Molekula CTLA-4 je jedním z nejdůležitějších kontrolních bodů imunity. Její aktivita tlumí nadměrnou imunitní odpověď efektorových T-buněk na cizorodý/antigenní podnět. V nádorovém mikroprostředí podporuje imunosupresivní účinek regulačních T-buněk a myeloidních supresorových buněk a tlumí protinádorovou aktivitu efektorových T-buněk. Inhibice signální aktivity CTLA-4 pomocí specifických monoklonálních protilátek významně napomáhá k uvolnění účinné protinádorové buněčné imunitní reakce. Ipilimumab je plně humánní IgG1 monoklonální protilátka, schopná se cíleně navázat na molekulu CTLA-4 a potlačit její imunosupresivní signální aktivitu. V monoterapii se ipilimumab účinně uplatnil zejména v léčbě metastazujícího melanomu. Jeho současné podávání s nivolumabem, protilátkou zacílenou na kontrolní bod imunitní reakce PD-1, vedlo k významnému zvýšení účinnosti protinádorové imunoterapie solidních nádorů.
The CTLA-4 molecule represents one of the most important immune checkpoints. It serves as an inhibitory coreceptor for T-cells. Its signalling activity suppress effective T-cell response upon antigenic stimuli. In tumour microenvironment CTLA-4 activity supports immunosuppressive effect of Treg and MDSC and impedes antitumour activity of effector T-cells. The inhibition of CTLA-4 signalling activity using specific monoclonal antibodies is an important step in restoration of effective antitumor immune cell reaction. Ipilimumab is a fully human monoclonal IgG1 antibody able to bind specifically CTLA-4 molecule and block its immunosuppressive signalling activity. Ipilimumab as monotherapy is an effective treatment of metastatic melanoma. Moreover, concomitant administration of ipilimumab and nivolumab, monoclonal antibody targeting another important immune checkpoint PD-1, significantly increased antitumour efficacy in the treatment of different solid cancers.
Imunoterapie monoklonálními protilátkami proti inhibičním receptorům CTLA-4 a PD-1 může vyvolávat imunitně zprostředkované nežádoucí účinky, projevující se převážně vznikem autoimunitních reakcí (irAEs - immune related adverse events, imunitně zprostředkované nežádoucí účinky). Dominantně postihují kůži, gastrointenstinální trakt, játra a žlázy s vnitřní sekrecí, mohou však ovlivnit funkci kteréhokoliv orgánu. Základním léčebným ovlivněním irAEs je podávání kortikosteroidů, v závažných případech v dávce 1-2 mg/kg intravenózně, s pomalým vysazováním po ústupu příznaků. Pozdní zahájení léčby, použití nízkých dávek nebo brzké ukončení aplikace kortikosteroidů může vést k návratu toxických reakcí, někdy i s fatálními následky. Pravidelné sledování pacientů včetně monitorace laboratorních hodnot je základem pro včasné odhalení nežádoucích účinků a zahájení léčby, které zabrání nutnosti předčasného ukončení imunoterapie pro závažnou toxicitu.
Anti-CTLA-4 and anti PD-1 immunotherapy can create immune mediated adverse events manifest themselves by development of autoimmune reactions (irAEs, immune related adverse events). Predominantly they affect skin, gastrointestinal tract, liver and endocrine glands, but can influence the function of any organ. The crucial treatment of irAEs is the administration of corticosteroids, severe adverse events should be treated with higher dose 1-2 mg/kg intravenously with slow taper after symptoms resolved. Late start of the treatment, low dose of corticosteroids, or fast taper can caused recurrence of toxicity sometimes with fatal consequences. Follow up on regular basis including monitoring laboratory values is the base for early detection of adverse events, which prevents the necessity of untimely termination of immunotherapy for severe toxicity.
- Keywords
- pembrolizumab,
- MeSH
- B7-H1 Antigen MeSH
- Programmed Cell Death 1 Receptor MeSH
- Antineoplastic Agents adverse effects MeSH
- Chemical and Drug Induced Liver Injury, Chronic MeSH
- Exanthema chemically induced MeSH
- Antibodies, Monoclonal, Humanized adverse effects MeSH
- Immunotherapy * adverse effects MeSH
- Ipilimumab MeSH
- Humans MeSH
- Melanoma * drug therapy MeSH
- Antibodies, Monoclonal adverse effects MeSH
- Skin Neoplasms drug therapy MeSH
- Thyroid Diseases chemically induced MeSH
- Drug-Related Side Effects and Adverse Reactions * MeSH
- Nivolumab MeSH
- Diarrhea chemically induced MeSH
- Check Tag
- Humans MeSH
This contribution reports the case of a young female patient with a cytotoxic T-lymphocyte antigen 4 (CTLA-4) heterozygous missense mutation giving rise to a broad range of autoimmune diseases, including central nervous system inflammation presenting as disseminated intramedullary and infiltrating brain lesions on MRI. Multiple sclerosis was one of the diagnoses considered. CTLA-4 is a negative immune regulator essential for the function of regulatory T-cells, themselves responsible for maintaining self-tolerance and immune homeostasis. Heterozygous germline mutations in CTLA-4 may lead to an autosomal dominant immune dysregulation syndrome with highly variable phenotype, including various immunodeficiency and autoimmune diseases, along with neurological manifestations.
- MeSH
- CTLA-4 Antigen genetics MeSH
- Autoimmune Diseases * MeSH
- Immune Tolerance MeSH
- Humans MeSH
- Mutation MeSH
- T-Lymphocytes, Regulatory MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
PURPOSE: Heterozygous mutations in CTLA4 lead to an inborn error of immunity characterized by immune dysregulation and immunodeficiency, known as CTLA-4 insufficiency. Cohort studies on CTLA4 mutation carriers showed a reduced penetrance (around 70%) and variable disease expressivity, suggesting the presence of modifying factors. It is well studied that infections can trigger autoimmunity in humans, especially in combination with a genetic predisposition. METHODS: To investigate whether specific infections or the presence of specific persisting pathogens are associated with disease onset or severity in CTLA-4 insufficiency, we have examined the humoral immune response in 13 CTLA4 mutation carriers, seven without clinical manifestation and six with autoimmune manifestations, but without immunoglobulin replacement therapy against cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1/2 (HSV 1/2), parvovirus B19 and Toxoplasma gondii. Additionally, we have measured FcγRIII/CD16A activation by EBV-specific IgG antibodies to examine the functional capabilities of immunoglobulins produced by CTLA4 mutation carriers. RESULTS: The seroprevalence between affected and unaffected CTLA4 mutation carriers did not differ significantly for the examined pathogens. Additionally, we show here that CTLA4 mutation carriers produce EBV-specific IgG, which are unimpaired in activating FcγRIII/CD16A. CONCLUSIONS: Our results show that the investigated pathogens are very unlikely to trigger the disease onset in CTLA-4-insufficient individuals, and their prevalence is not correlated with disease severity or expressivity.
- MeSH
- CTLA-4 Antigen genetics MeSH
- Immunoglobulin G MeSH
- Epstein-Barr Virus Infections * complications epidemiology MeSH
- Humans MeSH
- Antibodies, Viral MeSH
- Seroepidemiologic Studies MeSH
- Herpesvirus 4, Human * physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness. OBJECTIVE: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level. METHODS: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated. RESULTS: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed. CONCLUSION: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
- MeSH
- Agammaglobulinemia etiology MeSH
- CTLA-4 Antigen deficiency genetics MeSH
- Autoimmune Diseases etiology MeSH
- Child MeSH
- Adult MeSH
- Genetic Association Studies MeSH
- Transplantation, Homologous MeSH
- Lung Diseases, Interstitial etiology MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Child, Preschool MeSH
- Aged MeSH
- Immunologic Deficiency Syndromes complications genetics therapy MeSH
- Hematopoietic Stem Cell Transplantation MeSH
- Germ-Line Mutation * MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterized by lymphoproliferation, dysgammaglobulinemia, and multiorgan autoimmunity including cytopenias and colitis. OBJECTIVE: We examined the outcome of hematopoietic stem cell transplantation (HSCT) for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4 fusion protein (CTLA-4-Ig) therapy and pre-HSCT immune dysregulation on survival and immunologic outcome. METHODS: This was a retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Primary end points were overall survival (OS) and disease- and chronic graft-versus-host disease-free survival (DFS). Secondary end point was immunologic outcome assessed by immune dysregulation disease activity (IDDA) score. RESULTS: Forty patients were included over a 25-year period. Before HSCT, 60% received CTLA-4-Ig, and median (range) IDDA score was 23.3 (3.9-84.0). Median (range) age at HSCT was 14.2 (1.3-56.0) years. Patients received peripheral blood stem cell (58%) or marrow (43%) from a matched unrelated donor (75%), mismatched unrelated donor (12.5%), or matched family donor (12.5%). Median (range) follow-up was 3 (0.6-15) years, and 3-year OS was 76.7% (58-87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, disease of 28 of 30 surviving patients was in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity before HSCT (IDDA < 23, P = .002 and P = .006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant related in 7 of 8 patients. CONCLUSION: HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity.
- MeSH
- CTLA-4 Antigen * genetics MeSH
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Graft vs Host Disease MeSH
- Child, Preschool MeSH
- Retrospective Studies MeSH
- Hematopoietic Stem Cell Transplantation * MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Europe MeSH
- Keywords
- Pembrolizumab, Ipilimumab,
- MeSH
- CTLA-4 Antigen antagonists & inhibitors MeSH
- Programmed Cell Death 1 Receptor antagonists & inhibitors MeSH
- Antibodies, Monoclonal, Humanized administration & dosage MeSH
- Neck surgery pathology MeSH
- Humans MeSH
- Lymph Node Excision MeSH
- Melanoma * drug therapy genetics pathology MeSH
- Adolescent MeSH
- Lung Neoplasms drug therapy radiotherapy secondary MeSH
- Disease-Free Survival MeSH
- Drug Administration Schedule MeSH
- Check Tag
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.
- MeSH
- CTLA-4 Antigen genetics MeSH
- Child MeSH
- Adult MeSH
- Phenotype MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Mutation MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Immunologic Deficiency Syndromes diagnostic imaging genetics therapy MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Metastazující maligní melanom se řadí mezi nejobtížněji léčitelné diagnózy s mediánem přežití mezi 6 a 9 měsíci. Přežití 5 a více let se uvádí pouze v 1–2 % případů. Ročně umírá v ČR na melanom téměř 350 osob. Na první pohled se toto číslo nezdá dramatické, ale značně nabývá na významu při skutečnosti, že se jedná obvykle o jedince v produktivním věku. Dosavadním standardem léčby, který slouží k hodnocení účinnosti nových preparátů, je již 35 let dakarbazin, jehož léčebná odpověď se pohybuje v rozmezí 15–20 %. Výsledky klinických studií posledních dvou let zásadně změnily přístup k léčbě metastazujícího melanomu. Jako účinné se ukázaly dva směry, které jsou ve své biologické podstatě zcela odlišné: léčba imunomodulační zaměřená na aktivaci T-lymfocytů (a celého imunitního systému) a léčba cílená zaměřená na blokaci mutace genů v melanomu. Ipilimumab, monoklonální protilátka namířená proti antigenu CTLA-4, dokázal jako první molekula v historii statisticky signifikantně prodloužit celkové přežívání pacientů s metastazujícím melanomem.
Metastatic malignant melanoma is one of the cancers that are most difficult to treat, with a median survival ranging from six to nine months. The reported five-year or longer survival rates are 1-2 %. Melanoma accounts for nearly 350 deaths in the Czech Republic each year. At first sight, this number does not seem dramatic, but it becomes considerably more significant in the light of the fact that most deaths occur in the productive age group. Dacarbazine that has been the standard first-line therapy for 35 years and serves as a reference in testing novel drugs induces therapeutic response in 15-20 % of patients. The results of clinical trials obtained over the last two years have substantially changed the therapeutic approach to metastatic melanoma. Two therapeutic strategies differing in their biological nature have proved effective: immune modulation leading to activation of T-lymphocytes (and of the immune system in general) and therapy targeting the gene mutation in melanoma.
- Keywords
- anti-CTLA-4, gen BRAF,
- MeSH
- CTLA-4 Antigen immunology therapeutic use MeSH
- Immunomodulation MeSH
- Ipilimumab MeSH
- Humans MeSH
- Melanoma drug therapy immunology MeSH
- Neoplasm Metastasis MeSH
- Antibodies, Monoclonal immunology adverse effects therapeutic use MeSH
- Antibodies, Neoplasm immunology adverse effects therapeutic use MeSH
- Dose-Response Relationship, Drug MeSH
- Salvage Therapy MeSH
- Check Tag
- Humans MeSH
