- How immunotherapy and targeted therapy are changing gastrointestinal cancer treatment
- Stomach Cancer Immunotherapy - Cancer Research Institute (CRI)
- The link between viruses and cancer
In the study , published Dec. Manish Shah , the Bartlett Family Associate Professor in Gastrointestinal Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, and co-investigators report clinical evidence that an immunotherapy drug called pembrolizumab shows promise for treating patients whose disease progressed after receiving two types of chemotherapy cocktails.
This is a heavily pretreated patient population where further treatment has not been proven to work. Pembrolizumab belongs to a class of drugs that turns off the brakes on the immune system by blocking the interaction between a molecule on immune cells called PD-1 and a molecule on tumor cells called PD-L1. The single-arm, phase 2 clinical trial enrolled patients from 57 sites in 10 countries across the globe.
Treatment with pembrolizumab led to regression of esophageal cancer tumors in 10 percent of all patients and in 14 percent of patients, or 8 of 58, whose tumors expressed the PD-L1 protein. Although responses were pronounced in patients with PD-L1—positive tumors, the investigators observed antitumor activity regardless of PD-L1 status, suggesting that pembrolizumab could be effective in a broad range of patients.
Among the patients who did respond to treatment, some have been without any progression of their cancer for more than a year, which Dr. Metastatic esophageal cancer is a fatal disease with overall survival ranging from 10 to 12 months. Initial treatment, known as first-line therapy, calls for conventional chemotherapy, which is largely used to relieve pain, and has sparse evidence of long-term benefit.
Studies have shown that LAG-3 can be used as a potential immune marker [ 33 ]. Vaccine activates immune system against cancer and promising results in cancer vaccines have been obtained. Tumor-specific T cells are activated and expanded to produce a permanent anticancer effect. Previous studies have evaluated the safety and efficacy of this approach in patients with GC [ 34—38 ]. Vaccination with DCs has been examined as a tool to stimulate immunity for the treatment of cancer patients.
DC has a promising role in cancer vaccination, as determined by clinical trials. However, many issues remain unsolved regarding the design of the most effective vaccine now. First, RNA vaccines only need to transfect into cytoplasm.
How immunotherapy and targeted therapy are changing gastrointestinal cancer treatment
This means, they would not integrate into cell genome which has no potential to become an oncogenic element. Second, RNA is easily isolated from a limited tumor sample. RNA can be amplified by several technologies such as polymerase chain reaction. This makes large amounts of patient-specific antigens to be easily found and attacked by T lymphocytes, hence, immune responses against tumor are guaranteed [ 42 ].
Moreover, RNA vaccines are an attractive option in cancer immunotherapy because these vaccines are not human leukocyte antigen HLA restricted, so RNA vaccines are safe for and well tolerated by cancer patients [ 43 ].
Because of above reasons, there are an increasing number of researchers paying attention to RNA vaccines. Adoptive cell therapy has shown its ability of inducing partial or complete cancer regression. T cells were engineered by multiple ways such as expressing particular T-cell receptors or chimeric antigen receptors CARs to directly go against diverse target antigens. Adoptive cell therapy has shown promising outcomes against GC in several clinical trials [ 45 , 46 ].
As a result, significant longer OS was observed in the treatment group than in the control group who only received conventional therapy.
High-throughput technologies, especially NGS, have made it possible to highlight the entire mutation landscape in individual tumors [ 48 ]. Therefore, it is important to assess the expression level of PD-L1 in evaluating the prognosis of GC patients. However, upregulated PD-L1 expression is also associated with more chances of disease progression and poorer survival [ 53 , 54 ]. The situation is clear that using select checkpoint inhibitors in certain subtypes of GC cases may be more likely to achieve success than others.
However, because of the limitation of basic knowledge of micro-immune environment and checkpoints, further studies to optimize immunotherapy approaches in GC are needed. Genome editing is the insertion, deletion or replacement of DNA at a specific site in the genome of an organism or cell.
There are a number of recognized gene editing methods [ 55—57 ]. With endeavors of researchers in the whole world, the genome-wide specificities should be further improved, and the CRISPR-Cas9 system should become a more preferable technology that can be applied in all fields of life sciences. Gene therapy will be a big evolution in GC and genetic diseases. With the further insight in GC biology and with improvement of high-throughput molecular technologies, more and more useful TSAs and immunotherapy checkpoints can be identified.
Eventually, GC patients suitable for immunotherapy can be selected. In this article, we reviewed the useful checkpoint inhibitors, vaccine therapy and genome editing in GC. Although, so far, CAR engineering therapy has not been performed in GC, other immunotherapy clinical trials, as stated above, give us the confidence and hope for immune treatment in GC. Many drugs for GC are still in the early stage of development. Hence, several issues must be addressed.
First of all, high heterogeneity of GC makes it difficult to screen typical biomarkers. Identifying more biomarkers in an accurate but rapid manner and mobilizing tumor reactive lymphocytes in patients should be the focus of future studies. Secondly, a complex of GC immune microenvironment needs to be entirely understood to identify the GC subgroup that is more sensitive to immunotherapy.
For example, tumor-associated macrophages TAMs are rich in tumor environment. TAMs seem to be composed of a few distinct functional subgroups that share features of both M1 and M2 macrophages. It is still not clear how TAMs interact with tumor metastasis, angiogenic and immune suppression. But, it is a likely perfect target for cancer immunotherapy. Moreover, maintain the safety and avoid toxicity of immunotherapy present as another issue.
Finally, clinicians need to learn how to assess the response of immunotherapy. Response evaluation criteria in solid tumors response might not be enough to evaluate immune response. In addition, there is still not a globally adopted standard in GC immunotherapy. From our perspective, further investigation and better understanding of functions of immune system in various kinds of cancer would help optimize immunotherapy strategies in the future.
Stomach Cancer Immunotherapy - Cancer Research Institute (CRI)
Key Points Immunotherapy is considered as an innovative approach for GC. New immune checkpoints regulators could become more important with the understanding of immunogenomics of GC.
The current review article was partially funded by Item of national natural science foundation item number: , China. Qingfang Zhao is a postgraduate student at the Zhengzhou University. Her main research deals with basic and clinical study of digestive tract tumor. Her main research interests are long noncoding RNAs in cancers, especially gastric carcinoma. Lulu Guan is a master degree student in the Zhengzhou university.
The link between viruses and cancer
Her main research focuses on identification of miRNAs associated with gastric cancer. His main research interest focuses on identification of non coding RNAs associated with gastric cancer. Saiqi Wang is a research associate, The First Affiliated Hospital of Zhengzhou University, her main research interest is metastasis and chemoresistance in cancer. His main research interest focuses on identification of non coding RNAs associated with breast cancer. Xiaobing Chen is a professor of Hennan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, he is a doctoral supervisor, his main research interest is developing novel biomarkers for diagnosis and prognosis of gastric cancer.
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Volume Article Contents. Cancer vaccine. Adoptive cell therapy. Immunogenic genomics. Genome editing.
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Immunotherapy for gastric cancer: dilemmas and prospect Qingfang Zhao. Zhengzhou University, Zhengzhou, China. Oxford Academic. Google Scholar. Liang Cao. Lulu Guan. Liangyu Bie. Saiqi Wang.
Bojian Xie. Xiaobing Chen. Corresponding authors. Xiaokun Shen. Feiling Cao. Cite Citation. Permissions Icon Permissions. Abstract Gastric cancer remains the second most common cause of cancer-related death worldwide. Search ADS.