scholarly journals Chimeric Antigen Receptor–Modified Immune Effector Cell Therapies

2021 ◽  
Vol 27 (2) ◽  
pp. 90-91
Author(s):  
Eric L. Smith ◽  
Renier J. Brentjens
Keyword(s):  
Chimeric Antigen Receptor ◽  
Effector Cell ◽  
Antigen Receptor ◽  
Immune Effector Cell ◽  
Cell Therapies ◽  
Immune Effector

Next-Generation Implementation of Chimeric Antigen Receptor T-Cell Therapy Using Digital Health

2021 ◽  
pp. 668-678
Author(s):  
Rahul Banerjee ◽  
Nina Shah ◽  
Adam P. Dicker
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Effector Cell ◽  
Antigen Receptor ◽  
Machine Learning Algorithms ◽  
Immune Effector Cell ◽  
Next Generation ◽  
Immune Effector ◽  
Patient Reported ◽  
Car T

Chimeric antigen receptor T-cell (CAR-T) therapy is a paradigm-shifting immunotherapy modality in oncology; however, unique toxicities such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome limit its ability to be implemented more widely in the outpatient setting or at smaller-volume centers. Three operational challenges with CAR-T therapy include the following: (1) the logistics of toxicity monitoring, ie, with frequent vital sign checks and neurologic assessments; (2) the specialized knowledge required for toxicity management, particularly with regard to CRS and immune effector cell–associated neurotoxicity syndrome; and (3) the need for high-quality symptomatic and supportive care during this intensive period. In this review, we explore potential niches for digital innovations that can improve the implementation of CAR-T therapy in each of these domains. These tools include patient-facing technologies and provider-facing platforms: for example, wearable devices and mobile health apps to screen for fevers and encephalopathy, electronic patient-reported outcome assessments–based workflows to assist with symptom management, machine learning algorithms to predict emerging CRS in real time, clinical decision support systems to assist with toxicity management, and digital coaching to help maintain wellness. Televisits, which have grown in prominence since the novel coronavirus pandemic, will continue to play a key role in the monitoring and management of CAR-T–related toxicities as well. Limitations of these strategies include the need to ensure care equity and stakeholder buy-in, both operationally and financially. Nevertheless, once developed and validated, the next-generation implementation of CAR-T therapy using these digital tools may improve both its safety and accessibility.

scholarly journals Chimeric Antigen Receptor (CAR)-Modified Immune Effector Cell Therapy for Acute Myeloid Leukemia (AML)

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3617
Author(s):  
Utkarsh H. Acharya ◽  
Roland B. Walter
Keyword(s):  
Acute Myeloid Leukemia ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Effector Cell ◽  
Antigen Receptor ◽  
Immune Effector Cell ◽  
B Cell Malignancies ◽  
Immune Effector ◽  
Acute Myeloid

Despite the availability of an increasing number of targeted therapeutics and wider use of allogeneic hematopoietic stem cell transplantation, many patients with acute myeloid leukemia (AML) ultimately succumb to this disease. Given their remarkable efficacy in B-acute lymphoblastic leukemia and other CD19-expressing B cell malignancies, there is hope adoptive cellular transfer, particularly chimeric antigen receptor (CAR)-modified immune effector cell (IEC) therapies, may afford a novel, potent immune-based approach for the treatment of AML that complements or replaces existing ones and improves cure rates. However, it is unclear how best to translate the success of these therapies from B cell malignancies, where use of highly potent immunotherapies is facilitated by identified target antigens with near ubiquitous expression on malignant cells and non-fatal consequences from “on-target, off-tumor cell” toxicities. Herein, we review the current status of CAR-modified IEC therapies for AML, with considerations regarding suitable, relatively leukemia-restricted target antigens, expected toxicities, and interactions of the engineered cells with a profoundly immunosuppressive tumor microenvironment that restricts their therapeutic efficacy. With these challenges in mind, we will discuss possible strategies to improve the cells’ potency as well as their therapeutic window for optimal clinical use in AML.

scholarly journals Newly developed pseudogout arthritis after therapy with MAGE-A4 directed TCR T cells responded to treatment with tocilizumab

2021 ◽  
Vol 9 (7) ◽  
pp. e002716
Author(s):  
Sang T. Kim ◽  
Jean Tayar ◽  
Siqing Fu ◽  
Danxia Ke ◽  
Elliot Norry ◽  
...  
Keyword(s):  
T Cells ◽  
Synovial Fluid ◽  
Th17 Cells ◽  
Effector Cell ◽  
Calcium Pyrophosphate ◽  
Calcium Pyrophosphate Dihydrate ◽  
Immune Effector Cell ◽  
Cell Therapies ◽  
Immune Effector ◽  
Pyrophosphate Dihydrate

With durable cancer responses, genetically modified cell therapies are being implemented in various cancers. However, these immune effector cell therapies can cause toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Pseudogout arthritis is an inflammatory arthritis induced by deposition of calcium pyrophosphate dihydrate crystals. Here, we report a case of pseudogout arthritis in a patient treated with MAGE-A4 directed T cell receptor T cells, for fallopian tube cancer. The patient developed CRS and ICANS 7 days after infusion of the T cells. Concurrently, the patient newly developed sudden onset of left knee arthritis. Synovial fluid analyses revealed the presence of calcium pyrophosphate dihydrate crystal. Notably, the pseudogout arthritis was resolved with tocilizumab, which was administered for the treatment of CRS and ICANS. Immunoprofiling of the synovial fluid showed that the proportion of inflammatory interleukin 17 (IL-17)-producing CD4+ T (Th17) cells and amount of IL-6 were notably increased, suggesting a potential role of Th17 cells in pseudogout arthritis after T-cell therapy. To the best of our knowledge, this is the first reported case of pseudogout arthritis after cell therapy. Clinicians, especially hematologists, oncologists and rheumatologists, should be aware that pseudogout arthritis can be associated with CRS/ICANS.

scholarly journals Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events

2020 ◽  
Vol 8 (2) ◽  
pp. e001511
Author(s):  
Marcela V Maus ◽  
Sara Alexander ◽  
Michael R Bishop ◽  
Jennifer N Brudno ◽  
Colleen Callahan ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Clinical Practice Guideline ◽  
Practice Guideline ◽  
Effector Cell ◽  
Cancer Therapeutics ◽  
Immune Effector Cell ◽  
Cell Therapies ◽  
Immune Effector ◽  
Hematological Cancers ◽  
Immunotherapy Of Cancer

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.

scholarly journals Immune effector cell–associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy for lymphoma: predictive biomarkers and clinical outcomes

2020 ◽  
Author(s):  
Noa G Holtzman ◽  
Hao Xie ◽  
Soren Bentzen ◽  
Vivek Kesari ◽  
Ali Bukhari ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Clinical Outcomes ◽  
Chimeric Antigen Receptor ◽  
Effector Cell ◽  
Immune Effector Cell ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has emerged as effective for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as immune effector cell–associated neurotoxicity syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR T-cell therapy in R/R LBCL. Methods Patients (n = 45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, respectively. Results Twenty-five (56%) patients developed ICANS, 18 (72%) of whom had severe (CTCAE grades 3–4) ICANS. Median time to development of ICANS was 5 days (range, 3–11). Elevated pre-infusion (day 0 [D0]) fibrinogen (517 vs 403 mg/dL, upper limit of normal [ULN] 438 mg/dL, P = 0.01) and D0 lactate dehydrogenase (618 vs 506 units/L, ULN 618 units/L, P = 0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, P < 0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS), or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS. Conclusions ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, the majority of which were high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.

scholarly journals Feasibility of a Supportive Mobile Health App for Chimeric Antigen Receptor T-Cell Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3009-3009
Author(s):  
Rahul Banerjee ◽  
Bella Sykes ◽  
Nina Shah ◽  
Charalambos Andreadis ◽  
Peter H. Sayre ◽  
...  
Keyword(s):  
Pilot Study ◽  
Patient Education ◽  
Chimeric Antigen Receptor ◽  
Research Funding ◽  
Effector Cell ◽  
Immune Effector Cell ◽  
Immune Effector ◽  
Toxicity Monitoring ◽  
Car T ◽  
Mhealth Apps

Abstract BACKGROUND: The operationalization of chimeric antigen receptor (CAR-T) therapy for hematologic malignancies can be complex for patients and their caregivers. In the weeks before CAR-T therapy, patients must process large amounts of information and coordinate logistics involving caregivers, lodging, and transportation. Immediately following CAR-T therapy, patients must be monitored closely for toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In the months following CAR-T therapy, patients may be referred back to local oncologists without a clear plan for managing potential late effects such as hypogammaglobulinemia or neuropsychiatric complications (Chakraborty 2021). Mobile health (mHealth) apps may be able to improve the patient experience during CAR-T therapy by facilitating care coordination, home-based toxicity monitoring, and patient education (Banerjee 2021). By empowering patients and caregivers to better understand CAR-T therapy and actively participate in their care, mHealth tools may ultimately augment workflows for CAR-T clinics as well. However, the feasibility and acceptability of such supportive mHealth apps during CAR-T therapy have not been established. STUDY DESIGN: We have designed a "Companion for CAR-T" mHealth app to assist with care coordination, toxicity monitoring, and patient education during CAR-T therapy. Key components of the app are summarized in the Figure. In brief, pre-CAR-T components include educational videos and dynamic calendars to assist patients with coordinating logistics. Post-CAR-T components include app-based prompts to input body temperature daily, an electronic Immune Effector Cell-Associated Encephalopathy (eICE) screening tool for ICANS that can be administered by caregivers, and a patient-specific long-term survivorship care plan. Global app components include an 'Appointment Companion' to facilitate patient-provider discussions during appointments as well as a digital CAR-T wallet card to convey key health-related information to other healthcare providers. We plan to investigate the "Companion for CAR-T" app through a pilot study of 20 patients receiving commercially available CAR-T therapies for any hematologic malignancy at our institution. Co-primary endpoints include (1) app feasibility, defined as the percentage of patients who access all 5 core modules shown in the Figure at least once; and (2) app acceptability, defined as the percentage of patients who agree that the app was helpful during their experience with CAR-T therapy. Secondary endpoints include the incidence of fevers or eICE deficits recorded via the app. Exploratory endpoints include longitudinal trends in patient-reported outcomes such as emotional distress at each clinic visit. DISCUSSION: If feasibility and acceptability of the "Companion for CAR-T" app are demonstrated through this pilot study, we plan to launch a multicenter randomized Phase 2 study of this mHealth tool versus usual care to assess its effect on perceived stress and decisional conflict. Other important steps for our group include the translation of app content into different languages and the provision of tablet computing devices for patients who do not own smartphones. Once validated and expanded in these aforementioned ways, potential strengths of the "Companion for CAR-T" app include its ability to be personalized easily with information specific to individual CAR-T therapies, malignancies, and centers. Figure 1 Figure 1. Disclosures Banerjee: Sanofi: Consultancy; SparkCures: Consultancy; Pack Health: Research Funding. Sykes: Patient Discovery Solutions, Inc.: Current Employment. Shah: Amgen: Consultancy; Indapta Therapeutics: Consultancy; Sutro Biopharma: Research Funding; Sanofi: Consultancy; Teneobio: Research Funding; Precision Biosciences: Research Funding; Poseida: Research Funding; Karyopharm: Consultancy; Janssen: Research Funding; GSK: Consultancy; Kite: Consultancy; Nektar: Research Funding; Oncopeptides: Consultancy; CSL Behring: Consultancy; Bluebird Bio: Research Funding; BMS/Celgene: Research Funding; CareDx: Consultancy. Andreadis: Incyte: Honoraria; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; GenMAB: Research Funding; Merck: Research Funding; Novartis: Research Funding; Epizyme: Honoraria; Crispr Therapeutics: Research Funding; Atara: Consultancy, Honoraria; Karyopharm: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; BMS/Celgene: Research Funding. Martin: Amgen: Research Funding; GlaxoSmithKline: Consultancy; Oncopeptides: Consultancy; Janssen: Research Funding; Sanofi: Research Funding. Shore: Patient Discovery Solutions, Inc.: Current Employment. Sodowick: Patient Discovery Solutions, Inc.: Current Employment. Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees.

Multiplex gene silencing as a promising tool for development of next generation immune effector cell therapies

Cytotherapy ◽  
2021 ◽  
Vol 23 (5) ◽  
pp. S85
Author(s):  
A. Roussel-Gervais ◽  
A. Sakic ◽  
O. Cherpin ◽  
S. Ilmjärv ◽  
P. Salmon ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Effector Cell ◽  
Immune Effector Cell ◽  
Next Generation ◽  
Cell Therapies ◽  
Immune Effector ◽  
Promising Tool
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