway, both pathways used actively evade responses.44Töpfer Kempe Müller Schmitz Bachmann Cartellieri Schackert Temme Tumor evasion surveillance.J. Biomed. Biotechnol. 2011: 918471Crossref First-generation contained utilized CD3ζ.37June Scholar,38Dotti optimal relies co-stimulation, were included CARs. Initial focused canonical CD28 41BB.37June then, broad explored, OX40, CD27, ICOS.37June Scholar,45Rafiq Yeku O.O. Jackson H.J. Leeuwen Drakes Song Miele Li al.Targeted delivery PD-1-blocking scFv enhances anti-tumor vivo.Nat. 36: 847-856Crossref (161) 46Hombach A.A. Abken Costimulation revisited response benefits combined CD28-OX40 signalling.Int. 2935-2944Crossref (93) 47Collinson-Pautz M.R. Chang W.C. Khalil Crisostomo P.Y. 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Language: Английский

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Ivermectin: An Anthelmintic, an Insecticide, and Much More

Trends in Parasitology, Journal Year: 2020, Volume and Issue: 37(1), P. 48 - 64

Published: Nov. 11, 2020

Language: Английский

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Multifunctional nanoparticle-mediated combining therapy for human diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 1, 2024

Abstract Combining existing drug therapy is essential in developing new therapeutic agents disease prevention and treatment. In preclinical investigations, combined effect of certain known drugs has been well established treating extensive human diseases. Attributed to synergistic effects by targeting various pathways advantages, such as reduced administration dose, decreased toxicity, alleviated resistance, combinatorial treatment now being pursued delivering combat major clinical illnesses, cancer, atherosclerosis, pulmonary hypertension, myocarditis, rheumatoid arthritis, inflammatory bowel disease, metabolic disorders neurodegenerative Combinatorial involves combining or co-delivering two more for a specific disease. Nanoparticle (NP)-mediated delivery systems, i.e., liposomal NPs, polymeric NPs nanocrystals, are great interest wide range due targeted delivery, extended release, higher stability avoid rapid clearance at infected areas. This review summarizes targets diseases, clinically approved combinations the development multifunctional emphasizes strategies based on severe Ultimately, we discuss challenging NP-codelivery translation provide potential approaches address limitations. offers comprehensive overview recent cutting-edge NP-mediated combination

Language: Английский

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Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: July 18, 2022

Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cells response to therapy-induced hostile environment are largely unknown. As central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes integrate signaling pathways provide bioenergetic biosynthetic flexibility cells, which contributes multiple aspects tumor characteristics, including drug resistance. Therefore, targeting therapy overcoming has attracted increasing attention various types cancer. Multiple mitochondrial processes, dynamics, metabolism, apoptotic regulatory machinery, have been demonstrated be potential targets. However, recent insights into revealed complexity structure functions, elusive functions biology, inaccessibility mitochondria, posed challenges clinical application mitochondrial-based therapeutic strategies. discovery both novel mitochondria-targeting agents innovative approaches is urgently required. Here, we review most literature summarize molecular their intricate connection with In addition, an overview emerging strategies target effectively chemoresistance highlighted, emphasis on repositioning delivery approaches, may accelerate compounds therapy.

Language: Английский

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Drug repurposing for cancer therapy

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 18, 2024

Abstract Cancer, a complex and multifactorial disease, presents significant challenge to global health. Despite advances in surgical, radiotherapeutic immunological approaches, which have improved cancer treatment outcomes, drug therapy continues serve as key therapeutic strategy. However, the clinical efficacy of is often constrained by resistance severe toxic side effects, thus there remains critical need develop novel therapeutics. One promising strategy that has received widespread attention recent years repurposing: identification new applications for existing, clinically approved drugs. Drug repurposing possesses several inherent advantages context since repurposed drugs are typically cost-effective, proven be safe, can significantly expedite development process due their already established safety profiles. In light this, present review offers comprehensive overview various methods employed repurposing, specifically focusing on treat cancer. We describe antitumor properties candidate drugs, discuss detail how they target both hallmarks tumor cells surrounding microenvironment. addition, we examine innovative integrating with nanotechnology enhance topical delivery. also emphasize role play when used part combination regimen. To conclude, outline challenges associated consider future prospects these transitioning into application.

Language: Английский

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Phytochemicals as a Complement to Cancer Chemotherapy: Pharmacological Modulation of the Autophagy-Apoptosis Pathway

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: May 7, 2021

Bioactive plant derived compounds are important for a wide range of therapeutic applications, and some display promising anticancer properties. Further evidence suggests that phytochemicals modulate autophagy apoptosis, the two crucial cellular pathways involved in underlying pathobiology cancer development regulation. Pharmacological targeting apoptosis signaling using therefore offers strategy is complementary to conventional chemotherapy. In this review, we sought highlight molecular basis autophagic-apoptotic pathway understand its implication cancer, explore fundamental process as druggable target. We also aimed present recent advances address limitations faced phytochemical-based drugs.

Language: Английский

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Recent advances and limitations of mTOR inhibitors in the treatment of cancer

Cancer Cell International, Journal Year: 2022, Volume and Issue: 22(1)

Published: Sept. 15, 2022

Abstract The PI3K-Akt-mechanistic (formerly mammalian) target of the rapamycin (mTOR) signaling pathway is important in a variety biological activities, including cellular proliferation, survival, metabolism, autophagy, and immunity. Abnormal PI3K-Akt-mTOR signalling activation can promote transformation by creating environment conducive to it. Deregulation such system terms genetic mutations amplification has been related several human cancers. Consequently, mTOR recognized as key for treatment cancer, especially treating cancers with elevated due or metabolic disorders. In vitro vivo, which an immunosuppressant agent actively suppresses activity reduces cancer cell growth. As result, various sirolimus-derived compounds have now established therapies these medications are being investigated clinical studies. this updated review, we discuss usage other drugs preclinical studies well explain some challenges involved targeting

Language: Английский

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Unveiling the mechanisms and challenges of cancer drug resistance

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 12, 2024

Abstract Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer strategies are evolving due to innate acquired capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells survive progress under unfavorable conditions. Although the mechanism of drug being widely studied generate new target-based drugs with better potency than existing ones. However, broader flexibility in resistance, advanced therapeutic options efficacy need be explored. Combination therapy an alternative a success rate though risk amplified side effects commonplace. Moreover, recent groundbreaking precision immune ways overcome has revolutionized anticancer greater extent only limitation individual-specific needs further attention. This review will focus on challenges opted withstand current therapies at molecular level also highlights emerging -like immunological, stem cell-based may prove have potential challenge problem resistance.

Language: Английский

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Deep learning for drug repurposing: Methods, databases, and applications

Wiley Interdisciplinary Reviews Computational Molecular Science, Journal Year: 2022, Volume and Issue: 12(4)

Published: Feb. 8, 2022

Abstract Drug development is time‐consuming and expensive. Repurposing existing drugs for new therapies an attractive solution that accelerates drug at reduced experimental costs, specifically Coronavirus Disease 2019 (COVID‐19), infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). However, comprehensively obtaining productively integrating available knowledge big biomedical data to effectively advance deep learning models still challenging repurposing in other complex diseases. In this review, we introduce guidelines on how utilize methodologies tools repurposing. We first summarized the commonly used bioinformatics pharmacogenomics databases Next, discuss recently developed sequence‐based graph‐based representation approaches as well state‐of‐the‐art learning‐based methods. Finally, present applications of fight COVID‐19 pandemic outline its future challenges. This article categorized under: Data Science > Artificial Intelligence/Machine Learning

Language: Английский

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Polymeric Micellar Systems—A Special Emphasis on “Smart” Drug Delivery

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(3), P. 976 - 976

Published: March 17, 2023

Concurrent developments in anticancer nanotechnological treatments have been observed as the burden of cancer increases every year. The 21st century has seen a transformation study medicine thanks to advancement field material science and nanomedicine. Improved drug delivery systems with proven efficacy fewer side effects made possible. Nanoformulations varied functions are being created using lipids, polymers, inorganic peptide-based nanomedicines. Therefore, thorough knowledge these intelligent nanomedicines is crucial for developing very promising systems. Polymeric micelles often simple make high solubilization characteristics; result, they seem be alternative other nanosystems. Even though recent studies provided an overview polymeric micelles, here we included discussion on “intelligent” from We also summarized state-of-the-art most micellar respect treatments. Additionally, gave significant attention clinical translation potential treatment various cancers.

Language: Английский

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