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Autologous T cell therapy for MAGE-A4⁺ solid cancers in HLA-A*02⁺ patients: a phase 1 trial.

ABSTRACT: Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit-risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.

SUBMITTER: Hong DS

PROVIDER: S-EPMC9873554 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Autologous T cell therapy for MAGE-A4<sup>+</sup> solid cancers in HLA-A*02<sup>+</sup> patients: a phase 1 trial.

Hong David S DS Van Tine Brian A BA Biswas Swethajit S McAlpine Cheryl C Johnson Melissa L ML Olszanski Anthony J AJ Clarke Jeffrey M JM Araujo Dejka D Blumenschein George R GR Kebriaei Partow P Lin Quan Q Tipping Alex J AJ Sanderson Joseph P JP Wang Ruoxi R Trivedi Trupti T Annareddy Thejo T Bai Jane J Rafail Stavros S Sun Amy A Fernandes Lilliam L Navenot Jean-Marc JM Bushman Frederic D FD Everett John K JK Karadeniz Derin D Broad Robyn R Isabelle Martin M Naidoo Revashnee R Bath Natalie N Betts Gareth G Wolchinsky Zohar Z Batrakou Dzmitry G DG Van Winkle Erin E Elefant Erica E Ghobadi Armin A Cashen Amanda A Grand'Maison Anne A McCarthy Philip P Fracasso Paula M PM Norry Elliot E Williams Dennis D Druta Mihaela M Liebner David A DA Odunsi Kunle K Butler Marcus O MO

Nature medicine 20230109 1

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovaria ...[more]

PMID: 36624315

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Project description:Afamitresgene autoleucel, an HLA-restricted autologous specific peptide enhanced affinity receptor (SPEAR) T-cell therapy targeting MAGE-A4, was developed to treat HLA-A*02 positive patients with MAGE-A4 expressing solid tumors. A multicenter, dose-escalation, Phase 1 trial (NCT03132922) was conducted evaluating afamitresgene autoleucel in patients with relapsed or refractory (≥1 prior line of therapy) metastatic solid tumors. The primary endpoint was safety. The secondary endpoint was anti-tumor activity including overall response rate, best overall response, time to response, duration of response, duration of stable disease, progression-free survival and overall survival. Thirty-eight patients were treated with afamitresgene autoleucel across 9 tumor types, including 16 with synovial sarcoma (SS). Overall, afamitresgene autoleucel was well tolerated. The most common adverse events were cytopenias. Cytokine release syndrome occurred in 55% of all patients with severity grade ≤2 in 90% of reported cases. Overall response rate (ORR) was 24% and disease control rate (DCR) was 74% with objective responses in 7 patients with SS, 1 patient with non-small cell lung cancer, and 1 patient with head and neck squamous cell carcinoma. ORR in patients with SS, all prior treated with ifosfamide chemotherapy, was 44%, and DCR was 94%. Median progression-free survival and overall survival were 20.4 weeks (95% CI: 10.0, 52.1) and 58.1 weeks (95% CI: 36.3,-), respectively, for patients with SS and 12.3 weeks (95% CI: 10.857, 19.1) and 42.9 weeks (95% CI: 20.7, -), respectively, for the overall population. Translational findings demonstrated that afamitresgene autoleucel infiltrates into tumors, has an IFNγ-driven mechanism-of-action, and triggers adaptive immune responses. Overall, afamitresgene autoleucel has an acceptable safety profile with early and durable responses in HLA-A*02 positive patients with MAGE-A4 expressing solid tumors, especially in patients with metastatic SS. The recommended treatment regimen for Phase 2 evaluation involves lymphodepleting chemotherapy consisting of cyclophosphamide 600 mg/m2 x 3 days and fludarabine 30 mg/m2 x 4 days followed by afamitresgene autoleucel at a dose range of 1 to 10 billion transduced T-cells.

Dataset Information

Autologous T cell therapy for MAGE-A4⁺ solid cancers in HLA-A*02⁺ patients: a phase 1 trial.

Publications

Autologous T cell therapy for MAGE-A4<sup>+</sup> solid cancers in HLA-A*02<sup>+</sup> patients: a phase 1 trial.

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Dataset Information

Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial.

Publications

Autologous T cell therapy for MAGE-A4<sup>+</sup> solid cancers in HLA-A*02<sup>+</sup> patients: a phase 1 trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Autologous T cell therapy for MAGE-A4⁺ solid cancers in HLA-A*02⁺ patients: a phase 1 trial.