Immunterapi bröstcancer her2
Below, agents that have been approved by regulatory agencies are briefly described and the advantages and limitations of each strategy are summarized. A monoclonal antibody mAb to p in neu -transformed cell lines was subsequently shown to revert some of the characteristics to a non-transformed phenotype and inhibit tumour growth in mice , , This work spearheaded the concept of HER2-targeted therapy. You are using a browser version with limited support for CSS.
To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. The results using current testing methods are not unambiguous, complicating clinical decisions regarding use of anti-HER2 therapy. Ligand binding to the HER proteins results in homodimerization or heterodimerization of these receptors, leading to activation of downstream signalling pathways that promote cell division and growth and inhibit apoptosis HER2 overexpression or amplification leads to ligand-independent dimerization and abnormal signalling in addition to increased signalling through ligand-dependent heterodimerization With the introduction of the new HER2 low definition, additional diagnostic tools may need to be considered.
As HER2 is such a sensitive target, continued investigation to advance therapeutic benefit will undoubtedly lead to improvements in survival. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2-targeted therapy and new therapeutic approaches and agents, including strategies to harness the immune system. HER2 acts as an oncogene, and its amplification results in overexpression of the HER2 protein, a transmembrane receptor kinase.
The discovery that amplification or overexpression of HER2 was associated with extremely poor survival in BC ultimately led to the development of a monoclonal antibody mAb to HER2, trastuzumab 3 Box 1. HER2 expression is associated with poor prognosis, including early recurrence and metastatic disease in breast cancer 3 , , HER2 overexpression is also predictive of response to several HER2-targeted therapies, including monoclonal antibodies mAbs such as trastuzumab and pertuzumab, tyrosine kinase inhibitors TKIs — lapatinib, tucatinib — as well as antibody—drug conjugates ADCs such as ado-trastuzumab emtansine T-DM1 and trastuzumab deruxtecan.
Advanced BC was considered incurable, and treatment was purely palliative. Innovations in pathology, molecular biology and drug development have enabled HER2-positive breast cancer BC , a historically aggressive subtype, to become one with impressive outcomes. Immunotherapy is being approached from various angles including administering checkpoint inhibitors, linking effector T cells to HER2 antibodies, cellular therapy and vaccines 9 , 10 , 11 , A survey of the landscape of platforms being used to maximize HER2-targeted therapeutic efficacy are enumerated, which includes mAbs, tyrosine kinase inhibitors TKIs , ADCs, bispecific antibodies, immune system targeting agents, cellular therapy and targeted protein degraders.
Thank you for visiting nature. ERBB , consisting of two parts, v- erbA and v- erbB , was initially described in in an avian erythroblastosis retrovirus Eventually, erythroblastic leukaemia viral oncogene homologue 2 v-erbB2 was funnen to be closely homologous to EGFR Mouse and non-mouse cell lines were reported to be transformed by neuroblastoma, glioma and carcinoma DNA later named neu from malignant rat or mouse cell lines , A ,dalton protein was found to induce the transformation by neu ; the neu gene was homologous to erb-B , and p was related to EGFR 2 , , Sequencing studies revealed that the tyrosine kinase receptor named HER2 had extensive homology to neu , and both were located on chromosome 17 ref.
Immunotherapy to Treat Cancer
Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody—drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. Given the significance of HER2 status for prognosis and clinical decision-making for treatment, accurate assessment of this biomarker is crucial.
Therefore, extensive research is ongoing in the preclinical, translational and clinical arenas to develop original and more potent therapies for this exceptionally sensitive mål, HER2. The field was energized in when the first tyrosine kinase, epidermal growth factor receptor EGFR , was discovered followed bygd the identification of the neu or HER2 also known as ERBB2 gene in 1 , 2. Until this point, triple-negative and HER2-overexpressing disease were widely regarded as the most aggressive BC histologies, with unfavourable prognoses.
The tyrosine-binding domains of all but HER3 which has no catalytic tyrosine kinase activity are similar. Another approach is the development of bispecific antibodies, which use binding of two different HER2 epitopes to maximize efficacy 9.
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Bishop and H. Cohen and R. Levi-Montalcini awarded Nobel Prize in for discovery of growth factors and their receptors. The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug — the monoclonal antibody trastuzumab — almost 25 years ago.
In , Stanley Cohen discovered the protein responsible for incisor and eyelid opening in mice, termed epidermal growth factor EGF , thus beginning the journey from bench to bedside for HER2-targeted therapy , The intersection of two scientific fields generated knowledge that there was homology between oncogenes and growth factor receptors. However, newer and novel therapeutic strategies have led to markedly improved survival outcomes.
Ensuing research determined that only gene amplification with resultant overexpression of protein HER2 was needed for cellular transformation , Overexpression of HER2 was found to occur in human breast tumours, and HER2 signalling and transforming functions leading to growth were associated with a poor prognosis 3 , HER receptors contain an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain.
Advances in targeting HER2 include further exploitation of antibody—drug conjugates ADCs , altering the linkers, payload or antibody scaffold to optimize efficacy 7 , 8. This abnormal expression leads to a cascade of constitutive activation of downstream signalling pathways that promote uncontrolled tumour cell proliferation.