Checkmate awaiting strategy: unlocking the potential of chimeric antigen receptor T-cell therapy in uveal melanoma DOI Creative Commons
Ahmed H. Al Sharie,

S. Al-Omari,

Abdelwahab Aleshawi

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 18, 2025

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults with unique genomic and phenotypic features comparison to its cutaneous counterpart [1]. UM classified based on anatomical location it originates from, including choroid, ciliary body, iris Risk factors linked includes presence of atypical nevi, light eye color, fair skin freckles, occupational exposure irritants, many others [2]. The genetic landscape characterized by chromosomal rearrangements involving chromosomes 1, 3, 6, 8, along a broad spectrum oncogenic somatic mutations. Notably, mutations genes such as BAP1, EIF1AX, GNA11, GNAQ, SF3B1 are frequently observed [3]. Although several treatment modalities have been investigated over past decade local systemic interventions, prognosis remains poor [4,5]. Local control could be achieved but ultimately, 40% patients will develop distant metastasis, commonly liver [6]. Recent advances understanding tumorigenic process immune microenvironment enhanced prognostic assessments paved way for promising novel therapeutic approaches. However, progress development approaches has slow limited.Recently, CAR-T cells therapy recolonized field anti-cancer immunotherapy. Such success story remarkable efficacy durable clinical responses especially hematological malignancies shed role other [7]. incorporates synthetic receptors into lymphocytes, redirecting them recognize expressing specific target antigen. starts careful patient evaluation selection followed leukapheresis. Isolated purified lymphocytes genetically engineered express chimeric antigen (CARs). After lymphodepletion, infused response then monitored significant rates cell therapies led US Food Drug Administration (FDA) approval seven treatments, more currently being extensively studied both basic research. An emerging area research use melanoma, numerous preclinical studies ongoing trials exploring potential mainly targeting c-Met, CD70, GD2, VEGFR2 [8]. While garnered attention extensive melanomas, similar focus investigation notably scarce case UM, where application largely underexplored.Exploring reveals that laboratory investigations, minimal testing conducted thus far, any existing often part broader trials. Forsberg et al. utilization HER2 eradicate in-vitro in-vivo [9]. latter was humanized mouse model using NOD/SCID IL-2 receptor gamma knockout mice transgenic human IL-2The later nov. el mice. It found exhibits variable expressivity were able kill tumor in-vivo. demonstrated significantly greater against from non-responders compared autologous tumor-infiltrating lymphocyte (TIL) therapy. Worth mentioning, (TILs) aforementioned findings target-specific; confirmed loss upon CRISPR/Cas9-mediated disruption cells. Another targeted tyrosinase related protein 1 (TYRP1). Jilani TYRP1 uveal melanomas unresponsive checkpoint blockade [10]. team highlighted overexpression cancer vitro vivo murine/patient-derived models. Hackett outcomes, showing TYRP1-targeted CAR T activate antigen-specific exhibit cytotoxic activity vivo, irrespective MHC alleles expression [11]. Additionally, toxicity pigmented normal tissues, which seen TCR-expressing not present B7-H3 highly expressed representing innovative approach proposed applied Ventin coupled inducible caspase-9 (iCas9) suicide gene. iCas9.B7-H3 showed antitumor vivo; experimental models metastases [12]. outcome comparable blockage monoclonal antibody. HER2, TYRP1, safety profiles supports translational phase I trial.To best our knowledge, through review multiple registries, two investigating patients, although these specifically designed patients. GAIL-N trial (ClinicalTrials.gov identifier: NCT03635632) aims improve neuroblastoma, sarcoma, breast cancer, or cancers GD2. equipped C7R gene provides constant cytokine supply maintaining longer survival time transfused non-randomized, open label, Phase I, single group assignment stated 23 rd April, 2019 active recruiting an estimated number 94 participants. sponsored Baylor College Medicine no results available up this point time. NCT04119024) investigates IL-13Rα2-targeting stage IIIC IV metastatic solid tumors. after chemotherapy conditioning regimen endpoints detect maximum tolerated dose, adverse events profile anti-tumor responses. open-label, started 27 th November, eligible Jonsson Comprehensive Cancer Center.CAR-T finding should augmented comprehensive translation future hinges continued research, collaborative efforts between researchers, tailored strategies overcome challenges. challenges focused low specificity escape, improving eliminating CAR-T-related toxicities, overcoming immunosuppressive nature microenvironment, expense economics. With advancements, holds become effective option offering new hope patients.Authors contribution: All authors made contributions work. Each author participated conceptualization, process, writing, revision manuscript.Ethics statement: None.The declare generative artificial intelligence (AI) AI assisted technologies used writing during preparation manuscript. Funding: None.

Language: Английский

Heterogeneity and molecular landscape of melanoma: implications for targeted therapy DOI Creative Commons
Yasaman Zohrab Beigi, Hossein Lanjanian,

Reyhane Fayazi

et al.

Molecular Biomedicine, Journal Year: 2024, Volume and Issue: 5(1)

Published: May 10, 2024

Abstract Uveal cancer (UM) offers a complex molecular landscape characterized by substantial heterogeneity, both on the genetic and epigenetic levels. This heterogeneity plays critical position in shaping behavior response to therapy for this uncommon ocular malignancy. Targeted treatments with gene-specific therapeutic molecules may prove useful overcoming radiation resistance, however, diverse makeups of UM call patient-specific approach procedures. We need understand intricate develop targeted customized each patient's specific mutations. One promising approaches is using liquid biopsies, such as circulating tumor cells (CTCs) DNA (ctDNA), detecting monitoring disease at early stages. These non-invasive methods can help us identify most effective treatment strategies patient. Single-cellular brand-new analysis platform that gives treasured insights into diagnosis, prognosis, remedy. The incorporation data known clinical genomics information will give better understanding complicated mechanisms diseases exploit. In review, we focused panorama UM, achieve goal, authors conducted an exhaustive literature evaluation spanning 1998 2023, keywords like "uveal melanoma, “heterogeneity”. “Targeted therapies”," "CTCs," "single-cellular analysis".

Language: Английский

Citations

10
Uveal melanoma: Recent advances in immunotherapy DOI Open Access
Francesco Saverio Sorrentino, Francesco De Rosa,

Patrick Di Terlizzi

et al.

World Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 15(1), P. 23 - 31

Published: Jan. 22, 2024

Uveal melanoma (UM) is the most common primary intraocular cancer in adults. The incidence Europe and United States 6-7 per million population year. Although UMs can be successfully treated locally controlled by irradiation therapy or local tumor resection, up to 50% of UM patients develop metastases that usually involve liver are fatal within 1 To date, chemotherapy targeted treatments only obtain minimal responses with metastatic UM, which still characterized poor prognosis. No standard therapeutic approaches for its prevention treatment have been established. application immunotherapy agents, such as immune checkpoint inhibitors effective cutaneous melanoma, has shown limited effects ocular disease. This due UM’s distinct genetics, natural history, complex interaction system. Unlike melanomas mainly BRAF NRAS mutations, triggered a mutation GNAQ GNA11. As result, more immunotherapeutic approaches, vaccines, adoptive cell transfer, other new molecules currently being studied. In this review, we examine novel strategies clinical preclinical studies highlight latest insight development tailored UM.

Language: Английский

Citations

7
Checkmate awaiting strategy: unlocking the potential of chimeric antigen receptor T-cell therapy in uveal melanoma DOI Creative Commons
Ahmed H. Al Sharie,

S. Al-Omari,

Abdelwahab Aleshawi

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 18, 2025

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults with unique genomic and phenotypic features comparison to its cutaneous counterpart [1]. UM classified based on anatomical location it originates from, including choroid, ciliary body, iris Risk factors linked includes presence of atypical nevi, light eye color, fair skin freckles, occupational exposure irritants, many others [2]. The genetic landscape characterized by chromosomal rearrangements involving chromosomes 1, 3, 6, 8, along a broad spectrum oncogenic somatic mutations. Notably, mutations genes such as BAP1, EIF1AX, GNA11, GNAQ, SF3B1 are frequently observed [3]. Although several treatment modalities have been investigated over past decade local systemic interventions, prognosis remains poor [4,5]. Local control could be achieved but ultimately, 40% patients will develop distant metastasis, commonly liver [6]. Recent advances understanding tumorigenic process immune microenvironment enhanced prognostic assessments paved way for promising novel therapeutic approaches. However, progress development approaches has slow limited.Recently, CAR-T cells therapy recolonized field anti-cancer immunotherapy. Such success story remarkable efficacy durable clinical responses especially hematological malignancies shed role other [7]. incorporates synthetic receptors into lymphocytes, redirecting them recognize expressing specific target antigen. starts careful patient evaluation selection followed leukapheresis. Isolated purified lymphocytes genetically engineered express chimeric antigen (CARs). After lymphodepletion, infused response then monitored significant rates cell therapies led US Food Drug Administration (FDA) approval seven treatments, more currently being extensively studied both basic research. An emerging area research use melanoma, numerous preclinical studies ongoing trials exploring potential mainly targeting c-Met, CD70, GD2, VEGFR2 [8]. While garnered attention extensive melanomas, similar focus investigation notably scarce case UM, where application largely underexplored.Exploring reveals that laboratory investigations, minimal testing conducted thus far, any existing often part broader trials. Forsberg et al. utilization HER2 eradicate in-vitro in-vivo [9]. latter was humanized mouse model using NOD/SCID IL-2 receptor gamma knockout mice transgenic human IL-2The later nov. el mice. It found exhibits variable expressivity were able kill tumor in-vivo. demonstrated significantly greater against from non-responders compared autologous tumor-infiltrating lymphocyte (TIL) therapy. Worth mentioning, (TILs) aforementioned findings target-specific; confirmed loss upon CRISPR/Cas9-mediated disruption cells. Another targeted tyrosinase related protein 1 (TYRP1). Jilani TYRP1 uveal melanomas unresponsive checkpoint blockade [10]. team highlighted overexpression cancer vitro vivo murine/patient-derived models. Hackett outcomes, showing TYRP1-targeted CAR T activate antigen-specific exhibit cytotoxic activity vivo, irrespective MHC alleles expression [11]. Additionally, toxicity pigmented normal tissues, which seen TCR-expressing not present B7-H3 highly expressed representing innovative approach proposed applied Ventin coupled inducible caspase-9 (iCas9) suicide gene. iCas9.B7-H3 showed antitumor vivo; experimental models metastases [12]. outcome comparable blockage monoclonal antibody. HER2, TYRP1, safety profiles supports translational phase I trial.To best our knowledge, through review multiple registries, two investigating patients, although these specifically designed patients. GAIL-N trial (ClinicalTrials.gov identifier: NCT03635632) aims improve neuroblastoma, sarcoma, breast cancer, or cancers GD2. equipped C7R gene provides constant cytokine supply maintaining longer survival time transfused non-randomized, open label, Phase I, single group assignment stated 23 rd April, 2019 active recruiting an estimated number 94 participants. sponsored Baylor College Medicine no results available up this point time. NCT04119024) investigates IL-13Rα2-targeting stage IIIC IV metastatic solid tumors. after chemotherapy conditioning regimen endpoints detect maximum tolerated dose, adverse events profile anti-tumor responses. open-label, started 27 th November, eligible Jonsson Comprehensive Cancer Center.CAR-T finding should augmented comprehensive translation future hinges continued research, collaborative efforts between researchers, tailored strategies overcome challenges. challenges focused low specificity escape, improving eliminating CAR-T-related toxicities, overcoming immunosuppressive nature microenvironment, expense economics. With advancements, holds become effective option offering new hope patients.Authors contribution: All authors made contributions work. Each author participated conceptualization, process, writing, revision manuscript.Ethics statement: None.The declare generative artificial intelligence (AI) AI assisted technologies used writing during preparation manuscript. Funding: None.

Language: Английский

Citations

0