The idea of using immune system to treat cancer is not new, but stays in a concept level with little clinical progress for long. However, with the exciting clinical results of BMS’s ipilimumab in melanoma patients, immunotherapy receives more and more attention. In the 2012 American Society of Clinical Oncology (ASCO) annual conference, the Phase I/II results of BMS-936558 in metastatic Non-small-cell lung cancer (NSCLC) were presented, leading the immunotherapy into a new era. BMS-936558 is fully human mAb blocking the programmed death (PD-1) on activated T cells. The PD-1 receptor is an inhibitory T-cell receptor that limits the immune response after binding with its ligand PD-L1 and 2.  By over-expressing PD-L1, tumor cells escape immune system monitor.

In the Phase I/II trials, both efficacy and tolerability of the new anti-PD-1 mAb were tested. A total of 75 stage IV NSCLC patients who had received at least one systemic treatment were enrolled in the study.  After 12 cycles of mAb treatments, 19 patients showed different level of response and the overall response rate is as high as 18%.  More impressively, BMS-936558 achieved 36% overall response rate in squamous patients. Anti-PD-1 mAb has general acceptable toxicity, with grade 3-4 adverse events (AE) rate of 8%. The most common side effects include fatigue (17%) and nausea (11%). However, 2 patients died of treatment related pneumonitis.

The results of PD-1 immunotherapy are one of the biggest achievements for NSCLC treatment in recent years, especially for the 2^nd and 3^rd line therapy. Traditional chemotherapy usually has a 5-7% response rate, which is 1/3 of what Anti-PD-1 achieved.  This clearly shows the therapeutic potential of PD-1. Importantly, PD-1 seems to have better efficacy in squmaous patients whom have very limited drug choice. Meanwhile, PD-1 only has function when T cells are activated and in the inflammatory site. It has favorable side effects profile compared to CTLA-4 targets, which have much broader effects on T cell activity. The only concern physicians have are the 2 drug related peunomotitis death. It is still not clear that such severe toxicity is a general effects for all PD-1 target, or specific to Bristol’s antibody. BMY has already committed for further development and all these questions need to be answered in the follow-on trial. Roche and GSK also have their own anti-PD-1 products under early stage development for different indications.

Roche’s “armed antibody” becomes the other shining star in this years’ ASCO. Trastuzumab-MCC-DM1 (T-DM1) is the antibody-drug conjugate consisting of Roche’s major product trastuzumab (Herceptin) linked to cytotoxin metransine (DM1). After binding with HER-2 receptors, T-DM1 is internalized and then  delivers metansine specifically to tumor cells. During the plentary session on June 3rd, Dr. Blackwell reported the interim Phase III of T-DM1 in metastatic breast cancer patients.

A total of 991 Her2+ patients who had been previously treated with Trastuzumab and Taxane were enrolled in the study. They received either T-DM1 or Tykerb/Xeloda (TX) combination therapy.  T-DM1 successfully delayed tumor progression (PFS) by an average of 9.6 months, comparing to 6.4 month in TX combination. More importantly, T-DM1 significantly improves the overall survival rate. After 24 months of the study, 64% patients in T-DM1 arm remain alive, while the median survival of TX combination is only 23 months, which has already showed significant differences. On the safety side, T-DM1 is also well tolerated. The grade 3-5 side effects happen in 40.8% of patients, 17% lower compared to TX combination. This favorable safety profile may be due to the high targeted chemotherapy agent delivery. 

In the last a few years, there have been significant shifts towards next generation mAbs platform, antibody drug conjugates are one of them. Through collaboration and licensing, Roche, Abbott and Novartis all have their own technology platform and mAbs under clinical development. The success of T-DM1 will certainly become an “accelerator” to this technologies and we expect to see more clinical results in the near future.

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