PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer

Pei, Fengyun1,2; He, Wan3; Duan, Yinghua4; Yao, Qijun1,2; Zhao, Yandong5; Fan, Xinjuan5; Liu, Shuai6; Chen, Haiyang6; He, Fang6; Liu, Tingzhi7; Chen, Jiaoting7; Zheng, Yijia7; Li, Heping8; Guo, Xiaofang8; Shi, Lishuo9; Ling, Li10; Chen, Yaoxu11; He, Jiapeng11; Liu, Miao11; Huang, Mengli11; Bai, Yuezong11; Wang, Jianping1,2,12,13; Huang, Meijin1,2,12,13; Huang, Jun1,2,12,13

2024-06-01

10.1002/cam4.7224

CANCER MEDICINE   影响因子和分区

2045-7634

Background: Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies. Methods: In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, <= 10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics. Results: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 x 10(-8)). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively). Conclusions: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.

colorectal cancer neoadjuvant treatment PD-1 blockade pMMR/MSS

SCI

英语

其他

Oncology

Oncology

WOS:001249730300001

WILEY

Web of Science

1.Sun Yat Sen Univ, Affiliated Hosp 6, Dept Colorectal Surg, Guangzhou, Peoples R China
2.Sun Yat Sen Univ, Affiliated Hosp 6, Dept Gen Surg, Guangzhou, Peoples R China
3.Jinan Univ, Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1,Dept Oncol,Clin Med Coll 2, Shenzhen, Peoples R China
4.Sun Yat Sen Univ, Affiliated Hosp 1, Dept Tradit Chinese Med, Guangzhou, Peoples R China
5.Sun Yat Sen Univ, Affiliated Hosp 6, Dept Pathol, Guangzhou, Peoples R China
6.Sun Yat Sen Univ, Affiliated Hosp 6, Dept Radiat Oncol, Guangzhou, Peoples R China
7.Sun Yat Sen Univ, Affiliated Hosp 6, Dept Hematol, Guangzhou, Peoples R China
8.Sun Yat Sen Univ, Dept Med Oncol, Affiliated Hosp 1, Eastern Hosp, Guangzhou, Peoples R China
9.Sun Yat Sen Univ, Affiliated Hosp 6, Clin Res Ctr, Guangzhou, Peoples R China
10.Sun Yat Sen Univ, Sch Publ Hlth, Fac Med Stat & Epidemiol, Guangzhou, Peoples R China
11.3D Med Inc, Med Affairs, Shanghai, Peoples R China
12.Sun Yat Sen Univ, Affiliated Hosp 6, Guangdong Prov Key Lab Colorectal & Pelv Floor Dis, Guangzhou, Peoples R China
13.Guangdong Inst Gastroenterol, Guangzhou, Peoples R China

Pei, Fengyun,He, Wan,Duan, Yinghua,et al. PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer[J]. CANCER MEDICINE,2024,13(12).

Pei, Fengyun.,He, Wan.,Duan, Yinghua.,Yao, Qijun.,Zhao, Yandong.,...&Huang, Jun.(2024).PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer.CANCER MEDICINE,13(12).

Pei, Fengyun,et al."PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer".CANCER MEDICINE 13.12(2024).