Release date: 2017-10-10
In recent years, the success of immunotherapy is subverting the entire field of cancer treatment, the most representative of which are CTLA-4 antibodies, PD-1 antibodies and PD-L1 antibodies. As the most popular anti-tumor drug in recent years, it has benefited more and more patients: melanoma, non-small cell lung cancer, head and neck cancer, renal cell carcinoma, Hodgkin's lymphoma, bladder cancer, colorectal cancer. , stomach cancer...
Immunological checkpoint inhibitor (image source candlenetwork.com)
At present, a variety of checkpoint inhibitor drugs have been approved for marketing. The reason why these drugs are so popular is because it provides hope for patients with advanced cancer, after all, it has effects on a variety of tumors. However, it is worth noting that, although effective, the effectiveness of these drugs for most solid tumors is only 20%-40%. Therefore, how to expand the patient population benefiting from this tumor immunotherapy is one of the most popular research directions in the field, and immune combination therapy is considered by many researchers as the ultimate means to solve this problem.
1. CTLA-4 antibody combined with oncolytic virus
Recently, global biopharmaceutical giant Amgen (Anjin) announced the latest clinical data of an oncolytic virus combined checkpoint inhibitor CTLA-4 antibody in the treatment of melanoma. The results showed that this combination therapy doubled the overall response rate of patients compared to CTLA-4 antibody monotherapy.
This is a randomized, labelled Phase II clinical trial (Clinical No. NCT01740297) designed to evaluate the onset of oncolytic virus Imlygic (T-VEC) in combination with CTLA-4 antibody Yervoy (Ipilimumab) and Yervoy (Ipilimumab). Efficacy and safety of patients with unresectable melanoma.
ORR (picture source JCO)
A total of 198 patients were enrolled in the study, 98 of whom received combination therapy and 100 received Yervoy (Ipilimumab) monotherapy. The trial data showed that the overall response rate of the combined group was 39% (n = 38/98), whereas the single-agent group had an ORR of only 18% (n = 18/100). Among them, 13 patients in the combined group were completely patients, and 7 patients in the single drug group were completely relieved.
PFS (picture source JCO)
In addition, with regard to the safety of this combination therapy, another set of previously conducted clinical trials ending in dose-limiting toxic events indicated that no dose-limiting toxicity events or new safety warnings were found. Therefore, the combined treatment did not reduce the dose. Although all patients had at least one adverse event (AE) during the course of treatment, none of the patients stopped the treatment and all side effects were tolerated.
Adverse events (picture source JCO)
Taken together, this study reached its primary clinical endpoint. And for melanoma patients, the overall response rate of immunoconjugate therapy is significantly higher than Yervoy (ipilimumab) monotherapy, and has stronger anti-tumor activity.
This is not the first time that oncolytic virus joint checkpoint inhibitors have shown strong anti-tumor potential in clinical practice. Just last month, the internationally renowned journal Cell also just published PD-1 antibody Keytruda and dissolved. A large clinical data from the combination of tumor virus therapy Imlygic (T-VEC) in patients with melanoma.
2. PD-1 antibody combined with oncolytic virus
Clinical results (Source: Cell)
In a multicenter Phase 1b clinical trial involving 21 patients with metastatic melanoma, the researchers evaluated the safety and efficacy of the combination of the PD-1 antibody Keytruda and the oncolytic virus Imlygic (T-VEC). The results showed that the combination therapy increased the response rate of these patients to 62% and was much higher than the expected response rate (usually about 35%-40%) for treatment with Keytruda or T-VEC alone.
T cell infiltration in the tumor (Source: Cell)
At the beginning of the trial, patients received two intratumoral injections of T-VEC at intervals of 3 weeks. From week 6, patients received the same dose of intratumoral injection of T-Vec and intravenous injection of 200 mg Keytruda every two weeks. It was found that at week 6 (before the start of Keytruda treatment after 2 T-VEC treatments), T cells infiltrated most tumors. At week 30, T cells remained in this area, but most of the tumor cells disappeared.
In addition to the surprisingly significant increase in effectiveness, the safety of this combination has been confirmed. Compared to any of the monotherapy treatments, there is no major adverse event in the combination therapy, but it still needs a larger scale. Clinical trials to determine its efficacy.
Currently, this multicenter Phase III clinical trial is underway and will include 660 patients from more than 100 institutions to further evaluate PD-1 antibody Keytruda combined with oncolytic virus T-VEC in patients with metastatic melanoma. Effectiveness. (Clinical ID: NCT02263508)
Based on the excellent data of the above two clinical trials, Xiao Bian is very curious why the researchers chose the oncolytic virus as an allegorate of immune checkpoint inhibitors.
3, oncolytic virus perfect assist tumor immunotherapy
With the prevalence of immunotherapy, especially "immunoassay point inhibitors", the research community has recently developed a new classification of tumors: "hot tumors" and "cold tumors." If there are many immune cells that recognize cancer cells around the cancer cells, then the tumor is a "hot tumor" and vice versa.
The reason why researchers care about the hot and cold of cancer cells is because the now-important "immunization checkpoint inhibitors" have a very good effect on a large number of "hot tumors", while the "cold tumors" are basically ineffective.
It is well known that immunosuppressive agents initiate anti-cancer immune attacks by affecting different types of T cells. If there are no T cells in the tumor, then these inhibitors will not have a good therapeutic effect.
Oncolytic virus (picture source turnstonebio.com)
The oncolytic virus refers to a virus that has the ability to invade cancer cells. When they invade cancer cells, they will replicate in large amounts and cause cancer cells to rupture and die during replication. The end result is that a large number of oncolytic viruses form an infection against cancer cells, killing cancer cells. It is also worth noting that the oncolytic virus not only directly destroys the tumor cells, but also stimulates the host's anti-tumor immune response.
According to the mechanism of action of oncolytic viruses, the infection of tumor cells by oncolytic viruses can induce a large number of immune cells to invade tumors. Therefore, by intratumoral injection of oncolytic virus, the length of the oncolytic properties of the checkpoint inhibitors depends on the shortness of T cell invasion. It is possible to convert "cold tumors" into "hot tumors" to enhance the anti-tumor activity of immunotherapy.
About Imlygic(T-VEC)
In October 2015, the US FDA approved Amgen's first oncolytic virus, Imlygic (T-VEC), for the treatment of melanoma. In December of the same year, it obtained EU CHMP (European Pharmaceutical Quality Administration Committee for Human Drugs). A license for the treatment of melanoma in the skin and lymph nodes.
Reference source
Http://
Http://
Doi:10.1016/j.cell.2017.08.027
http://ascopubs.org/doi/abs/10.1200/JCO.2017.73.7379
Https://medicalxpress.com/news/2017-09-immunotherapy-combination-safe-percent-effective.html
Source: Medical Maike (WeChat emedclub_com)
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