Editor's Note: At the Guangzhou Colorectal Cancer Summit Forum and the 22nd Guangdong Colorectal Cancer Academic Conference held from August 5-10, 2024, Dr. Zhizhong Pan from Sun Yat-sen University Cancer Center delivered an insightful presentation titled "The Journey of Colorectal Cancer Immunotherapy Research: Experiences from Sun Yat-sen University Cancer Center." After the conference, Professor Pan granted us an interview, and we have compiled the content below for our readers.Oncology Frontier: With the advent of immunotherapy as a revolutionary post-surgery treatment, coupled with the aid of chemotherapy, radiotherapy, and targeted therapy, colorectal cancer treatment has entered a new phase. Among these, immune checkpoint inhibitor (ICI) therapy has become a primary method in colorectal cancer immunotherapy. In your opinion, what are the current hotspots or challenges in research and treatment in this field?
Dr. Zhizhong Pan: The biggest challenge in colorectal cancer immunotherapy is that patients with pMMR tumors, due to their low immunogenicity (these tumors are considered “cold” tumors), are largely unresponsive to immunotherapy. The question we face is how to implement strategies to alter or enhance the immunogenicity of these patients to improve the efficacy of immunotherapy.
We typically take the following measures:
- Identify patients with high immunogenicity: Through genomic or NGS analysis, we can identify biomarkers indicative of high immunogenicity, which helps in selecting patients who are highly sensitive and likely to respond to immunotherapy.
- Increase immunogenicity through gene methylation: Specific genes can be methylated to enhance their immunogenicity.
- Reshape the genetic phenotype of the immune microenvironment and combine it with anti-angiogenic drugs: This approach can enhance the immunogenicity of patients.
- Combine radiotherapy and chemotherapy to promote the release of immunogenicity: Our earlier clinical research, recently published in CANCER CELL, discovered that for pMMR-type locally advanced rectal cancer, CAPOX chemotherapy combined with sintilimab and long-course radiotherapy altered the immunogenicity of patients, significantly improving the pCR rate compared to CAPOX chemotherapy and long-course radiotherapy alone (44% vs. 26%).
Finally, beyond the conventional detection of MMR and TMB status, we need to explore more molecular biomarkers that reflect immunogenicity to identify more therapeutic targets and further improve the coverage and efficacy of immunotherapy.
Oncology Frontier: As a crucial marker of MMR protein deficiency, MSI stability has become a key indicator in guiding treatment strategies for colorectal cancer patients. How should we use the MMR/MSI classification system to guide immunotherapy decisions for CRC patients?
Dr. Zhizhong Pan: With the availability of immunotherapy, we have started conducting preliminary MMR immunohistochemical testing on newly diagnosed colorectal cancer patients to identify those with dMMR status. This is particularly important in cases involving locally advanced colorectal cancer where organ preservation or combined organ resection, such as for the rectum or duodenum, is a consideration. In such cases, we can screen for MMR immunohistochemistry to select sensitive patients for neoadjuvant therapy, aiming for better R0 resection rates and improved functional and organ preservation.
Oncology Frontier: Sun Yat-sen University Cancer Center has conducted a series of studies on colorectal cancer immunotherapy, achieving remarkable results. Could you share some insights into this work?
Dr. Zhizhong Pan: The multidisciplinary team (MDT) at Sun Yat-sen University Cancer Center has explored colorectal cancer immunotherapy in several key areas, which I will summarize as follows:
- For dMMR-type colorectal cancer patients: Our research has found that PD-1 antibody monotherapy, dual immunotherapy, or combined anti-angiogenic drugs can increase the pCR rate. However, whether this translates into improved long-term survival remains to be confirmed by more data. For pMMR patients, combining radiotherapy and chemotherapy with immunotherapy can achieve a higher pCR rate, leading to better organ preservation. We observed that a significant proportion of patients who achieved CR opted for a wait-and-see approach without surgery. We hope to extend follow-up time to achieve long-term survival goals.
- Exploring epigenetic remodeling and combined anti-angiogenic and immunotherapy: This strategy has shown very promising results for pMMR-type advanced colorectal cancer, especially in patients with liver metastases, with significant improvements in ORR and median PFS. This suggests it may be a viable treatment option. President Xu Ruihua is leading a nationwide Phase III clinical trial to evaluate the efficacy of a three-drug immunotherapy combination compared head-to-head with second-line FOLFIRI plus bevacizumab after first-line FOLFOX chemotherapy failure. If successful, this trial could bring three-drug immunotherapy to the second line, offering hope for a cure.
- Clinical research on low rectal cancer within 5 cm of the anus: We are currently conducting studies to evaluate whether complete tumor regression can be achieved after full-course neoadjuvant chemoradiotherapy and immunotherapy, with the ultimate goal of organ preservation. The results are highly anticipated.
- MRD (Minimal Residual Disease) as a hot topic: Research shows that patients who are MRD-positive after radical colorectal cancer surgery have a higher risk of recurrence and mortality. MRD positivity can detect recurrence earlier than imaging, making it an excellent prognostic predictor. What strategies should we adopt for MRD-positive patients? Should we intervene, and if so, how? Should traditional chemotherapy or other treatments be used? These questions require more clinical research for evidence-based answers. Currently, the MD Anderson Gastrointestinal Oncology Group is conducting a clinical trial that analyzes mutated gene fragments in MRD-positive patients, encoding these fragments into mRNA to replicate small proteins. These proteins train the patient’s immune system to recognize residual cancer cells expressing small molecules. Can mRNA vaccines prevent colorectal cancer recurrence after radical surgery? The results are eagerly awaited.
Expert Profile
Dr. Zhizhong Pan
- Medical Doctor, Professor, Chief Physician, Doctoral Supervisor
- Director of Colorectal Surgery, Sun Yat-sen University Cancer Center
- Chief Expert in Colorectal Cancer Surgery
- Director of Laparoscopic Surgery Training Base, Chinese Medical Doctor Association
- Vice Chairman of the Oncology Surgery Committee, Chinese Research Hospital Association
- Vice Chairman of the Tumor Metastasis Committee, Chinese Medical Doctor Association Anorectal Surgeon Branch
- Vice Chairman of the Comprehensive Diagnosis and Treatment of Digestive Tumors Committee, Chinese Medical Care International Exchange Promotion Association
- Fellow of the American College of Surgeons (FACS)
- Chairman of the Chinese Colorectal Cancer MDT Alliance
- Recipient of three national projects, four provincial and ministerial fund projects, and initiator of 30 prospective and retrospective clinical studies
- Co-author of over 300 published papers, including 94 SCI articles as corresponding (or co-corresponding) author in internationally influential journals
- Former Vice Chairman of the Colorectal Cancer Committee, Chinese Anti-Cancer Association and Chairman of the Guangdong Colorectal Cancer Committee
- Recipient of the 2020 “National Famous Doctor · Outstanding Achievement Award” and listed in the Top 100 Chinese Famous Doctors for five consecutive years
