Immune checkpoint inhibitor

from Wikipedia, the free encyclopedia

An immune checkpoint inhibitor (also immune checkpoint inhibitor ) is a molecule having an immune checkpoint inhibits. In oncology , anti-inflammatory immune checkpoints are blocked. These molecules are used in immunotherapy and are currently only monoclonal antibodies .

properties

11 Hegasy CTLA4 PD1 Immunotherapy.png

The immune system has both costimulatory (activating) and inhibitory (inhibitory) signaling pathways. These regulatory mechanisms influence the strength and intensity of an immune response . Normally, these mechanisms serve u. a. the avoidance of autoimmune reactions . Those signaling pathways with an inhibitory effect are referred to as co-inhibitory immune checkpoints and cause a downregulation of the T cell activation or the T cell effector function. The immune checkpoints with an inflammatory effect are referred to as co-stimulatory immune checkpoints.

Treatment of malignancies with immune checkpoint inhibitors

With regard to tumor diseases , it is known that tumor cells can use these immune checkpoints in order to escape recognition by the immune system ( immune evasion ). This immunosuppressive milieu of some tumors is generated by the production of inhibitory cytokines , the recruitment of immunosuppressive immune cells and the upregulation of co-inhibitory receptors , the negatively regulating immune checkpoints . This knowledge led to the development of checkpoint inhibitors which “switch off” immunosuppressive signals by breaking a receptor-ligand bond. In this way, the immune system of the organism can recognize and fight the degenerate cancer cells.

Treatment with checkpoint inhibitors has revolutionized oncology in recent years. Metastatic tumors such as melanoma , the course of which has so far been little influenced, have become treatable. For other tumors, such as NSCLC (non-small cell lung cancer), treatment with checkpoint inhibitors could replace chemotherapy with many side effects, and in some cases even surpass it. However, checkpoint inhibitors can also have significant side effects. The partial deactivation of the "friend-foe recognition" of killer cells can lead to life-threatening autoaggressive diseases, e.g. B. the lungs, the liver or the kidneys. Numerous studies on treatment with checkpoint inhibitors have been ongoing since the beginning of the 2010 years . Therefore, the evidence of effectiveness and the approval status of the preparations can change at short notice. The following drugs are used or tested:

effect Pharmacon Trade name Manufacturer Malignancies
CTLA-4 inhibitor Ipilimumab Yervoy Bristol-Myers Squibb Melanoma, renal cell carcinoma
Tremelimumab not yet approved Medimmune ( Astra Zeneca ) Testing with various entities
PD-1 antibody Nivolumab Opdivo Bristol-Myers Squibb malignant melanoma, NSCLC , renal cell carcinoma , Hodgkin's lymphoma , hepatocellular carcinoma , ENT squamous cell carcinoma , urothelial carcinoma , colorectal carcinoma
Pembrolizumab Keytruda Merck Sharp & Dohme malignant melanoma, NSCLC, renal cell carcinoma, Hodgkin's lymphoma, ENT squamous cell carcinoma, urothelial carcinoma
Cemiplimab Libtayo Sanofi / Regeneron Metastatic or locally advanced squamous cell carcinoma of the skin
Spartalizumab not yet approved Novartis Metastatic melanoma
PD-L1 antibody Atezolizumab Tecentriq Roche NSCLC, renal cell carcinoma, urothelial carcinoma, breast carcinoma
Durvalumab Imfinzi Astra Zeneca Urothelial carcinoma, NSCLC
Avelumab Bavencio Merck KGaA Urothelial carcinoma, Merkel cell carcinoma

The tumors listed in the table were successfully tested. However, this does not mean that they are effective in all cases and that they are approved. The latter can be found in the articles for the individual preparations.

Immune checkpoint inhibitors are z. B. Antibodies against CTLA-4 (ipilimumab), PD-1 (nivolumab) and PD-L1 (atezolizumab, durvalumab and avelumab). After the antibody has been infused, the antibody is bound to these proteins, which act as immune checkpoints. As a result, the cells that carry one of these proteins on the cell surface and bind the antibody are temporarily (or as long as the therapeutic antibody is circulating in the body) attacked by immune cells and removed from the body by macrophages (temporary cell depletion ). These processes lead to an intensification of the immune response against the tumor, so that its strategy of immune evasion is counteracted. Therefore, immune checkpoint inhibitors are used in cancer immunotherapy , including in combination with cancer vaccines .

The PD-L1 antibody avelumab was compared with the VEGF inhibitor axitinib in advanced renal cell carcinoma in the JAVELIN Renal 101 study , a randomized phase III study, with the tyrosine kinase inhibitor sunitinib . A significantly longer recurrence-free survival was achieved with avelumab and axitinib. In patients with PD-L1 positive tumors, the median recurrence-free survival was 13.8 months with avelumab and axitinib and 7.2 months with sunitinib. Even when including the PL-L1-negative tumor cases, equally good results were achieved.

Therapeutic monoclonal antibodies (initially the anti-CTLA-4 antibody ipilimumab and then the anti-PD-1 antibodies nivolumab and pembrolizumab) were developed against these immune-reaction-reducing molecules and initially evaluated in studies on metastatic malignant melanoma . Treatment with these antibodies showed a clinical effect that was not observed in comparison with the usual therapies and also a different side effect profile characterized by autoimmune phenomena .

Nobel Prize for the discovery of immune checkpoints

In 2018, James Patrick Allison and Tasuku Honjo received the Nobel Prize in Physiology or Medicine . Allison and his group at the University of California at Berkeley discovered CTLA-4 and found that this protein weakened the immune response. Allison was able to use a mouse model to show that this mechanism can be used to fight cancer. Tasuku Honjo and his research group discovered that PD-1 has a dampening effect on the immune response. Based on this research, a number of effective drugs for treating cancer have been developed. Honjo recognized that dampening the immune response could also be useful in the case of autoimmune diseases , allergies and transplant rejection .

Applications

Immune checkpoint inhibitors are currently used in the treatment of melanoma , non-small cell lung cancer, and clear cell renal cell carcinoma and squamous cell carcinoma.

literature

  • Patrick Terheyden, Angela Krackhardt, Thomas Eigenler: System therapy of melanoma. Use of immune checkpoint inhibitors and inhibition of intracellular signal transduction. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f., (July 22) 2019, pp. 497–504.

Individual evidence

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