The pCR rate of the neoadjuvant PD-1 monoclonal antibody for the treatment of colorectal cancer by Professor Yanhong Deng’s team was as high as 88%, and was invited to be published by the Lancet Gastrointestinal and Liver Disease Sub-Journal

Foreword Recently, the authoritative medical journal "Lancet" sub-issue "The Lancet Gastroenterology and Hepatology" (2020 Impact Factor: 18.
486) published online the latest research results in the field of colorectal cancer immunotherapy by Professor Deng Yanhong's team at the Sixth Affiliated Hospital of Sun Yat-sen University——" Neoadjuvant teriprimab (anti-PD-1 monoclonal antibody) with or without celecoxib (COX-2 inhibitor) for the treatment of mismatch repair protein defects (dMMR) or highly unstable microsatellites (MSI-H) ) Single-center, parallel, non-controlled, randomized, phase II clinical trial (PICC) for locally advanced colorectal cancer"
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This study is the first report in the world based on anti-PD-1 monoclonal antibody, single agent or combined with COX-2 inhibitor, preoperative neoadjuvant immunotherapy for patients with locally advanced colorectal cancer with dMMR/MSI-H prospective Sexual clinical trials
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The results of the study showed that the pathological complete response (pCR) rate of patients in the teriprizumab combined with celecoxib group was as high as 88%, and the pCR rate of the teriprizumab monotherapy group was 65%
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This breakthrough achievement fills the gap in the field of neoadjuvant anti-PD-1 monotherapy for locally advanced colorectal cancer in dMMR/MSI-H, and has been specially invited for fast-track publication
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Taking this opportunity, this platform specially invites Professor Deng Yanhong to accept an exclusive interview on research-related issues, which are organized as follows
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Reporter: Hello Professor Deng, congratulations for publishing your breakthrough results again! What is your starting point and background for designing PICC research? Professor Deng Yanhong: Thank you! We all know that colorectal cancer is the second largest cancer in the world, and the incidence of colorectal cancer in China continues to rise, and the urban incidence has jumped to the second place.

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Our team has been committed to the research of precision medicine treatment for colorectal cancer
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In fact, the PICC study is based on the outstanding efficacy of two cases
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After the ASCO meeting in 2015, everyone knows that MSI-H colorectal cancer is particularly sensitive to immune checkpoint inhibitors represented by PD-1 antibody due to its unique onset characteristics and microenvironmental characteristics, and it is more likely to be The earlier you use it, the more sensitive it is
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Our center is the first institution in the country to conduct MSI-H testing.
In 2018, a Lynch syndrome patient's second tumor occurred in the upper rectum.
Due to the young age and the need for fertility preservation, the patient refused radiotherapy and chemotherapy
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After full informed consent, we gave PD-1 antibody treatment, and the patient's final surgery result showed pCR
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Later, his mother was also diagnosed with rectal cancer, and obtained complete clinical remission (cCR) after using PD-1 antibody
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In 2019, the analysis of these two cases was published on "Oncolimmnunology", and this result was also cited by the National Comprehensive Cancer Network (NCCN) Colon Cancer Guidelines (2021.
V2)
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Based on the outstanding efficacy of the above two patients, we began this PICC study in 2019 to explore the efficacy of PD-1 antibody alone or in combination with celecoxib in the neoadjuvant treatment of locally advanced colorectal cancer
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Reporter: Why do you focus on neoadjuvant therapy for dMMR/MSI-H colorectal cancer patients? Professor Deng Yanhong: Based on two points, we focus on this topic: First, our team has carried out a series of studies in the field of neoadjuvant colorectal cancer.
From 2010, we began to explore the FOWARC study of chemotherapy alone to partially replace radiotherapy and chemotherapy to three-drug neoadjuvant treatment of the rectum.
The FOTUNE studies of cancer are all cited in NCCN guidelines
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With the development of precision drug treatment, treatment selection guided by molecular classification is imperative.
How to further increase the efficacy of neoadjuvant treatment and create more opportunities for surgery is also the direction our team has been working hard on
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The FOxTROT study showed that after 106 patients with locally advanced dMMR or MSI-H colon cancer received FOLFOX neoadjuvant chemotherapy, 101 (95%) patients were almost completely insensitive to chemotherapy
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Therefore, it is of great significance to find an effective neoadjuvant treatment plan for patients with dMMR/MSI-H colorectal cancer
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Second, neoadjuvant may be more effective than adjuvant and first-line treatment
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Patients with metastatic colorectal cancer with dMMR/MSI-H have been confirmed to be sensitive to anti-PD-1 immunotherapy
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However, with the development of the disease, the physical status or immune function of patients with organ metastasis has declined.
Even if the first-line anti-PD-1 immunotherapy is used, the effective rate is only 44%, and up to 30% of the patients have the primary disease.
Resistance
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In addition, different from the mechanism of chemotherapy that directly kills tumor cells, PD-1 inhibitors need to rely on the interaction between T cells, tumor cells, and antigen-presenting cells to form a tumor immune microenvironment that can recruit immune cell aggregation.
A certain number and volume of tumor cells are required.
For colon cancer patients with only micrometastasis, the immune microenvironment makes the possibility of these cells interact very low
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There is a wider tumor neoantigen library in the tumor before surgery, and it is easier to deliver T lymphocytes to the tumor microenvironment when the lymphatic and blood vessels are intact.
Therefore, the use of anti-PD-1 immunotherapy before surgery may be more convenient than postoperative use.
Effective
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Reporter: Why did you choose the domestically produced PD-1 combined with COX-2 inhibitor? Professor Deng Yanhong: In recent years, with the continuous enhancement of the R&D strength of China's local innovative pharmaceutical companies, the clinical data of domestic PD-1 represented by teriprizumab is also very good.

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It is precisely because of the development of local enterprises that it is much more convenient for us to carry out research initiated by researchers than 5 or 10 years ago, so that PICC research can be carried out and completed.
The current results also prove that our choice is correct.
Of
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In addition, cyclooxygenase-2COX-2 may participate in the occurrence of colorectal cancer through mechanisms such as promoting tumor angiogenesis, inhibiting tumor cell apoptosis, participating in oxidative cancer induction pathways, influencing cell cycle changes, and leading to abnormal cell proliferation signaling.
We The team is also continuing to pay attention to the anti-tumor effect of COX/COX-2 inhibitors in colorectal cancer
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Unfortunately, the anti-tumor effects of COX-2 inhibitors have failed in combination with targeting and chemotherapy
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However, according to our team’s previous in vitro studies and reports in the literature, COX-2 inhibitors may improve the efficacy of PD-1 antibodies, so we chose to combine COX-2 inhibitors with PD-1
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Reporter: Could you briefly introduce the design plan and results of the PICC trial? Professor Deng Yanhong: The PICC study is a single-center, parallel, uncontrolled, randomized, phase II clinical study
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Patients with colorectal cancer whose clinical stage is T3-T4 or Tany N+ and confirmed by histopathology as dMMR/MSI-H are mainly included
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Before undergoing surgical resection, the included patients were randomly assigned to the teriprizumab group (teriprizumab, 3 mg/kg, D1, q2w) or teriprizumab combined with celecoxib according to 1:1 The group (teriprizumab, 3mg/kg, D1, q2w; celecoxib, 200mg, bid, q2w) received 6 cycles of neoadjuvant therapy
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The primary endpoint of the study is pCR
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The study finally enrolled 34 patients, 17 cases in each of the teriprizumab combined with celecoxib treatment group and the teriprizumab single-agent treatment group
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All patients received corresponding treatment and R0 resection according to the study plan
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The results of the study showed that 15 patients (88%; 95% CI, 64%-99%) in the treatment group of teriprizumab combined with celecoxib achieved pCR, and 16 patients (94%; 95% CI, 71%-100%) patients achieved major pathological complete remission (MPR); 11 patients (65%; 95%CI, 38%-86%) in the teriprizumab monotherapy group achieved pCR, and 17 patients (100 %; 95%CI, 81%-100%) to reach MPR
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The median follow-up time was 14.
5 months.
All patients were alive and did not relapse
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In the neoadjuvant treatment stage, 10 patients (59%) in each group had grade 1-2 treatment-related adverse events, and only one patient had treatment-related adverse events of grade 3 and above
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There were no treatment-related surgical delays in either group
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This result indicates that the neoadjuvant treatment of locally advanced colorectal cancer with or without celecoxib shows good tolerability and a positive pCR rate
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Reporter: Could you please talk about the guiding significance of the research results for the current clinical practice? Professor Deng Yanhong: I think the PICC study may change the guidelines because we mentioned earlier that the pCR rate of conventional neoadjuvant FOLFOX chemotherapy for colon cancer is less than 5%, and even for rectal cancer, the pCR rate of concurrent radiotherapy and chemotherapy is less than 30%
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The results of our study showed that the pCR rate of teriprizumab alone reached 65%, and the pCR rate of combined treatment reached 88%, which was significantly higher than historical controls.
Previous studies have shown that pCR is positively correlated with long-term survival.
Therefore, The research data should support the use of PD-1 monotherapy (teriprilimab) or combined with celecoxib for neoadjuvant therapy in patients with MSI-H colorectal cancer, especially in patients with low rectal or borderline resectable patients
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In addition, the outstanding efficacy of preoperative treatment also raises the possibility of whether these patients can avoid surgery, especially for patients with low rectum, which may create more opportunities to preserve the anus
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Professor Thierry André from the Department of Oncology, Saint Anthony Hospital, France (Keynote-177, IDEA-France and MOSAIC and other research major investigators) published a concurrent review that this neoadjuvant immunotherapy strategy is effective for the organ function of patients with dMMR/MSI-H rectal cancer It has important clinical significance to protect and weaken colon cancer patients
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Reporter: Based on the results of the PICC trial, do you and your team have any follow-up plans? Professor Deng Yanhong: There are three things to do in the follow-up.
The first is long-term follow-up.
Although pCR is a good surrogate indicator, for locally advanced colorectal cancer, the gold standard is the 3-year disease-free survival rate.
We look forward to seeing it.
To the same outstanding long-term follow-up results
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Secondly, we are planning to further expand the sample size.
Although the COX-2 inhibitors have seen an increase in the pCR value in the PICC study, it has not yet reached a statistical difference.
I believe that after expanding the sample, the difference is significant
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Third, expand the center and further determine the efficacy of single drugs or combinations in multiple centers to make the results more credible and repeatable
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This research is composed of a multidisciplinary team composed of the Department of Oncology, Colorectal Surgery, Pathology, Imaging, Endoscopic Surgery, and Clinical Research Center of the Sixth Affiliated Hospital of Sun Yat-sen University, as well as Professor Ling Li from the School of Public Health, Sun Yat-sen University, Rutgers, USA This was done in collaboration with Professor Liu Hao from the University School of Public Health
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Among them, Hu Huabin, Kang Liang, Zhang Jianwei, Wu Zehua are the first authors of the paper, and Deng Yanhong is the corresponding author
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[Professor Deng Yanhong's team photo] [Professor Deng Yanhong's resume] Professor Deng Yanhong, chief physician, doctoral supervisor, post-doctoral co-supervisor, assistant to the dean of the Sixth Affiliated Hospital of Sun Yat-sen University, director of the tumor center, and director of the clinical research center
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Studying in Seattle, United States, Fred Hutchinson/University of Washington Cancer Research Center
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The FOWARC research he presided over received ASCO oral reports twice, and he published more than 80 papers in high-level academic journals such as J Clin Oncol, JAMA, Lancet Oncology, and presided over a number of national key research and development projects, the National Natural Science Foundation of China, and the Natural Science of Guangdong Province.
Science Foundation
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Guangdong Provincial Special Support Program Young Top Talents, Guangdong Provincial Medical Outstanding Young Talents, 2016 National Science and Technology Progress Second Prize (5th), 2018 Guangdong Province Science and Technology Progress First Prize (4th), 2020 Ministry of Education Science and Technology Progress First Prize Award (third), the 6th Wuzhou Women's Science and Technology Award of the Chinese Women's Physician Association
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Main academic appointments: Member of the expert group of Chinese Colorectal Cancer Diagnosis and Treatment Standards (National Health Commission) Vice President of Oncology Branch of Chinese Geriatrics Association Vice Chairman of CSWOG Colorectal Cancer Professional Committee of China Southern Association for Clinical Research Standing Committee Member of the Standing Committee of the Chinese Anti-Cancer Association Tumor Precision Therapy Professional Committee Member of the Standing Committee of the CSCO Colorectal Cancer Professional Committee of the Chinese Society of Clinical Oncology Vice Chairman of the Youth Committee of the Colorectal Tumor Branch of the Chinese Medical Doctor Association Committee Chairman