Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of disrupted lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. Clinical manifestations include ...lymphadenopathy, splenomegaly, and autoimmune cytopenias. A number of new insights have improved the understanding of the genetics and biology of ALPS. These will be discussed in this review.
A number of key observations have been made recently that better define the pathophysiology of ALPS, including the characterization of somatic FAS variant ALPS, the identification of haploinsufficiency as a mechanism of decreased Fas expression, and the description of multiple genetic hits in FAS in some families that may explain the variable penetrance of the disease. In addition, ALPS has been shown to be a more common condition, as patients diagnosed with other disorders, including Evans syndrome and common variable immune deficiency, have been found to have ALPS. Finally, the treatment of the disease has changed as splenectomy and rituximab have been shown to have unexpected ALPS-specific toxicities, and mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease.
On the basis of novel advances, the diagnostic algorithm and recommended treatment for ALPS have changed significantly, improving quality of life for many patients.
Patients with autoimmune multilineage cytopenias are often refractory to standard therapies requiring chronic immunosuppression with medications with limited efficacy and high toxicity. We present ...data on 30 patients treated on a multicenter prospective clinical trial using sirolimus as monotherapy. All children (N = 12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response (CR), including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within 1 to 3 months of starting sirolimus. Double-negative T cells were no longer detectable in most, yet other lymphocyte populations were spared, suggesting a targeted effect of sirolimus. We also treated 12 patients with multilineage cytopenias secondary to common variable immunodeficiency (CVID), Evans syndrome (ES), or systemic lupus erythematosus (SLE), and most achieved a CR (N = 8), although the time to CR was often slower than was seen in ALPS. Six children with single-lineage autoimmune cytopenias were treated and only 2 responded. Sirolimus was well tolerated with very few side effects. All of the responding patients have remained on therapy for over 1 year (median, 2 years; range, 1 to 4.5 years). In summary, sirolimus led to CR and durable responses in a majority of children with refractory multilineage autoimmune cytopenias. The responses seen in ALPS patients were profound, suggesting that sirolimus should be considered as a first-line, steroid-sparing treatment of patients needing chronic therapy. The results in other multilineage autoimmune cytopenia cohorts were encouraging, and sirolimus should be considered in children with SLE, ES, and CVID. This trial was registered at www.clinicaltrials.gov as #NCT00392951.
•Sirolimus monotherapy is a safe and effective steroid-sparing agent, improving autoimmune cytopenias in highly refractory patients.•Sirolimus is particularly active in ALPS and should be an early therapy option for patients who require chronic therapy.
Cellular therapy: Immune‐related complications Oved, Joseph H.; Barrett, David M.; Teachey, David T.
Immunological reviews,
July 2019, 2019-07-00, 20190701, Letnik:
290, Številka:
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Journal Article
Recenzirano
Odprti dostop
The advent of chimeric antigen receptor T (CAR‐T) and the burgeoning field of cellular therapy has revolutionized the treatment of relapsed/refractory leukemia and lymphoma. This personalized “living ...therapy” is highly effective against a number of malignancies, but this efficacy is tempered by side effects relatively unique to immunotherapies, including CAR‐T. The overwhelming release of cytokines and chemokines by activated CAR‐T and other secondarily activated immune effector cells can lead to cytokine release syndrome (CRS), which can have clinical and pathophysiology similarities to systemic inflammatory response syndrome and macrophage activating syndrome/hemophagocytic lymphohistiocytosis. Tocilizumab, an anti‐IL6 receptor antibody, was recently FDA approved for treatment of CRS after CAR‐T based on its ability to mitigate CRS in many patients. Unfortunately, some patients are refractory and additional therapies are needed. Patients treated with CAR‐T can also develop neurotoxicity and, as the biology is poorly understood, current therapeutic interventions are limited to supportive care. Nevertheless, a number of recent studies have shed new light on the pathophysiology of CAR‐T‐related neurotoxicity, which will hopefully lead to effective treatments. In this review we discuss some of the mechanistic contributions intrinsic to the CAR‐T construct, the tumor being treated, and the individual patient that impact the development and severity of CRS and neurotoxicity. As CAR‐T and cellular therapy have redefined the concept of personalized medicine, so too will personalization be necessary in managing the unique side effects of these therapies.
Gene therapy with CD34+ cells transduced with a lentivirus vector carrying a β-globin gene was performed in 22 patients. At a median of 26 months, all the patients were either transfusion-independent ...or had a major reduction in transfusion requirements.
Chimeric antigen receptor–modified T cells have demonstrated efficacy in chronic lymphoid leukemia, an indolent disease. They have now been shown to have efficacy in two patients with rapidly ...progressive, treatment-refractory acute lymphoid leukemia.
Patients with relapsed and chemotherapy-refractory pre–B-cell ALL have a poor prognosis despite the use of aggressive therapies such as allogeneic hematopoietic stem-cell transplantation
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and bispecific CD19 antibody fragments.
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Chimeric antigen receptor–modified T cells that target the lineage-specific antigens CD19 and CD20 have been reported to be effective in adults with CLL and B-cell lymphomas.
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However, the effects of chimeric antigen receptor T cells on ALL blasts, a more immature leukemia that progresses more rapidly, have not been fully investigated. In particular, there has been uncertainty about whether chimeric antigen receptor T cells would expand in vivo in patients . . .
In this study, adoptively transferred T cells transfected with anti-CD19 and activating signal–generating molecules led to complete remission in 90% of patients with relapsed and refractory acute ...leukemia, and overall survival at 6 months was 78%.
Engineered T-cell therapy is a new strategy for the treatment of relapsed and refractory acute lymphoblastic leukemia (ALL), which is associated with an extremely poor prognosis in adults and remains a leading cause of death from childhood cancer.
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In initial proof-of-principle clinical trials involving patients with chronic lymphocytic leukemia (CLL), chimeric antigen receptor–modified T cells that target CD19 produced a durable complete remission in a small number of patients.
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Our group and others then extended these findings to relapsed and refractory B-cell ALL, and we found profound responses in a small number of children and adults.
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Chimeric . . .
OBJECTIVE:Initial success with chimeric antigen receptor–modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine ...release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor–modified T cell therapy.
DESIGN:Retrospective cohort study.
SETTING:Academic children’s hospital.
PATIENTS:Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor–modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495).
INTERVENTIONS:All subjects received chimeric antigen receptor–modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab.
MEASUREMENTS AND MAIN RESULTS:Eighteen subjects (46%) developed grade 3–4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8–20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement.
CONCLUSIONS:Grade 3–4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.
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