With the great success of anti-PD-1/PD-L1 immunotherapy in areas such as melanoma and non-small cell lung cancer, the journal Science listed cancer immunotherapy as one of the top 10 scientific breakthroughs in December 2013, and since then immunotherapy has become super obvious in cancer treatment, and at the 2015 ASCO Annual Meeting it was no exception and remains the biggest highlight, so which study was the most important this year? So, which study is the most important breakthrough this year? Although several immunotherapy studies were announced in the Plenary session, I believe that the NCT01876511 study of anti-PD-1 immunotherapy in advanced cancer based on MMR (mismatch repair) status from Johns Hopkins Hospital (Le, et al; LBA100, 2015 ASCO), which was presented orally in the Immunotherapy session on May 30, 2015, is the most important. LBA100, 2015 ASCO), was undoubtedly the biggest highlight of the conference, even though it was only a 41-case, single-arm, phase II study, and even though it did not make it to the plenary podium. Why? Because it opened up a new era in immunotherapy: genotyping-based immunotherapy with enrichment, bringing back the light to advanced cancers where traditional chemotherapy, targeted therapy, and even unenriched immunotherapy have failed, and Professor Venook, Chair of the ASCO Academic Committee, named the study the highlight. And another event happened that makes it impossible to take this small phase II clinical study lightly: on May 30, the same day as the oral presentation at ASCO, the New England Journal of Medicine (NEJM), the world’s leading medical journal, published the full study online simultaneously (Le, et al, NEJM, 2015; May 30; DOI: 10, 1056/NEJM). : 10, 1056/NEJMoa1500596). This is rare in the history of the NEJM, and I think it is clear that the NEJM’s move has positioned this study as an important milestone in immunotherapy. Let’s start with the basics of this study: The NCT01876511 study was designed to explore the value of anti-PD-1 immunotherapy guided by MMR (DNA mismatch repair) status in advanced cancer. Three groups of patients were selected for single-arm treatment based on MMR status: i.e., bowel cancer with MMR mutation (dMMR), bowel cancer with normal MMR (pMMR), and other tumors with dMMR; patients were all advanced cases who had failed all current standard treatments and then received the anti-PD-1 immunotherapy drug pembrolizumab (a product of Merck Sharp & Dohme, Inc. approved by the FDA in September 2014 for immunotherapy of advanced melanoma, trade name Keytruda) at 10 mg/kg administered every 2 weeks. The study is a single-arm phase II clinical study with the primary study endpoints of irORR (immune-related objective response rate) and irPFS (immune-related progression-free survival) at 20 weeks. The study was planned to enroll 71 patients, and the primary study endpoint was actually met at enrollment of 41 patients (11 with dMMR bowel cancer, 21 with pMMR bowel cancer, and 9 with dMMR other tumors (specifically, 4 with potbelly/bile duct cancer, 2 with endometrial cancer, 2 with small bowel cancer, and 1 with gastric cancer)). The 20-week irORR for the three groups were: 40%, 0, and 71%, respectively; 20-week irPFS: 78%, 11%, and 67%; and ORR and DCR (disease control rate, including CR, PR, and SD) as assessed by conventional RECIST were: (1) 40% and 90% for the dMMR bowel cancer group; (2) 0 and 11% for the pMMR bowel cancer group; (3) 71% for the other tumors in the dMMR group. (3) other tumors in the dMMR group 71%, 71%. The median PFS and OS in the dMMR group were not yet achieved, while those in the pMMR bowel cancer group were 2, 2 months and 5, 0 months, respectively, with HR = 0, 103, 95% CI 0, 029-0, 373, p<0, 001 for PFS; HR = 0, 216, 95% CI 0, 047-1, 0, p = 0, 02, for OS. Interestingly, this study also performed a genome-wide tumor somatic mutation Genome-wide tumor somatic mutation analysis was also performed in this study, and overall, dMMR tumors showed an average of 1782 mutations, much higher than the 73 mutations in pMMR tumors (p = 0, 007), and the number of mutations was also significantly correlated with PFS (p = 0, 02). What, then, can this study teach us? The following questions should be the most important ones: Why did you find MMR? After listening to this report, almost everyone's first question should be: How did the investigators come up with the idea of MMR? The success of the new cancer immunotherapy, represented by anti-PD-1/PD-L1, has been obvious to all, and the industry is most concerned about which cancer type it will overcome next time to bring hope to those patients in despair. No one expected that this time, the olive branch of life would be extended to colorectal cancer, which has long been considered ineffective for immunotherapy. Unlike other solid tumors such as melanoma, kidney cancer and non-small cell lung cancer, only a few patients with mCRC have responded to treatment. Therefore, mCRC has been considered as an insensitive tumor for immunotherapy. However, scholars in China and abroad have not completely given up on this disease and have been searching for clues that may benefit from immunotherapy. Until this time, the same treatment, the same drug, and the same disease have achieved great success simply because of genotyping screening. This storyline of anti-PD-1 immunotherapy based on MMR status is the same as the one that determined the efficacy of anti-EGFR targeted therapy in advanced bowel cancer through KRAS screening years ago, with molecular marker-guided population enrichment again playing a key role. So, how did the investigators come up with the idea for MMR? From the background analysis delivered by the authors in the NEJM study paper, the following points are important: 1. Focus on characterization of rare and typical cases: In the long-term follow-up results of the phase I study of the anti-PD-1 antibody MDX-1106 (i.e., nivolumab, trade name Opdivo) conducted in 2010 and 2012 (2010 JCO; 2012 NEJM). Only 1 of the 33 patients with mCRC enrolled responded to treatment, but the outcome was impressive, with a complete remission (CR) that lasted 3 years. The investigators began to wonder what was so special about this patient; 33 patients with advanced bowel cancer were enrolled in the study and only 1 was effective, suggesting that this particular group was small, less than 5%. 2. Commonality of immunotherapy efficacy: Tumor cell mutations produce new epitopes, or neo-antigens, which are structurally different from the body's normal antigens and are equivalent to adding a "label" to tumor cells, making them more likely to be recognized by the immune system as "foreign antigens". These phenomena all point to a common possibility - the recognition of nascent antigens generated by excessive mutations by the body's own immune system is an important prerequisite and key to the effectiveness of anti-PD1/PD-L1 immunotherapy. 3. Insights from other effective tumor species: This association of hypermutation with immunotherapy efficacy is not a coincidence, as similar phenomena have been observed in previous studies of CTLA-4 antibody for melanoma and PD-1 antibody for NSCLC, i.e., hypermutated tumors respond better to immunotherapy, with melanoma due to UV induction and NSCLC due to smoking induction, making both tumor species Both tumor types are hypermutated, and these are the two tumor types with the best efficacy against PD-1/PD-L1 immunotherapy. Combining these points, the investigators hypothesized that MMR mutations may be associated with anti-PD-1 immunotherapy because of the low percentage of dMMR/MSI-H in patients with advanced CRC (less than 5%), a percentage similar to the percentage of mCRC patients benefiting from immunotherapy; and because microsatellite instability due to dMMR makes somatic mutations more likely to occur within the tumor, with mutations The number of genes was 10 or even 100 times higher than in pMMR (MMR normal) tumors. Finally, further analysis revealed that the only case of intestinal cancer that had CR after anti-PD-1 immunotherapy was indeed of the MSI-H phenotype (2012 Clinical Cancer Research), and that PD-L1 expression was detected on the surface of lymphocytes and macrophages infiltrating around the tumor. So, a great hypothesis arose that there was probably some intrinsic link between MMR and anti-PD-1/PD-L1 therapy. What happened next was a natural progression, as researchers began to confirm this hypothesis with trials, which led to the phase II clinical study we see today. How does MMR affect immunotherapy? In fact, the association between dMMR and the immune system is not a figment of the imagination, nor is dMMR activation of the immune system a completely new concept. Pathologically observed dMMR colon cancer patients are often associated with increased lymphocytic infiltration and a cytokine-rich tumor microenvironment, resulting in a specific pathological phenomenon known as MSI-H-like pathology. This is thought to be a specific immune response to the tumor that accompanies the MMR mutation, which explains the relationship between dMMR and the immune system, and has been used for a long time to This theory has been used for a long time to explain the better prognosis of early-stage bowel cancer with dMMR. How do MMR mutations make the tumor a target of the immune system? As mentioned earlier, MSI due to MMR mutations causes tumors to produce a large number of somatic mutations, which in turn produce a large number of neoantigens that can be easily recognized by the immune system. However, the recognition of dMMR-induced neoantigens by the immune system is only the first step of antitumor immunity, and whether the immune system can be further activated and exert anti-tumor effects is governed by many factors. Recently, it has been found that the tumor microenvironment can express many ligands related to immune monitoring sites, such as PD-1, PD-L1, CTLA-4, etc., so that the immune microenvironment activated by dMMR is disturbed by inhibitory signals, and therefore is in a "stagnant" state, just like a high-speed train with the "brake" applied. The reason why PD-1/PD-L1 is called the immune monitoring point is that the activation of this pathway can inhibit the function of activated T cells, which is like a "brake"; anti-PD-1/PD-L1 treatment can release the immune suppression of T cells, which is equivalent to releasing the "brake", so that the immune system can be fully activated and finally achieve the attack and clearance of tumor cells. Up to this point, the association between dMMR and immunotherapy may be realized through the following processes: the microsatellite instability caused by dMMR induces more gene mutations, thus generating nascent antigens; these nascent antigens are more easily recognized by the body's own immune system due to structural abnormalities and initiate anti-tumor immunity; the immunosuppressive factors in the tumor microenvironment activate the PD-1/PD-L1 pathway of T cells, resulting in the suppression of T cell activity; and the immunosuppressive factors in the tumor microenvironment activate the PD-1/PD-L1 pathway of T cells. Blocking the PD-1/PD-L1 pathway can release the immunosuppressive state, allowing the immune system to attack the tumor cells and finally achieve the clearance of tumor cells. Of course, the relationship between MMR and immunotherapy may be more complicated than we think. From the available research data, this is the first gene alteration that has nothing to do with target expression amplification, upstream or downstream. It is not the MMR itself that plays the role of target or gene modification or immune modification. The key that can initiate the whole immune system to recognize the tumor is those new mutations (neoantigens) that arise subsequently, so, from this perspective, the MMR mutation-MSI/H, plays a role of immune stimulation, perhaps the first level of the cascade response, is the trigger, and there is nothing more for her to do subsequently. It can be understood that MMR helps to screen people who are effective for PD1 treatment, and it can be understood that after MMR of precision immunotherapy guided by genotyping, how to find enrichment means for immunotherapy? As a new type of treatment, immunotherapy is not applicable to all tumors and all patients, so how to enrich the effective population is the next problem we face. From the analysis of available data, the MMR mutation well modifies the immune status of the tumor, making it easier to be recognized by the body's immune system. This is only well responded in this study: firstly, the same disease, advanced colorectal cancer, can be inferred from the clinical efficacy that the immune modification of the tumor by dMMR and pMMR is completely different; secondly, while other dMMR tumors included in this study, besides CRC of dMMR, also have good efficacy against PD-1 treatment, these tumors include endometrial cancer, gastric cancer, bile duct cancer and These tumors included endometrial, gastric, bile duct, and small bowel cancers, all of which are lynch syndrome-associated carcinomas, suggesting that these diseases, although of different origins, are effective against the same treatment modality due to the commonality of dMMR at the genetic level. However, the incidence of dMMR is low in other malignancies such as melanoma and NSCLC, and the high effectiveness of these tumors against PD-1/PD-L1 therapy clearly cannot be explained by dMMR. Although a correlation between the number of mutations and efficacy has also been observed in melanoma and NSCLC studies, suggesting that de novo antigens generated by mutations may be a potential predictor of efficacy of immunotherapy. Clearly, there must also be an immune modification mechanism behind this that is different from that of MMR. Similarly, in pMMR intestinal cancer and a large number of other cancers that have failed to respond to current immunotherapy, exploring better immune modification mechanisms is the key to unlocking the door to successful immunotherapy. The next issue is that MMR mutations are an early molecular event, rare in mCRC, and the incidence of dMMR in colorectal cancer decreases progressively with stage: around 15-20% in stage II, 5-10% in stage III, and <5% in stage IV; in a study reported at the 2012 ESMO Congress that included 3063 cases (including CAIRO, CAIRO2, COIN, and In a meta-analysis of 3063 patients with advanced colorectal cancer (including the CAIRO, CAIRO2, COIN and FOCUS studies) reported at the 2012 ESMO Congress, the incidence of dMMR was only 5,0%. Interestingly, this study found that patients with dMMR had a worse prognosis compared to pMMR, which is the exact opposite of the better prognosis of dMMR in stage II bowel cancer. This information suggests that, first, we do not know enough about the relationship between MMR and bowel cancer and immunotherapy. Second, the proportion of dMMR is very small, so where does the road lead for the 95 percent of patients with pMMR bowel cancer? When will the emerging immunotherapy be available to the general public? Regardless, the initial success of dMMR-based anti-PD-1 immunotherapy is a glimmer of hope, and if proven, it will be a great blessing for patients, even though it is only applicable to 5% of patients. More importantly, the dMMR research story certainly provides new ideas for the future development of immunotherapy. Just like the story of ALK gene rearrangement-positive patients benefiting from crizotinib treatment, dMMR-based anti-PD-1 immunotherapy may be a major advancement in the treatment of advanced bowel cancer after RAS gene-based individualized targeted anti-EGFR therapy, which will be the first step in the new era of "precision medicine" and lead to the spring of precision colorectal cancer treatment!