The upsurge of research and development of Immuno-Oncology (IO) therapeutic drugs has been in full swing in recent years, which dominates the commanding point of public opinion in the field of drug research and development. After PD1/PD-L1, who can become the next classic pathway for tumor escape?
General situation of Immuno-Oncology (IO) therapy.
IO is another new treatment after surgery, radiotherapy and chemotherapy. In recent years, it has been highly concerned because IO treatment has completely changed the way of traditional drug treatment, it plays a role in killing tumors by activating the body’s own immune system. Since the fortress was breached from the inside, it is necessary to prescribe the right medicine, rearm the defeated immune system and attack the tumor again. However, its development history is not plain sailing, but has been snubbed for a long time before it has gradually stepped onto the historical stage, following the listing of PD1/PD-L1 antibodies in a number of pharmaceutical enterprises. There has been a blowout development in a variety of ways of Immuno-Oncology.
IO treatment begins to enter the era of “a hundred schools of thought contend”
Following the research on global tumor immunity conducted by the Cancer Institute in 2017, the results of the continued statistical survey by TANG show that 3394 active agents appeared in all stages of pipelines in 2018, an increase of 67 percent over 2017. It is suggested that Immuno-Oncology begins to enter the era of “a hundred schools of thought contend”, and may play an irreplaceable role in tumor therapy in the future.
These active agents include T cell immunoregulation, other immunoregulation, cancer vaccine, cell therapy, oncolytic virus and CD3 targeting double antibody. IO therapy is working in a variety of forms, such as other immunoregulators, cancer vaccines, and oncolytic viruses, and the proportion of Immuno-Oncology has increased to the 2018 research and development pipeline.
T cell immune-regulation.
At present, T cell immunomodulation is the hottest topic in major molecular drug conferences, with PD1/PD-L1 monoclonal antibodies and CTLA-4 monoclonal antibodies as the representative of immune blocking antibodies. In addition to the international Big Pharmas such as BMS, BSD, Roche and AZ, which were listed on the PD1/PD-L1 antibody a few years ago, the PD1/PD-L1 of the other Pharmas, which is familiar to all of us from 2018 to 2019, has also been listed one after another.
In addition to antibodies to PD1/PD-L1, other macromolecules on T cells, agents, which may be involved in escape immunosuppressive receptors and immune costimulatory receptors, are also being carried out in various clinical trials. It includes double antibodies that block and activate two different receptors.
Cell therapy.
Since 2017, when the two CD19-CART models of Novartis and Kite (Kymriah and Yescarta) were approved for sale, cell therapy has also been blowing a dazzling wind. Compared with 2017, cell therapy activeagents increased by 113% in 2018, the largest increase among all kinds of Immuno-Oncology methods. From this, we can also see the obsession and pursuit of new immunotherapy among major drug companies. We will strive to take the lead in opening up our own world in new fields.
Cell therapy, in addition to T cells fitted with the GPS device, other immune cells are also trying to be targeted and activated, at the ASCO conference in Chicago in early May 2019, Several drug companies have shown that CTL cell therapy, TIL cell therapy and DC cell therapy have produced a good response in different tumor patients in the early clinical stage, and we also expect these cell therapy to give us more surprises in the middle and later stages of clinical practice.
CD3 targeting double antibody.
At present, there are only two CD3 targeted antibodies on the market worldwide, catumaxomab and blinatumomab, so this category of immunotherapy needs to be further filled. As can be seen from the global R & D pipeline in 2017 and 2018, the number of R & D routes increased by 98 percent in 2018, but most of these treatments are in preclinical and clinical phase I, and rarely advance to clinical phase II.
New target drugs
According to statistics, the global IO R & D pipeline in 2018 covered 417 targets, an increase of 50 percent over 2017. For example, JAK1 is now a new target for IO therapy in 2018. Fred Hutchinson Cancer Research Center has launched a Phase I clinical trial (official title: A Pilot Study Examining the Impact of the JAK1 Inhibitor INCB39110 On the Sarcoma Immuno-Oncology Microenvironment).
In addition, it is reported in literature that many new IO therapeutic targets are in line. In a short period of one year, the sudden increase in new targets not only shows that the industry has a wave of enthusiasm for Immuno-Oncology, but also reflects the passion of various research and development drug companies for First-in-class drugs, and all want to be the No.1, which form a differentiated competitive advantage against PD1/PD-L1 monoclonal antibodies. After PD1/PD-L1, who can become the next classic pathway for tumor escape? Scientists are eager to see through their eyes.
In 2018, the top three targets of Immuno-Oncology were CD19, PD1 and PD-L1, and the corresponding therapeutic methods of these three targets were cell therapy and T cell targeted immunoregulation. Based on the clinical effects of CAR-T cell therapy and PD1/PD-L1 monoclonal antibody therapy, it may still be the mainstream of Immuno-Oncology in the next few years, of course, we also look forward to the next star target.
Conclusion
A large number of IO drugs represented by PD1/PD-L1 monoclonal antibodies have demonstrated this principle and have had a lasting response to some patients in clinical trials of melanoma, Hawking’s lymphoma, lung cancer and renal cell carcinoma. In addition, the current double antibodies that bridge killer T cells and tumor cells and release brakes, pedal throttle to activate T cells have also been put on the agenda, IO treatment has great potential in the future.
On the other hand, drug development has always been a combination of challenges and opportunities. The failure of phase III clinical trials of IDO1 inhibitors last year and the failure of phase III clinical trials of PD1/PD-L1 monoclonal antibodies (including “K” and “O”) this year have once again sounded the alarm about the risks of IO drug development. Therefore, the exploration and thinking of tumor immune mechanism and the screening and detection of biomarker in clinical trials may be helpful to guide the selection of clinical patients and the rational and continuous use of drugs. It is also an important factor related to the success or failure of drug development.