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1.
Article in English | MEDLINE | ID: mdl-37646585

ABSTRACT

ABSTRACT: Implementation of a comprehensive point-of-care ultrasound (POCUS) program for nurse practitioners (NPs) and physician assistants (PAs) in an intensive care unit (ICU) setting improves their diagnostic and therapeutic skills and enhances patient care. Overcoming staffing, IT infrastructure, and administrative challenges has allowed our critical care medicine service to develop a successful program that empowers NPs and PAs and boosts their professional growth. Our POCUS program underscores the necessity of institutional support, dedicated mentorship, collaboration with qualified faculty, and creation and maintenance of a curriculum that adheres to accepted national guidelines. Insights gained from our experiences can serve as a valuable resource for institutions aiming to develop their own POCUS programs.

2.
Nat Med ; 29(7): 1710-1717, 2023 07.
Article in English | MEDLINE | ID: mdl-37400640

ABSTRACT

In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor (CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion. The primary endpoint was the rate of severe (grade ≥3) ICANS. Key secondary endpoints included the rates of all-grade cytokine release syndrome (CRS) and ICANS and overall disease response. Among 31 treated patients, 74% received axicabtagene ciloleucel, 13% received brexucabtagene ciloleucel and 4% received tisagenlecleucel. All-grade ICANS occurred in 19%, and severe ICANS occurred in 9.7% of patients. There were no grade 4 or 5 ICANS events. All-grade CRS occurred in 74%, and severe CRS occurred in 6.4% of patients. The overall disease response rate was 77% with 65% complete response rate. These initial results show that prophylactic anakinra resulted in a low incidence of ICANS in patients with lymphoma receiving anti-CD19 CAR T-cell therapy and support further study of anakinra in immune-related neurotoxicity syndromes.


Subject(s)
Lymphoma, Large B-Cell, Diffuse , Neurotoxicity Syndromes , Humans , Adult , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Interleukin 1 Receptor Antagonist Protein/adverse effects , Neurotoxicity Syndromes/etiology , Lymphoma, Large B-Cell, Diffuse/pathology , Antigens, CD19
3.
Eur Heart J ; 44(22): 2029-2042, 2023 Jun 09.
Article in English | MEDLINE | ID: mdl-36939851

ABSTRACT

AIMS: Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. METHODS AND RESULTS: From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden. CONCLUSION: Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.


Subject(s)
Heart Failure , Neoplasms , Receptors, Chimeric Antigen , Humans , Receptors, Chimeric Antigen/therapeutic use , Interleukin-6 , Biomarkers , C-Reactive Protein , Troponin , Cell- and Tissue-Based Therapy
4.
N Engl J Med ; 387(13): 1196-1206, 2022 09 29.
Article in English | MEDLINE | ID: mdl-36170501

ABSTRACT

BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells. CONCLUSIONS: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).


Subject(s)
Immunotherapy, Adoptive , Multiple Myeloma , Receptors, Chimeric Antigen , Receptors, G-Protein-Coupled , B-Cell Maturation Antigen/therapeutic use , Cytokine Release Syndrome/etiology , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/etiology , Receptors, Chimeric Antigen/therapeutic use , Receptors, G-Protein-Coupled/therapeutic use , T-Lymphocytes
5.
Crit Care Med ; 50(1): 81-92, 2022 01 01.
Article in English | MEDLINE | ID: mdl-34259446

ABSTRACT

OBJECTIVES: To report the epidemiology, treatments, and outcomes of adult patients admitted to the ICU after cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. DESIGN: Retrospective cohort study. SETTING: Nine centers across the U.S. part of the chimeric antigen receptor-ICU initiative. PATIENTS: Adult patients treated with chimeric antigen receptor T-cell therapy who required ICU admission between November 2017 and May 2019. INTERVENTIONS: Demographics, toxicities, specific interventions, and outcomes were collected. RESULTS: One-hundred five patients treated with axicabtagene ciloleucel required ICU admission for cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome during the study period. At the time of ICU admission, the majority of patients had grade 3-4 toxicities (66.7%); 15.2% had grade 3-4 cytokine release syndrome and 64% grade 3-4 immune effector cell-associated neurotoxicity syndrome. During ICU stay, cytokine release syndrome was observed in 77.1% patients and immune effector cell-associated neurotoxicity syndrome in 84.8% of patients; 61.9% patients experienced both toxicities. Seventy-nine percent of patients developed greater than or equal to grade 3 toxicities during ICU stay, however, need for vasopressors (18.1%), mechanical ventilation (10.5%), and dialysis (2.9%) was uncommon. Immune Effector Cell-Associated Encephalopathy score less than 3 (69.7%), seizures (20.2%), status epilepticus (5.7%), motor deficits (12.4%), and cerebral edema (7.9%) were more prevalent. ICU mortality was 8.6%, with only three deaths related to cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Median overall survival time was 10.4 months (95% CI, 6.64-not available mo). Toxicity grade or organ support had no impact on overall survival; higher cumulative corticosteroid doses were associated to decreased overall and progression-free survival. CONCLUSIONS: This is the first study to describe a multicenter cohort of patients requiring ICU admission with cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy. Despite severe toxicities, organ support and in-hospital mortality were low in this patient population.


Subject(s)
Biological Products/toxicity , Critical Illness , Cytokine Release Syndrome/chemically induced , Immunotherapy, Adoptive/adverse effects , Neurotoxicity Syndromes/etiology , Receptors, Chimeric Antigen , Adult , Aged , Comorbidity , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/therapy , Female , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Neurotoxicity Syndromes/mortality , Neurotoxicity Syndromes/therapy , Patient Acuity , Retrospective Studies , Sociodemographic Factors , United States
6.
Blood Adv ; 5(17): 3397-3406, 2021 09 14.
Article in English | MEDLINE | ID: mdl-34432870

ABSTRACT

Patients who develop chimeric antigen receptor (CAR) T-cell-related severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and endothelial activation. The EASIX (Endothelial Activation and Stress Index) score (lactate dehydrogenase [LDH; U/L] × creatinine [mg/dL]/platelets [PLTs; 109 cells/L]) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low PLTs have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and 2 new modified EASIX formulas (simplified EASIX, which excludes creatinine, and modified EASIX [m-EASIX], which replaces creatinine with CRP [mg/dL]), calculated peri-CAR T-cell infusion, would be associated with development of severe (grade ≥ 3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T cells (NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel or tisagenlecleucel. The 3 formulas showed similar predictive power for severe CRS and ICANS. However, low PLTs and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (area under the curve [AUC] at lymphodepletion, 80.4%; at day -1, 73.0%; and at day +1, 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC, 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cell-related toxicities.


Subject(s)
Hematopoietic Stem Cell Transplantation , Neurotoxicity Syndromes , Receptors, Chimeric Antigen , Cytokine Release Syndrome , Humans , T-Lymphocytes
7.
Transplant Cell Ther ; 27(3): 233-240, 2021 03.
Article in English | MEDLINE | ID: mdl-33781518

ABSTRACT

CD19-targeted chimeric antigen receptor (CAR) T cells have shown excellent activity against relapsed and refractory (R/R) diffuse large B cell lymphoma (DLBCL). CAR T cell therapy is associated with early toxicities, including cytokine release syndrome and neurotoxicity. The incidence and severity of these toxicities has been associated in part with baseline disease and patient characteristics, which also may impact overall survival (OS) and progression-free survival (PFS). However, there are limited data on patient selection and how to better predict toxicities or outcomes. Indexes used in patients with DLBCL, such as the International Prognostic Index (IPI and age-adjusted IPI [aaIPI]) and in transplantation recipients, such as the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), have not been evaluated in this setting. Here we evaluated 4 indices- IPI, aaIPI, HCT-CI, and the Charlson Comorbidity Index (CCI)-and their associations with early CAR T cell related-toxicities and outcomes. We demonstrated an association between high-risk IPI or aaIPI and inferior PFS in patients with R/R DLBCL treated with CAR T cell therapy. We also found an association between aaIPI and IPI with OS and neurotoxicity, respectively. CCI was not associated with toxicities or outcomes, and owing to the small sample size, we could not draw a conclusion regarding associations with the HCT-CI. Both the IPI and aaIPI are widely used tools that can now provide better information to guide selection of patients who would best benefit from CD19 CAR T cell therapy.


Subject(s)
Lymphoma, Large B-Cell, Diffuse , Receptors, Chimeric Antigen , Cell- and Tissue-Based Therapy , Humans , Immunotherapy, Adoptive , Lymphoma, Large B-Cell, Diffuse/therapy , Prognosis
9.
J Immunother Cancer ; 8(2)2020 12.
Article in English | MEDLINE | ID: mdl-33335028

ABSTRACT

Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric and adult patients in a number of disease states, as 'living drugs,' their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients.


Subject(s)
Drug-Related Side Effects and Adverse Reactions/immunology , Immunologic Factors/immunology , Immunotherapy/methods , Guidelines as Topic , Humans , Retrospective Studies
10.
Blood Adv ; 4(15): 3776-3787, 2020 08 11.
Article in English | MEDLINE | ID: mdl-32780846

ABSTRACT

Factors contributing to hematopoietic recovery following chimeric antigen receptor (CAR) T-cell therapy have not been well studied. In an analysis of 83 patients with hematologic malignancies treated with CAR T-cell therapy, we describe patterns of hematopoietic recovery and evaluate potentially associated factors. We included patients who received axicabtagene ciloleucel (n = 30) or tisagenlecleucel (n = 10) for B-cell lymphoma, CD19-28z CAR T therapy for B-cell acute lymphoblastic leukemia (NCT01044069; n = 37), or B-cell maturation antigen targeting CAR T cells for multiple myeloma (NCT03070327; n = 6). Patients treated with CAR T cells who had not progressed, died, or received additional chemotherapy had "recovered" (per definition in Materials and methods section) hemoglobin, platelet, neutrophil, and white blood cell counts at rates of 61%, 51%, 33%, and 28% at month 1 postinfusion and 93%, 90%, 80%, and 59% at month 3 postinfusion, respectively. Univariate analysis showed that increasing grade of immune effector cell-associated neurological syndrome (ICANS), baseline cytopenias, CAR construct, and higher peak C-reactive protein or ferritin levels were statistically significantly associated with a lower likelihood of complete count recovery at 1 month; a similar trend was seen for cytokine release syndrome (CRS). After adjustment for baseline cytopenia and CAR construct, grade ≥3 CRS or ICANS remained significantly associated with the absence of complete count recovery at 1 month. Higher levels of vascular endothelial growth factor and macrophage-derived chemokines, although not statistically significant, were seen patients without complete count recovery at 1 month. This remains to be studied further in larger prospective studies.


Subject(s)
Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Receptors, Chimeric Antigen , Cell- and Tissue-Based Therapy , Hematologic Neoplasms/therapy , Humans , Immunotherapy, Adoptive , Prospective Studies , Receptors, Chimeric Antigen/genetics , Vascular Endothelial Growth Factor A
11.
Blood Cancer J ; 10(8): 79, 2020 08 05.
Article in English | MEDLINE | ID: mdl-32759935

ABSTRACT

CD19-targeted chimeric antigen receptor (CAR) T cell therapy is an effective treatment for diffuse large B cell lymphoma (DLBCL). In addition to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), B cell aplasia and hypogammaglobulinemia are common toxicities predisposing these patients to infections. We analyzed 60 patients with DLBCL treated with FDA-approved CD19 CAR T cells and report the incidence, risk factors, and management of infections during the first year after treatment. A total of 101 infectious events were observed, including 25 mild, 51 moderate, 23 severe, 1 life-threatening, and 1 fatal infection. Bacteria were the most common causative pathogens. The cumulative incidence of overall, bacterial, severe bacterial, viral, and fungal infection at 1 year were 63.3%, 57.2%, 29.6%, 44.7%, and 4%, respectively. In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS was associated with an increased risk of infections and prolonged admission. Impaired performance status and history of infections within 30 days before CAR T cell therapy was a risk factor for severe bacterial infection. In conclusion, infections were common within the first 60 days after CAR T cell therapy, however, they were not associated with an increased risk of death.


Subject(s)
Antigens, CD19/immunology , Immunotherapy, Adoptive/adverse effects , Infections/etiology , Lymphoma, Large B-Cell, Diffuse/therapy , Adult , Aged , Aged, 80 and over , Anti-Infective Agents/therapeutic use , Female , Humans , Immunotherapy, Adoptive/methods , Incidence , Infections/immunology , Infections/therapy , Lymphoma, Large B-Cell, Diffuse/immunology , Male , Middle Aged , Risk Factors , Treatment Outcome , Young Adult
12.
Blood Adv ; 4(13): 3024-3033, 2020 07 14.
Article in English | MEDLINE | ID: mdl-32614964

ABSTRACT

Cytokine release syndrome (CRS) immune effector cell-associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell-mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.


Subject(s)
Lymphoma, Large B-Cell, Diffuse , Receptors, Antigen, T-Cell , Antigens, CD19 , Humans , Immunotherapy, Adoptive , Lymphoma, Large B-Cell, Diffuse/therapy , T-Lymphocytes
13.
J Crit Care ; 58: 58-64, 2020 08.
Article in English | MEDLINE | ID: mdl-32361219

ABSTRACT

PURPOSE: A task force of experts from 11 United States (US) centers, sought to describe practices for managing chimeric antigen receptor (CAR) T-cell toxicity in the intensive care unit (ICU). MATERIALS AND METHODS: Between June-July 2019, a survey was electronically distributed to 11 centers. The survey addressed: CAR products, toxicities, targeted treatments, management practices and interventions in the ICU. RESULTS: Most centers (82%) had experience with commercial and non-FDA approved CAR products. Criteria for ICU admission varied between centers for patients with Cytokine Release Syndrome (CRS) but were similar for Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Practices for vasopressor support, neurotoxicity and electroencephalogram monitoring, use of prophylactic anti-epileptic drugs and tocilizumab were comparable. In contrast, fluid resuscitation, respiratory support, methods of surveillance and management of cerebral edema, use of corticosteroid and other anti-cytokine therapies varied between centers. CONCLUSIONS: This survey identified areas of investigation that could improve outcomes in CAR T-cell recipients such as fluid and vasopressor selection in CRS, management of respiratory failure, and less common complications such as hemophagocytic lymphohistiocytosis, infections and stroke. The variability in specific treatments for CAR T-cell toxicities, needs to be considered when designing future outcome studies of critically ill CAR T-cell patients.


Subject(s)
Critical Care/standards , Cytokine Release Syndrome/prevention & control , Practice Patterns, Physicians' , Receptors, Chimeric Antigen/immunology , Humans , Immunotherapy, Adoptive , Intensive Care Units , Surveys and Questionnaires , United States
14.
Blood Adv ; 4(4): 676-686, 2020 02 25.
Article in English | MEDLINE | ID: mdl-32084260

ABSTRACT

Various grading systems are currently used for chimeric antigen receptor (CAR) T-cell-related toxicity, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). We compared the recently proposed American Society for Transplantation and Cellular Therapy (ASTCT) grading system to other grading scores in 2 populations of adults: patients (n = 53) with B-cell acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T-cells (clinicaltrials.gov #NCT01044069), and patients (n = 49) with diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene-ciloleucel (axi-cel) or tisagenlecleucel after US Food and Drug Administration approval. According to ASTCT grading, 82% of patients had CRS, 87% in the B-ALL and 77% in the DLBCL groups (axi-cel: 86%, tisagenlecleucel: 54%), whereas 50% of patients experienced ICANS, 55% in the B-ALL and 45% in the DLBCL groups (axi-cel: 55%, tisagenlecleucel: 15%). All grading systems agreed on CRS and ICANS diagnosis in 99% and 91% of cases, respectively. However, when analyzed grade by grade, only 25% and 54% of patients had the same grade in each system for CRS and ICANS, respectively, as different systems score symptoms differently (upgrading or downgrading their severity), leading to inconsistent final grades. Investigation of possible management implications in DLBCL patients showed that different recommendations on tocilizumab and steroids across current guidelines potentially result in either overtreating or delaying treatment. Moreover, because these guidelines are based on single products and different grading systems, they cannot be universally applied. To avoid discrepancies in assessing and managing toxicities of different products, we propose that unified grading be used across clinical trials and in practice and that paired management guidelines with product-specific indications be developed.


Subject(s)
Lymphoma, Large B-Cell, Diffuse , Neurotoxicity Syndromes , Receptors, Chimeric Antigen , Adult , Cytokine Release Syndrome , Humans , T-Lymphocytes
15.
Cancer Immunol Res ; 7(7): 1047-1053, 2019 07.
Article in English | MEDLINE | ID: mdl-31113804

ABSTRACT

We present a case of a patient with multiply relapsed, refractory myeloma whose clinical course showed evidence of a synergistic abscopal-like response to chimeric antigen receptor (CAR) T-cell therapy and localized radiotherapy (XRT). Shortly after receiving B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy, the patient required urgent high-dose steroids and XRT for spinal cord compression. Despite the steroids, the patient had a durable systemic response that could not be attributed to XRT alone. Post-XRT findings included a second wave of fever and increased CRP and IL6, beginning 21 days after CAR T cells, which is late for cytokine-release syndrome from CAR T-cell therapy alone on this trial. Given this response, which resembled cytokine-release syndrome, immediately following XRT, we investigated changes in the patient's T-cell receptor (TCR) repertoire over 10 serial time points. Comparing T-cell diversity via Morisita's overlap indices (CD ), we discovered that, although the diversity was initially stable after CAR T-cell therapy compared with baseline (CD = 0.89-0.97, baseline vs. 4 time points after CAR T cells), T-cell diversity changed after the conclusion of XRT, with >30% newly expanded TCRs (CD = 0.56-0.69, baseline vs. 4 time points after XRT). These findings suggest potential synergy between radiation and CAR T-cell therapies resulting in an abscopal-like response.


Subject(s)
B-Cell Maturation Antigen/immunology , Drug Resistance, Neoplasm , Immunotherapy, Adoptive/methods , Multiple Myeloma/therapy , Radiotherapy/methods , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , Combined Modality Therapy , Female , Humans , Middle Aged , Multiple Myeloma/immunology , Remission Induction
16.
Anesth Analg ; 129(2): 434-441, 2019 08.
Article in English | MEDLINE | ID: mdl-31124841

ABSTRACT

Cancer immunotherapy has entered a new era with the recent introduction of genetically engineered T-cells that express chimeric antigen receptors (CARs) capable of recognizing and destroying tumor cells. Several clinical trials in patients with relapsed or refractory B-cell malignancies have demonstrated complete remission rates ranging from 50% to 90%, with long-term data suggestive of a possible curative response. CAR T-cell therapy is currently under investigation for earlier use in these disease processes and in various other solid and liquid tumors. CAR T-cell therapy is associated with a unique postinfusion toxicity profile including cytokine-release syndrome and neurotoxicity. These toxicities are usually reversible but can be fatal, requiring close vigilance and prompt treatment often in an intensive care unit (ICU) setting. CAR T-cell therapy is currently restricted to designated centers possessing expertise in acute toxicity management, but wider use is likely if early therapeutic successes are replicated. As perioperative and critical care physicians, anesthesiologists may encounter such patients in the perioperative or ICU setting and should become familiar with this unique and novel therapeutic modality capable of causing extreme cardiovascular and respiratory compromise. This review will describe the immunobiology of CAR T-cells, their relevance to cancer treatment, clinical aspects of their therapeutic use in cancer chemotherapy, toxicities related to CAR T-cell use, and their therapeutic management.


Subject(s)
Immunotherapy, Adoptive/trends , Neoplasms/therapy , Receptors, Chimeric Antigen/immunology , T-Lymphocytes/transplantation , Animals , Humans , Immunotherapy, Adoptive/adverse effects , Neoplasms/genetics , Neoplasms/immunology , Receptors, Chimeric Antigen/genetics , Risk Factors , T-Lymphocytes/immunology , Treatment Outcome
17.
Biol Blood Marrow Transplant ; 25(6): e211-e212, 2019 06.
Article in English | MEDLINE | ID: mdl-30910604

Subject(s)
Cytokines , Consensus
18.
Biol Blood Marrow Transplant ; 25(4): 625-638, 2019 04.
Article in English | MEDLINE | ID: mdl-30592986

ABSTRACT

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.


Subject(s)
Cytokine Release Syndrome/therapy , Immunotherapy/methods , Receptors, Antigen, T-Cell/therapeutic use , Cytokine Release Syndrome/pathology , Guidelines as Topic , Humans
20.
Crit Care Med ; 46(9): 1402-1410, 2018 09.
Article in English | MEDLINE | ID: mdl-29939878

ABSTRACT

OBJECTIVES: Chimeric antigen receptor T-cell therapy, a type of immune effector therapy for cancer, has demonstrated encouraging results in clinical trials for the treatment of patients with refractory hematologic malignancies. Nevertheless, there are toxicities specific to these treatments that, if not recognized and treated appropriately, can lead to multiple organ failure and death. This article is a comprehensive review of the available literature and provides, from a critical care perspective, recommendations by experienced intensivists in the care of critically ill adult chimeric antigen receptor T-cell patients. DATA SOURCES: PubMed and Medline search of articles published from 2006 to date. STUDY SELECTION: Clinical studies, reviews, or guidelines were selected and reviewed by the authors. DATA EXTRACTION: Not available. DATA SYNTHESIS: Not available. CONCLUSIONS: Until modifications in chimeric antigen receptor T-cell therapy decrease their toxicities, the intensivist will play a leading role in the management of critically ill chimeric antigen receptor T-cell patients. As this novel immunotherapeutic approach becomes widely available, all critical care clinicians need to be familiar with the recognition and management of complications associated with this treatment.


Subject(s)
Hematologic Neoplasms/therapy , Immunotherapy, Adoptive/adverse effects , Receptors, Chimeric Antigen/therapeutic use , Adult , Critical Care , Critical Illness , Decision Trees , Humans , Neurotoxicity Syndromes/diagnosis , Neurotoxicity Syndromes/therapy , Practice Guidelines as Topic
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