The 39th Annual Meeting of the European Society of Medical Oncology (ESMO2014) was held from September 26 to 30, 2014, and three keynote lectures were given by Prof. Carl June from the University of Pennsylvania, Prof. Michael Stratton from the Sanger Institute, a leading genome sequencing research center in the UK, and Prof. René Bernards and Prof. Jan HMSchellens from the Netherlands Cancer Institute. Bernards and JanHMSchellens from the Netherlands Cancer Institute, who shared refreshing research results and latest ideas about precision immunotherapy, gene labeling, and rational drug combination therapy. Zhang Xiubing, Department of Medical Oncology, Nantong Second People’s Hospital Achieving Precision Immunotherapy Prof. June said that a multicenter clinical phase II study using CAR-T cells to treat childhood ALL is currently being implemented, and that CAR-T cells may eventually replace bone marrow transplantation if sufficiently long-lasting effects are achieved. Beyond leukemia and lymphoma, modified T cells can be used for other tumors. A large number of CARs targeting different surface molecules are currently under investigation for a wide range of tumors. The beginning of the dream of cancer immunotherapy dates back to Virchow’s description of immune infiltration of tumors in 1863. This was followed by a long research journey that culminated in the approval of the US Food and Drug Administration (FDA) in 2010-2011 for Sipuleucel-T, an autoimmunotherapy drug for prostate cancer, and ipilim umab, a fully human monoclonal antibody for melanoma. Professor June noted that there have been 3 major advances in cancer immunotherapy in recent years. ipilimumab showed overall survival (OS) benefit in melanoma in 2011. blockade of programmed cell death molecule 1 (PD-1) and PD ligand 1 (PD-L1) showed benefit in melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma from 2011-2014. From 2011 to 2014, chimeric antigen receptor-modified T cells (CAR-T) showed sustained disease remission in B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). The mechanism of action of CAR-T cells is the redirection of specific T cells. The use of gene transfection technology allows T cells to express CARs, resulting in new antigen specificity and the ability to kill tumor cells in an antigen-dependent manner, which is advantageous over the cytotoxic effects of T cells, with the additional advantage that T cells are not cross-resistant to chemotherapy and that their ultimate effect is cytolysis rather than swelling.June et al. studied [New England Journal of Medicine (N Engl J Med 2011, 365:725)] found that DDCART19, a CAR-T cell that targets CD19 and contains the CD137 (co-stimulatory receptor on T cells) and CD3zeta (components of T cell antigen receptor signaling) signaling domains, exists in vivo as a memory CAR+ T cell in addition to its effector (cytotoxic) cell It persists for a long time in the form of memory CAR+ T cells, retaining its anti-CD19 effector cell function. June et al. applied CART19 to treat three patients with CLL, all of whom had advanced incurable leukemia. It was found that each infused CAR-T cell and its progeny could kill more than 1000 tumor cells, thus making CAR-T a “serial killer”. For ALL, a total of 30 pediatric and adult patients have been treated with CART19, with a 6-month OS rate of 78% and complete remission (CR) in 90% of patients. Human immunodeficiency virus (HIV) CD4zeta-CAR is the first CAR to be tested in clinical trials, and studies have shown that 37 of 39 patients infused with CD4zeta-modified T cells were able to remain in peripheral blood mononuclear cells for up to 11 years; and no serious adverse events were detected during follow-up, confirming the safety of genetically modified T cells. Capturing the genetic labeling of human cancer mutation process There are often multiple mutations in the final cancer genome, some of which may occur early but have weak oncogenic effects, while others occur mid- to late-stage but have strong oncogenic effects. Identifying the trajectory of different mutations will help to understand the process of cancer development. Professor Stratton pointed out that a large number of cancer genome sequencing results are available, and the analysis of these genes has given us a lot of information, such as discovering mutated oncogenes, understanding the biological process of cancer development, identifying drug targets, understanding the emergence of cellular subclones and metastases, discovering infectious agents associated with oncogenes, predicting response and regression to treatment, finding DNA that can be detected and monitored early monitoring DNA, and recognizing mutational processes in carcinogenesis. All human cells undergo various mutations throughout their lifetime due to cell division, intracellular DNA replication and reassortment, radiation, exposure to carcinogens such as smoking, and some compounds, but there are also repair mechanisms in human genes that can repair damage and inhibit carcinogenesis on their own. TP53 was one of the first tumor suppressor genes identified, and studies have found six major mutations in TP53 and other genes types: C>T, C>A, C>G, T>A, T>C, T>G. Different major mutation types exist in different tumors, and these mutation types are also associated with different tumorigenic factors. For example, C>T mutations are predominant in skin cancer patients, while UV radiation can cause C>T mutations; C>A mutations are predominant in lung cancer patients, while it happens that smoking can cause C>A mutations. This suggests that people with risk factors may be able to be monitored early for cancer development by testing for mutations. Professor Stratton et al. conducted a study in which 7042 cancer patients suffering from 30 cancer types were analyzed and a total of 4942984 mutations were obtained. The non-negative matrix decomposition method (NMF) was applied to extract the labels of gene mutations and then assess the contribution of each mutation trace to the mutation of cancer genes in each patient and explain its association with tumor epidemiology, gene expression, mutated genes correlation. Their analysis of mutation tags summarized more than 20 different mutation tags, some of which are present in many types of tumors. One of the mutation tags can be attributed to cytosine deamidation upon activation of the APOBEC enzyme family, which is characterized by C>T and C>G substitution mutations located in the TpCpN trinucleotide region. In addition, hypermutated DDkataegis located in small genomic regions are also present in many tumors and are also characterized by mutations consistent with the APOBEC-induced mutations described above, suggesting a potential role of the APOBEC enzyme family in this regard. Overall, analysis of all mutation tags revealed that some were associated with the patient’s age at tumor diagnosis, known mutagenic exposures or DNA stability defects, and many more were due to unknown causes. Further elucidation of the mutational processes represented by these tags can suggest information about tumorigenesis, prevention and treatment. Exploring Rational Drug Combinations With thousands of drugs in development, it is unrealistic to study these drugs in randomized combinations. Instead, studies of intracellular signaling pathways will help find reasonable combinations. Professor Bernards said that previous studies have found that inhibition of BRAF in melanoma and colorectal cancer, which also express BRAF, yielded very different responses, with response rates as high as 81% in melanoma with low expression of epidermal growth factor receptor (EGFR) and only 5.2% in colorectal cancer with high expression of EGFR. Further studies revealed that there is a negative feedback regulation of the BRAF pathway on EGFR, and that inhibition of BRAF leads to activation of the EGFR pathway in BRAF-mutated colorectal cancer patients, whereas concomitant inhibition of EGFR sensitizes BRAF-mutated colorectal cancer cells to BRAF inhibitors. In vivo studies in animals have demonstrated that simultaneous inhibition of EGFR and BRAF can achieve good antitumor effects. Prof. Schellens further presented several studies of BRAF inhibitors combined with EGFR inhibitors in patients with BRAF-mutated colorectal cancer. Clinical phase I results showed that this combination regimen was well tolerated and high antitumor activity was observed, with objective response rates of approximately 30% and disease control rates of approximately 75% to 90%. For KRAS mutated tumors, inhibition of the downstream protein MEK eliminates its negative feedback regulation of human epidermal growth factor receptor (HER)-2 and HER-3, resulting in upregulation of the expression and activity of the latter. Thus, the combination strategy of MEK inhibitors with pan-HER inhibitors for KRAS mutated tumors deserves to be explored in the future. In addition, Prof. Bernards also pointed out that downstream signaling of the receptor tyrosine kinase (RTK) family, such as EGFR and ErbB3, requires PTPN11/SHP2 mediation, and studies have shown that knockdown of SHP2 in colon cancer cells restores their sensitivity to BRAF inhibitors, and similarly to MEK inhibitors. This suggests that SHP2 may be a candidate target for combination therapy with BRAF and MEK inhibitors. Prof. Schellens pointed out that treatment options for novel metastatic colorectal cancer will probably be selected based on the mutation status of BRAF, KRAS, and NRAS.