First-line ADP-A2M4CD8 T-cell Receptor T-cell Therapy plus Pembrolizumab in Head and Neck Cancers: An Additional Cohort of the Phase 1 SURPASS Trial

• Published in: International journal of radiation oncology, biology, physics Vol. 118; no. 5; pp. e84 - e85
• Main Authors: Ho, A., Garcia-Consuegra, A., Saro, J., Sauer, A., Cristiani, S., Brophy, F.E., Streets, S., Norry, E., Gillison, M., Charlson, J., Bover, M., Zugazagoitia, J., Calvo, E., Ugidos, L., Bruixola, G., Garcia, V. Moreno, Hong, D.S., Rubio-Pérez, J., Aggen, D.H.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.04.2024
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2024.01.187

ADP-A2M4CD8 is an autologous CD4+ and CD8+ T-cell therapy under investigation for treatment of advanced cancers in human leukocyte antigen (HLA)-A*02–eligible participants. It expresses a genetically modified T-cell receptor (TCR) targeting melanoma-associated antigen A4 (MAGE-A4) and an additional CD8α co-receptor to increase functionality of CD4+ T cells. ADP-A2M4CD8 monotherapy has demonstrated an acceptable benefit-risk profile in the ongoing Phase 1 SURPASS trial (NCT04044859), with clinical responses in multiple tumor types in the late-line setting. As of November 23, 2022, in four SURPASS patients with head and neck (H&N) squamous cell carcinoma, best overall responses were three partial responses and one stable disease (median [range] duration of response, 8.7 [7.4–20.1] weeks) (Hong DS, et al. Presentation S152, AHNS 2023, Montreal, Canada). These results, along with data that suggest inhibition of immunosuppressive pathways may enhance ADP-A2M4CD8 anti-tumor activity (Kim PS, Ahmed R. Curr Opin Immunol. 2010;22:223; Gray KG, et al. Clin Cancer Res. 2020;26:6003), provided rationale for opening a new SURPASS cohort investigating safety and efficacy of first-line ADP-A2M4CD8 TCR T-cell therapy combined with pembrolizumab in patients with H&N cancers. The dedicated H&N cohort will comprise ≤15 participants with newly metastatic or unresectable locally advanced H&N tumors with combined PD-L1 positive score ≥1 who are receiving pembrolizumab with or without chemotherapy as first-line standard-of-care therapy, with no evidence of disease progression before lymphodepletion. Key eligibility criteria include ≥30% of tumor cells expressing MAGE-A4 (≥2+ by immunohistochemistry); positivity for HLA-A*02:01, 02:02, 02:03, or 02:06 alleles; measurable disease per RECIST v1.1 before lymphodepletion; and ECOG performance status of 0 or 1. Participants will undergo leukapheresis, and collected T cells will be transduced with a lentiviral vector expressing the MAGE-A4-specific TCR and CD8α co-receptor and expanded ex vivo. Lymphodepletion chemotherapy consisting of cyclophosphamide 600 mg/m2/day for 3 days and fludarabine 30 mg/m2/day for 4 days is administered, followed by ADP-A2M4CD8 infusion (1–10 × 109 transduced T cells). Participants will then continue to receive pembrolizumab 400 mg every 6 weeks for ≤2 years, or unacceptable toxicity or disease progression. Primary and secondary objectives are to evaluate safety and anti-tumor activity, respectively. TBD In a dedicated H&N cohort, participants will receive ADP-A2M4CD8 in combination with pembrolizumab in the first-line setting to evaluate the efficacy and safety of the combination. Study sponsor: Adaptimmune; writing/editing: Excel Scientific Solutions, funded by Adaptimmune.