MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial

Rohaan, Maartje W.; Gomez-Eerland, Raquel; Berg, Joost H. van den; Foppen, Marnix H Geukes; Zon, Maaike van; Raud, Brenda; Jedema, Inge; Scheij, Saskia; Boer, Renate de; Bakker, Noor; Broek, Daan van den; Pronk, Loes M.; Grijpink-Ongering, Lindsay G; Sarı, Ayşegül; Kessels, Rob; Haak, Marjolein van den; Mallo, Henk; Karger, Matthias; Wiel, Bart A. van de; Zuur, Charlotte L.; Duinkerken, Charlotte W.; Lalezari, Ferry; Thienen, J.V. van; Wilgenhof, Sofie; Blank, Christian U.; Beijnen, Jos H.; Nuijen, Bastiaan; Haanen, John B.A.G.

doi:10.1016/j.iotech.2022.100089

Cited by 12 publications

(5 citation statements)

References 45 publications

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“…However, targeting TAAs brings a high risk of on-target, off-tumor adverse effects as healthy tissues can express these antigens. As shown in a phase I/II clinical trial infusing anti–MAGE-A3/12 TCR gene-modified T cells plus IL-2 after NMA-LD chemotherapy, 3 patients developed severe neurological toxicity possibly through cross-reactivity between MAGE-A3 and MAGE-A12 (expressed in the brain), which was fatal in 2 patients 76 . The best explanation for the neurological toxicity, although not yet fully understood, is an on-target off-tumor effect of the TCR therapy.…”

Section: Other Adoptive Cell Transfer Therapies In Melanomamentioning

confidence: 97%

“…As shown in a phase I/II clinical trial infusing anti-MAGE-A3/12 TCR gene-modified T cells plus IL-2 after NMA-LD chemotherapy, 3 patients developed severe neurological toxicity possibly through cross-reactivity between MAGE-A3 and MAGE-A12 (expressed in the brain), which was fatal in 2 patients. 76 The best explanation for the neurological toxicity, although not yet fully understood, is an on-target off-tumor effect of the TCR therapy. Alternatively, to circumvent on-target off-tumor toxicity, an approach targeting tumor-specific viral antigens or neoantigens could be designed, as these are highly tumor-specific and not expressed in healthy tissue.…”

Section: T-cell Receptormentioning

confidence: 99%

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Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma

Los,

Klobuch,

Haanen

2024

Cancer J

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Major progress in prolonging survival of patients with advanced melanoma has been made in the past decade because of the development and approval of immune checkpoint inhibitor and targeted therapies. However, for nonresponding or relapsing patients, their prognosis is still dismal. Based on clinical trial data, treatment with adoptive cell therapies holds great promise. In patients with metastatic melanoma progressing on or nonresponsive to single-agent anti–programmed cell death 1, infusion of tumor-infiltrating lymphocytes can produce responses in up to half of patients, with durable complete responses in up to 20%. Genetic modification of peripheral blood T cells with T-cell receptors derived from tumor-specific T cells, or with chimeric antigen receptors, has the potential to further improve treatment outcomes in this refractory population. In this review, we will discuss the historical development, current status, and future perspectives of adoptive T-cell therapies in melanoma.

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Section: Other Adoptive Cell Transfer Therapies In Melanomamentioning

confidence: 97%

Section: T-cell Receptormentioning

confidence: 99%

Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma

Los,

Klobuch,

Haanen

2024

Cancer J

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“…Clinical trials targeting TDAs, such as melanoma antigen recognized by T cells 1 (MART-1) ( 10 – 13 ), glycoprotein 100 (gp100) ( 11 ), or carcinoembryonic antigen (CEA) ( 14 ), showed some clinical responses, but several toxicities were described because of their low expression in normal tissues. In the first clinical trial evaluating MART-1–specific TCR-T cells in patients with melanoma, the objective response rate (ORR) did not exceed 12% (2 of 17) ( 10 ).…”

Section: The Repertoire Of Targetable Antigens In Clinical Trialsmentioning

confidence: 99%

“…Although clinical response was slightly improved in one of the trials, with ORR of 30% (6 of 20) and 0% (0 of 13), respectively, several serious cutaneous, ocular, and auditive toxicities were described because of low expression of MART-1 in normal melanocytes ( 11 , 12 ). More recently, a clinical trial using a different TCR for MART-1 had to be prematurely terminated because of severe toxicities as described before and the death of one patient ( 13 ). Similar results were observed with TCR-T cells targeting gp100.…”

Section: The Repertoire Of Targetable Antigens In Clinical Trialsmentioning

confidence: 99%

TCR-engineered T cell therapy in solid tumors: State of the art and perspectives

Baulu

Gardet

Chuvin³

et al. 2023

Sci. Adv.

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T cell engineering has changed the landscape of cancer immunotherapy. Chimeric antigen receptor T cells have demonstrated a remarkable efficacy in the treatment of B cell malignancies in hematology. However, their clinical impact on solid tumors has been modest so far. T cells expressing an engineered T cell receptor (TCR-T cells) represent a promising therapeutic alternative. The target repertoire is not limited to membrane proteins, and intrinsic features of TCRs such as high antigen sensitivity and near-to-physiological signaling may improve tumor cell detection and killing while improving T cell persistence. In this review, we present the clinical results obtained with TCR-T cells targeting different tumor antigen families. We detail the different methods that have been developed to identify and optimize a TCR candidate. We also discuss the challenges of TCR-T cell therapies, including toxicity assessment and resistance mechanisms. Last, we share some perspectives and highlight future directions in the field.

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“…Under the correct conditions, several melanocytic markers provide compelling evidence for melanocytic origin and melanoma. The antibodies melan-A and melanoma-associated resistance to treatment 1 (MART-1) are both responses to the same antigen (melanoma antigen recognized by T-cells) [35]. Detecting melanoma with MelanA/MART-1 is more sensitive than HMB-45, one of the most widely used melanoma biomarkers [36].…”

Section: Clinical Indicatorsmentioning

confidence: 99%

Melanoma Epidemiology: Symptoms, Causes, and Preventions

Jeihooni¹,

Harsini²,

Imani³

et al. 2023

Melanoma - Standard of Care, Challenges, and Updates in Clinical Research

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Melanoma arises from melanocyte cells. Melanoma spreads faster than basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) if not diagnosed and treated early. Melanocyte tumors cause malignant melanoma. The preponderance of these cells is in the skin, gut, and eye. Melanoma is a rare kind of skin cancer, although it causes 75% of skin cancer deaths. Melanocytes create melanin, a dark pigment, in the skin. Despite years of lab and clinical research, early surgical removal of tiny cancers remains the most successful treatment. The deadliest skin cancer is melanoma. Skin melanocytes are involved. Melanocytes produce skin pigment melanin. Melanin protects skin against ultraviolet (UV) radiation. Skin cancer is the most common form in the United States. When diagnosed early, skin cancer can be treated with topical medications, office therapies, or outpatient surgery. Dermatologists treat skin disorders and conditions. Skin cancer causes less than 1% of cancer fatalities. Detection and treatment of melanoma in its early stages are typically curable. Once melanoma spreads further into the skin or other organs, it becomes incurable and potentially lethal. Early detection of melanoma in the United States is anticipated to result in a 5-year survival rate of roughly 99%.

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MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial

Cited by 12 publications

References 45 publications

Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma

Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma

TCR-engineered T cell therapy in solid tumors: State of the art and perspectives

Melanoma Epidemiology: Symptoms, Causes, and Preventions

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