This issue is composed by Professor Kong Dalu, Director of the Colorectal Department of Tianjin Medical University Cancer Hospital, as the executive editor. Experts in the field of colorectal cancer surgery are specially invited to share their academic views, with a total of 7 is

Editor's note: [expert group draft] is based on ingenuity and respect for the original intention. This issue is composed by Professor Kong Dalu, Director of the Colorectal Department of Tianjin Medical University Cancer Hospital, as the executive editor. Experts in the field of colorectal cancer surgery are specially invited to share their academic views. A total of 7 issues are provided for communication.

The first issue

Executive editor: Professor Kong Dalu

Title: Progress in immunotherapy of MSI-H/dMMR type colorectal cancer

Author: Wang Wenpeng, Tianjin Medical University Cancer Hospital Colorectal Department

Expert profile

Professor Kong Dalu Tianjin Medical University

Tianjin Medical University Director and Chief Physician of the Colorectal Oncology Department of the Cancer Hospital

Member of the Tianjin Municipal People’s Political Consultative Conference

Deputy Leader of the Colorectal Oncology Group of the Oncology Branch of the Chinese Medical Association

Standing Member of the Colorectal Cancer Professional Committee of the Chinese Anti-Cancer Association

Nano-Oncology Professional Committee of the Chinese Anti-Cancer Association Standing Committee Member

Chairman of the Chinese Colorectal Cancer MDT Alliance

Member of the Chinese NOSES Alliance

Standing Committee Member of the Oncology Surgery Professional Committee of the Chinese Association of Research Hospitals

Member of the Surgical Professional Committee of the Nodal Committee of the Chinese Medical Doctor Association

Vice President of the Anorectal Physician Branch of the Tianjin Medical Doctor Association

Tianjin Medical Deputy leader of the Colorectal Surgery Group of the Chinese Society of Surgery

Deputy director of the Medical and Health Committee of the Tianjin Association for the Development of Education, Science, Culture, Health and Sports

Member of the Standing Committee of the Colorectal Tumor Professional Committee of the Beijing Oncology Society

Wang Wenpeng Doctor

Colorectal Tumors of Tianjin Cancer Hospital Surgeon, lecturer, MD.

The first author has published six articles in SCI and Chinese core journals. The latest incidence of cancer in China released by the National Cancer Center, colorectal cancer ranks second in incidence and mortality. Four, both are on the rise year by year. Immune checkpoint inhibitor treatment is currently a hot topic in colorectal cancer research, and microsatellite instability (MSI) or mismatch repair gene status (MMR) is the best predictor of the efficacy of immunotherapy in colorectal cancer. Based on MSI/MMR, it is divided into highly microsatellite unstable (MSI-H)/mismatch repair gene deficient (dMMR) type and microsatellite stable (MSS)/mismatch repair gene intact (pMMR) type, among which MSI- The H/dMMR type accounts for approximately 15% of colorectal cancers and belongs to the "sensitive population" to immunotherapy, while the MSS/pMMR type belongs to the "ineffective population" to immunotherapy.

1. Mechanism of immunotherapy for MSI-H/dMMR colorectal cancer

Patients with MSI-H/dMMR colorectal cancer have significant expression of cell programmed death -ligand 1 (PD-L1)/PD-L2 on the surface of tumor cells Up-regulated, it can bind to the PD-1 receptor on effector T cells to inhibit the immune killing effect of T cells on tumor cells. Immune checkpoint inhibitors can block the binding of PD-L1/PD-L2 to the PD-1 receptor. Thereby enhancing the body's immune system to kill tumor cells.

In addition, studies have found that tumor gene mutation load is also positively correlated with the effect of colorectal cancer immunotherapy. This may be because tumor cells with high tumor mutation load express more polypeptide antigens, and these antigens are easily absorbed by the body. Immune cells recognize non-self cells, thereby inducing T cells to activate and kill cancer cells. The tumor cells of patients with MSI-H/dMMR colorectal cancer are often accompanied by a high mutation load in tumor genes.

2. The efficacy of immune checkpoint inhibitor PD-1 monoclonal antibody monotherapy in the treatment of MSI-H/dMMR metastatic colorectal cancer (mCRC) in sensitive populations

KEYNOTE-016 Phase II clinical trial study 2015 early results show Paboli The objective response rate (ORR) of sensitive mCRC patients who failed standard regimens with zizumab was 40%^[1]. Later, the study included more sensitive people with drug-resistant MSI-H/dMMR mCRC. The 2017 clinical trial results showed that the ORR and disease control rate (DCR) of mCRC patients who were resistant to standard treatment were 52% and 89%, and all patients were Median progression-free survival time (PFS) and overall survival (OS) time ^[2] were not reached. CheckMate-142 is an open, multi-center phase II clinical trial. This study has three cohorts. One of the cohorts is to study the single-agent nivolumab in the MSI-H/dMMR mCRC population who have failed standard treatments. Its ORR is 31.1% and DCR is 69%.None of the patients who responded to treatment reached the median response time ^[3] .

The above two studies are about the use of PD-1 monoclonal antibodies in the treatment of MSI-H/dMMR mCRC after failure of second-line or third-line chemotherapy. The KEYNOTE-177 phase III clinical trial evaluated the efficacy of single-agent pembrolizumab in the first-line treatment of MSI-H/dMMR mCRC. A total of 307 patients with MSI-H/dMMR mCRC who had not received any previous treatment were enrolled at a 1:1 ratio. The proportion was randomly divided into the immunotherapy group and the chemotherapy + targeting group. The ORRs of the immunotherapy group and the chemotherapy + targeting group were 43.8% and 33.1% respectively. Among patients who experienced ORR, 83% of patients in the immunotherapy group continued to respond during 24 months of treatment, while only 35% of patients in the chemotherapy + targeting group continued to respond.^[4]

3. The efficacy of the combination of immune checkpoint inhibitor PD-1 monoclonal antibody in the treatment of MSI-H/dMMR type mCRC sensitive population

CheckMate-142 Another cohort study content is to evaluate the relationship between PD-1 monoclonal antibody and cytotoxic T cells Antigen-4 (CTLA-4) monoclonal antibody combined with immunotherapy for MSI-H/dMMR mCRC that has failed previous chemotherapy. CTLA-4 monoclonal antibody can promote T lymphocyte membrane surface CTLA-4 and its ligand CD80/86 by blocking the binding Cell activation, thereby enhancing the body's immune system to kill tumor cells. In this study, the ORR of nivolumab combined with ipilimumab in the treatment of MSI-H/dMMR mCRC was 55%, and the median response time was not reached. The 12-month PFS and OS were 71% and 85% respectively^[5] .

Hochster et al. conducted a phase Ib study of PD-1 monoclonal antibody drug (ateezolizumab) combined with anti-angiogenic drug (bevacizumab) in the treatment of first-line or above second-line chemotherapy-resistant MSI-H/dMMR mCRC. Ten mCRC patients have been enrolled in the study. The ORR is 30%, the DCR is as high as 90%, the sustained effective response time is long, the average follow-up time is 11.1 months, the median OS has not been reached, and it is well tolerated^[6] .

COMMIT is an ongoing clinical phase III randomized controlled trial . It plans to enroll 347 patients with MSI-H/dMMR mCRC who have not received any treatment in the past. They will be divided into two groups. One group will receive mFOLFOX6/bevacizumab. anti+atezolizumab combination therapy, and the other group was mFOLFOX6/bevacizumab therapy. The primary endpoint is PFS, and the secondary endpoints are OS, ORR, DCR and adverse events. The results of this research are highly anticipated ^[7].

4. The efficacy of immune checkpoint inhibitor PD-1 monoclonal antibody in preoperative neoadjuvant immunotherapy for early-stage MSI-H/dMMR colorectal cancer

NICHE trial is a trial from the Netherlands to evaluate PD-1 monoclonal antibody A study of volumab combined with the CTLA-4 monoclonal antibody ipilimumab for neoadjuvant immunotherapy in patients with early-stage colorectal cancer. The study included a total of 40 patients with stage I to III colorectal cancer. The results are exciting. Among the 20 patients with MSI-H/dMMR type, 19 patients had pathological major response (residual cancer cells 10%, mPR) after surgery, and 12 patients had no cancer cells found in the postoperative tumor specimens. Complete response (pCR). This trial shows that neoadjuvant immunotherapy is safe and feasible. Surprisingly, PD-1 monoclonal antibodies have almost no effect in patients with MSS/pMMR type mCRC, but in early MSS/pMMR type bowel cancer, 27% of patients developed immune responses ^[8] .

VOLTAGE is a study evaluating the safety and efficacy of surgery after neoadjuvant chemoradiotherapy + immunotherapy for localized advanced colorectal cancer. In this study, there were 5 patients with MSI-H/dMMR colorectal cancer, and 3 of them achieved pCR and mPR. ATOMIC is an ongoing phase III randomized controlled study. This study recruits 700 patients with MSI-H/dMMR type III colorectal cancer. The patients are divided into two groups. One group receives FOLFOX + atezolizumab for 6 months. Afterwards, single-agent atezolizumab treatment was continued for 6 months, and the other group received FOLFOX chemotherapy for 6 months. The primary endpoint of the trial was DFS, and the secondary endpoint was OS or adverse events. The results of the patients in this study have not yet been announced and are worth looking forward to.^[9].

5. Summary

Immune checkpoint inhibitor PD-1 monotherapy has an ORR of 31.1% to 52% in the treatment of MSI-H/dMMR mCRC that has been resistant to first-line or above second-line treatment. The ORR of those who have not received any previous treatment is 43.8%; the ORR of combined immunotherapy with PD-1 monotherapy + CTLA-4 monoclonal antibody and PD-1 monotherapy combined with anti-VEGF antibody in the treatment of MSI-H/dMMR mCRC with previous first-line or above second-line resistance was 55% respectively. , 30%. Although the ORR of the latter combination therapy is unsatisfactory, the DCR is as high as 90%. In addition, when the results were released, the number of participants was only 10; the results of the combination of preoperative neoadjuvant immunotherapy are very exciting, with an ORR of 80%. ~95%, but the number of participants is small, and further expansion of the sample size is needed to confirm. The above studies show that immunotherapy for MSI-H/dMMR colorectal cancer is highly effective and the tumor response time is long-lasting. Two clinical trials, COMMIT and VOLTAGE, are ongoing. They have a large number of recruits and are more convincing. They can further clarify the effect of chemotherapy combined with immunotherapy. The results are exciting.

Professor Kong Dalu commented:

Colorectal cancer is a common malignant tumor in my country, and related research on colorectal cancer is also a hot spot in cancer treatment. Like other cancer types, with the in-depth research on the mechanism of tumorigenesis, the development of colorectal cancer Diagnosis and treatment models are also developing towards individualization and precision. Stratifying colorectal cancer patients based on the presence of MSI-H or dMMR at the molecular diagnostic level is also a reflection of precise diagnosis and treatment. The author of this article summarizes and analyzes the relevant research on the immunotherapy mechanism of MSI-H/dMMR colorectal cancer and the application of immune checkpoint inhibitors in the neoadjuvant treatment of metastatic colorectal cancer and non-metastatic colorectal cancer. For immunotherapy Its application in MSI-H/dMMR colorectal cancer has certain reference significance.

References

1.Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 2015. 372(26): p. 2509-20.

2.Le, D.T., et al. al., Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science, 2017. 357(6349): p. 409-413.

3.Overman, M.J., et al., Nivolumab in patients with metastatic DNA mismatch repair -deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncology, 2017. 18(9).

4.Andre, T., et al., Pembrolizumab in Microsatellite- Instability-High Advanced Colorectal Cancer. N Engl J Med, 2020. 383(23): p. 2207-2218.

5.Lonardi, S., et al., Combination of nivolumab (nivo) + ipilimumab (ipi) in the treatment of patients (pts) with deficient DNA mismatch repair (dMMR)/high microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC): CheckMate 142 Study. Annals of Oncology, 2017. 28: p. vi3.

6.Hochster, H.S. , et al., Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC). Journal of Clinical Oncology, 2017. 35(4_suppl): p. 673-673.

7.NIH-ClinicalTrials.gov. Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in treating patients with Deficient DNA Mismatch Repair Metastatic Colorectal Cancer, the COMMIT Study.2021. https://clinicaltrials.gov/ct2 /show/NCT02997228.

8.Chalabi, M., et al., LBA37_PRNeoadjuvant ipilimumab plus nivolumab in early stage colon cancer. Annals of Oncology, 2018. 29(suppl_8).

9.Yuki, S., et al., SO- 37 Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stability and microsatellite instability-high, locally advanced rectal cancer (EPOC 1504). Annals of Oncology, 2020. 31.

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