Long-term survival of patients with advanced-stage carcinoma is still an area where research is far from successful. In the field of melanoma, the approval of ipilimumab in 2011 has made a novel immuno-oncology agent available. This therapeutic approach also raises hopes for other metastatic cancers – different agents are being tested in different settings.
(lg) For patients with advanced cancer, there are still no optimal treatment options. Despite the three main pillars of treatment (surgery, radiation, and cytotoxic or targeted therapies), survival remains poor for many patients with advanced solid tumors. For metastatic lung, colorectal, renal, and melanoma, 5-year survival rates range from 3.9% to 16% [1]. When a cure is no longer possible, the stated goal of research is to achieve long-term survival if possible. Approvals such as abiraterone in mCRPC [2], pertuzumab, trastuzumab, and docetaxel in mBC [3], and regorafenib in mCRC [4] (2011, 2012, and 2013 in Switzerland) have already significantly improved median overall survival in many patient groups. However, the above survival rates show that there is still much to be done.
A relatively new therapeutic approach, known as immuno-oncology, is now breaking new ground. This approach uses the natural ability of the body’s immune system to fight cancer. Consequently, in contrast to conventional therapies, the tumor is not directly targeted [5]. The basis for this is the patient’s immune response, which in principle is always the same, regardless of whether it is a flu-like infection or cancer. Normally, the immune system reacts to tumor cells by means of B and T cells, as these can be distinguished from healthy tissue on the basis of foreign or unknown antigens. The cells are destroyed or at least controlled by the immune response. Cancer cells now circumvent the destructive response of the immune system by bypassing signaling pathways. Either no antigens are represented on the surface or those that the body classifies as “normal”. Further, cancer cells can release chemicals that suppress an immune response [6,7]. The goal of immuno-oncology is, among other things, to influence the very same signaling pathways that tumor cells use to evade their recognition and destruction.
Ipilimumab (Yervoy
®
) is a fully human monoclonal antibody that leads to a non-specific disinhibition of cytotoxic T lymphocytes via binding to the transmembrane protein CTLA-4, thereby enhancing the cellular immune response. It is approved for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy. Survival rates improved significantly with treatment, with 1- and 2-year survival rates of 46 and 25%, respectively, compared with 25 and 14% in the comparator arm on standard therapy [8].
Ipilimumab is administered intravenously every three weeks and only needs to be used four times. However, treatment requires close monitoring of side effects. In most cases, these are autoimmune-mediated reactions such as colitis, hepatitis, and hypophysitis [9]. Recognizing side effects is not trivial, as attention must also be paid to nonspecific signs such as fatigue, headaches, or changes in mental status. Thus, medical monitoring and special knowledge is required here: patients should be instructed precisely and sensitized accordingly. However, severe side effects occur in only 10% of cases. As a countermeasure, high-dose cortisone is used, which should be phased out over a long period of time and accordingly very slowly. Good consultation and coordination with the primary care physician is advised here.
What further research in this area still has to offer? Preliminary studies with nivolumab have also shown encouraging results in NSCLC (non-small cell lung cancer), melanoma and RCC (renal cell carcinoma), for example. Nivolumab is a PD 1 antibody. PD 1 is a 55kD type 1 transmembrane protein and belongs to the CD28 family of costimulatory T cell receptors, similar to CTLA-4. The combination of nivolumab and ipilimumab is also currently being tested in the treatment of melanoma. In addition to melanoma, other areas of BMS in which the two substances mentioned as well as lirilumab are currently being tested in clinical trials are cancers of the gastrointestinal and urogenital tracts, the lung and in hematological applications.
A major advantage of immuno-oncology is that by mobilizing the body’s own immune system after an induction phase of the appropriate drug, permanent treatment is probably not necessary, wherein there is a chance of long-term stable disease.
Source: Pre-ASCO Press Conference: Immunooncology, May 23, 2014, Zurich.
Literature:
- Surveillance, Epidemiology and End Results (SEER) Program. http://seer.cancer.gov.
- De Bono, et al: NEJM 2011; 364: 1995-2005.
- Baselga J, et al: NEJM 2013; 366: 109-119.
- Grothery A, et al: Lancet 2013; 381: 303-312.
- Borghael H, et al: Eur J Pharmacol 2009; 625: 41-54.
- Drake CG, Jaffee E, Pardoll DM: Adv Immunol 2006; 90: 51-81.
- Frumento G, et al: Endocr Metab Immune Disord Drug Targets 2006; 6(3): 233-237.
- Hodi FS, et al: NEJM 2010; 363: 711-723.
- Hanaizi Z, et al: Eur J Cancer 2012; 48(2): 237-242.
InFo Oncology & Hematology 2014; 2(6): 2
