Neoadjuvant PD-1 Blockade Combined With Chemotherapy Followed by Concurrent Immunoradiotherapy in Locally Advanced Anal Canal Squamous Cell Carcinoma Patients: Antitumor Efficacy, Safety and Biomarker Analysis

Anal canal squamous cell carcinoma (ACSCC) is an exceedingly rare malignant neoplasm with challenges in sphincter preservation, treatment toxicities and long-term survival. Little is known concerning the activity of PD-1 antibodies in locally advanced ACSCC. This study reports on the efficacy and to...

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Published in:	Frontiers in immunology 2022-01, Vol.12, p.798451-798451
Main Authors:	Xiao, WeiWei, Yuan, Yan, Wang, SuiHai, Liao, Zhidong, Cai, PeiQiang, Chen, BaoQing, Zhang, Rong, Wang, Fang, Zeng, ZhiFan, Gao, YuanHong
Format:	Article
Language:	eng
Subjects:	Adult Aged Anal Canal - metabolism Anal Canal - pathology anal canal squamous cell carcinoma Antibodies, Monoclonal, Humanized - administration & dosage Antibodies, Monoclonal, Humanized - adverse effects Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Anus Neoplasms - metabolism Anus Neoplasms - therapy Biomarkers, Tumor - metabolism Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - therapy Cisplatin - administration & dosage Cisplatin - adverse effects Cohort Studies Combined Modality Therapy Dermatitis - etiology Docetaxel - administration & dosage Docetaxel - adverse effects Female Humans Immunology locally advanced Middle Aged neoadjuvant Neoadjuvant Therapy - methods PD-1 blockade PD-L1 Pilot Projects Programmed Cell Death 1 Receptor - antagonists & inhibitors Programmed Cell Death 1 Receptor - metabolism Radioimmunotherapy - adverse effects Radioimmunotherapy - methods Treatment Outcome
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Summary:	Anal canal squamous cell carcinoma (ACSCC) is an exceedingly rare malignant neoplasm with challenges in sphincter preservation, treatment toxicities and long-term survival. Little is known concerning the activity of PD-1 antibodies in locally advanced ACSCC. This study reports on the efficacy and toxicities of a neoadjuvant PD-1 blockade combined with chemotherapy followed by concurrent immunoradiotherapy in ACSCC patients, and describes biomarkers expression and mutation signatures. In this cohort study, patients were treated as planned, including four cycles of neoadjuvant PD-1 antibody toripalimab combined with docetaxol and cisplatin, followed by radiotherapy and two cycles of concurrent toripalimab. Multiplex immunofluorescence staining (mIHC) with PD-L1, CD8, CD163, Pan-Keratin and DAPI was performed with the pretreatment tumor tissue. Whole exome sequencing was performed for the primary tumor and peripheral blood mononuclear cells. The primary endpoint was the complete clinical response (cCR) rate at 3 months after overall treatment. Acute and late toxicities graded were assessed prospectively. Five female patients with a median age of 50 years old (range, 43-65 years old), finished treatment as planned. One patient had grade 3 immune related dermatitis. Two patients had grade 3 myelosuppression during neoadjuvant treatment. No severe radiation-related toxicities were noted. Four patients with PD-L1 expression >1% achieved a cCR after neoadjuvant treatment. and the other patient with negative PD-L1 expression also achieved a cCR at 3 months after radiotherapy. All the patients were alive and free from disease and had a normal quality of life, with 19.6-24 months follow up. Inconsistent expression of PD-L1 and CD163 was detected in 3 and 5 patients, respectively. TTN, POLE, MGAM2 were the top mutation frequencies, and 80 significant driver genes were identified. Pathway analysis showed enrichment of apoptosis, Rap1, Ras, and pathways in cancer signaling pathways. Eight significantly deleted regions were identified. This small cohort of locally advanced ACSCC patients had quite satisfactory cCR and sphincter preservation rate, after neoadjuvant PD-1 antibody toripalimab combined with chemotherapy followed by concurrent immunoradiotherapy, with mild acute and long-term toxicities.
ISSN:	1664-3224 1664-3224