Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology

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  • 1 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 2 University of Michigan Rogel Cancer Center;
  • | 3 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 4 University of Wisconsin Carbone Cancer Center;
  • | 5 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 6 City of Hope National Medical Center;
  • | 7 St. Jude Children's Research Hospital/The University of Tennessee Health Science Center;
  • | 8 Yale Cancer Center/Smilow Cancer Hospital;
  • | 9 Roswell Park Comprehensive Cancer Center;
  • | 10 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 11 O'Neal Comprehensive Cancer Center at UAB;
  • | 12 Moffitt Cancer Center;
  • | 13 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 14 UCLA Jonsson Comprehensive Cancer Center;
  • | 15 UC Davis Comprehensive Cancer Center;
  • | 16 Fred & Pamela Buffett Cancer Center;
  • | 17 Abramson Cancer Center at the University of Pennsylvania;
  • | 18 Huntsman Cancer Institute at the University of Utah;
  • | 19 University of Colorado Cancer Center;
  • | 20 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 21 Fox Chase Cancer Center;
  • | 22 Vanderbilt-Ingram Cancer Center;
  • | 23 UC San Diego Moores Cancer Center;
  • | 24 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 25 Stanford Cancer Institute;
  • | 26 Mayo Clinic Cancer Center;
  • | 27 Memorial Sloan Kettering Cancer Center;
  • | 28 Duke Cancer Institute;
  • | 29 The University of Texas MD Anderson Cancer Center;
  • | 30 UT Southwestern Simmons Comprehensive Cancer Center; and
  • | 31 National Comprehensive Cancer Network

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.

Overview

CAR T cells represent a newer class of immunotherapy agents that is increasingly being incorporated into the treatment regimens of certain refractory or relapsed hematologic malignancies, specifically subtypes of B-cell non-Hodgkin lymphoma (NHL), adult and pediatric B-cell acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). CAR T cells are genetically reprogrammed T cells that express CARs, synthetic receptors that can be designed to target tumor surface antigens.1,2 This treatment is a type of adoptive cell therapy and can be referred to as a “living drug.”3 The intent of CAR T-cell therapy is to induce a potent antitumor immune response by merging the specificity of an antibody with the cytotoxic and memory functionality of T cells.2,4,5 Currently approved CAR T-cell anticancer therapies are generated from autologous T lymphocytes that are genetically modified to recognize and kill tumor cells that express specific antigens.610 Although CAR T-cell therapy has uniquely powerful activity in several B-cell malignancies, it is also accompanied by specific toxicities requiring specialized expertise in management. This text provides an overview of CAR T-cell therapies and NCCN recommendations for the management of CAR T-cell–related toxicities in patients with cancer based on available evidence and clinical experience. For a discussion of the efficacy data for CAR T-cell therapies, see the NCCN Guidelines for treatment of cancer by site at NCCN.org.

Design and Structure of CARs

CARs are engineered proteins that include an antigen recognition domain, a hinge region, a transmembrane domain, and at least 1 intracellular domain (Figure 1).3,11,12 The antigen recognition domain is an extracellular targeting domain derived from a single chain fragment variable that mimics an antibody’s antigen binding region and recognizes specific antigens expressed on the surface of tumor cells in an HLA-independent manner. For currently approved CAR T cells, the single chain fragment variable recognizes either cluster of differentiation 19 (CD19), for B-ALL and B-NHL, or B-cell maturation antigen (BCMA), for MM.610 Some agents under investigation have antigen recognition domains with a different structure or target novel antigens. For example, the antigen recognition domain of ciltacabtagene autoleucel is comprised of 2 llama-derived single variable domain on a heavy chain domains that can bind 2 distinct BCMA epitopes.13

Figure 1.
Figure 1.

(Top) For the full activation and proliferation of T cells, 2 signals are required. Signal 1 results from the interaction between the peptide antigen expressed on the antigen presenting cell (APC) and the T-cell receptor. Signal 2 results from the interaction between a costimulatory receptor (such as CD28 or 4-1BB) expressed on T cells and its corresponding ligand expressed on APCs. (Bottom) Chimeric antigen receptors (CARs) are modular structures comprised of an antigen recognition domain, a hinge domain, a transmembrane domain, and at least 1 intracellular domain. Intracellular domains of currently available CAR T cells include a costimulatory domain (derived from CD28 or 4-1BB) and a T-cell activation domain. Incorporation of both types of intracellular domains in a single construct is thought to enable CARs to transduce both signal 1 and signal 2 on binding to the tumor antigen, thereby enhancing the activation and proliferation of CAR T cells.

Citation: Journal of the National Comprehensive Cancer Network 20, 4; 10.6004/jnccn.2022.0020

CAR T-cell therapies typically have an immunoglobulin-like hinge domain that separates the antigen recognition domain from the transmembrane domain.14 Approved agents have an IgG4, CD28, or CD8α hinge domain.610 Optimization of this domain may increase access to the antigen and improve the efficiency of CAR expression and activity.14

It is critical for CAR constructs to have a transmembrane domain, which enables the CARs to be embedded within the T-cell membrane, and may contribute to CAR T-cell signaling.14 Most available CAR T-cell therapies use a CD8α or CD28 transmembrane domain.610

Early studies also found that CAR constructs require a domain to activate T cells, also known as a T-cell activation domain.3 All approved agents use a CD3ζ signaling domain for this function.610

Although the T-cell activation domain was the only intracellular domain included in “first-generation” CAR T-cell constructs, currently available “second-generation” CAR constructs now also include either a CD28 or 4-1BB intracellular costimulatory construct.3,610,15 The binding of a costimulatory receptor such as CD28 or 4-1BB to its cognate ligand on an antigen-presenting cell (APC) provides an additional signal for normal T-cell activation; therefore, inclusion of a CD28 or 4-1BB costimulatory domain within CAR constructs enhances the activation, proliferation, and antitumor activity of CAR T cells (Figure 1).15,16 Different costimulatory domains appear to be associated with changes in expansion kinetics, persistence, and possibly toxicity.15 Unfortunately, efforts to evaluate the superiority of each type of costimulatory domain based on efficacy and safety data have been inconclusive due to various factors, such as differences in other CAR domains, clinical trial design, and toxicity grading systems.15 Newer-generation CAR constructs with more or different costimulatory domains, as well as with a variety of antigen targets, including solid tumor antigens, are currently under active development.17

Targets of Currently Approved CAR T Cells

CD19

CD19 is a transmembrane glycoprotein that is a member of the immunoglobulin superfamily and is an important regulator of B-cell signaling and B-cell activation.1821 Due to its expression at all stages of B-cell differentiation, except for hematopoietic stem cells, CD19 is considered a reliable B-cell biomarker.2123 Importantly, CD19 is retained on cells that have undergone neoplastic transformation.21,23 Increased expression of CD19 has been found on most B-cell tumors, including B-cell ALL, chronic lymphocytic leukemia, and B-cell lymphomas.2228 Currently approved CD19 CAR T-cell therapies include tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel.6,7,9,10

BCMA

BCMA is a transmembrane protein that is a member of the tumor necrosis factor receptor superfamily.2931 Expressed on the surface of mature B cells, but not naïve B cells or other hematopoietic cells, BCMA is thought to promote the survival of plasma cells in the bone marrow.29,30,32,33 BCMA was identified as a promising biomarker and drug target for MM based on several findings. Serum BCMA levels were observed to be higher in patients with MM compared with those without MM.34,35 Multiple studies found that BCMA is expressed in malignant cells from patients with MM.3539 Furthermore, overexpression of BCMA promoted cell proliferation in both in vitro and in vivo models.40 Currently the only BCMA-targeting CAR T-cell therapy approved in the United States is idecabtagene vicleucel, which was approved in 2021 for the treatment of MM.8 Ciltacabtagene autoleucel is another BCMA-targeted CAR T-cell therapy that is being considered by the FDA for approval for the treatment of relapsed or refractory MM.41

Overall CAR T-Cell Treatment Schema

CAR T-cell therapy is a multistep process that can take several weeks to complete.42 The first step is leukapheresis, the procedure of collecting white blood cells (including T cells) from a patient’s blood.4,43,44 The cells are subsequently sent to a laboratory, where T cells are isolated, activated, and transduced with a CAR transgene (typically delivered via a lentiviral or retroviral vector). Transduced T cells are then expanded, harvested, and prepared for infusion.4,4345 Finally, patients are infused with the CAR T cells. Prior to infusion, patients undergo lymphodepletion chemotherapy (LDC). The goal of LDC is to prevent immunologic rejection of the infused CAR T cells to maximize their expansion and persistence. LDC typically consists of fludarabine and cyclophosphamide.610,46,47 Bendamustine is an alternative option before tisagenlecleucel infusion in patients with relapsed or refractory diffuse large B-cell lymphoma who had a prior grade 4 hemorrhagic cystitis with cyclophosphamide or developed a resistance to a previous cyclophosphamide-containing regimen.10 Depending on the product, patients may be treated on an inpatient or outpatient basis. However, outpatient therapy requires a robust infrastructure for rapid evaluation and intervention for toxicity.

CAR T-Cell Therapy–Related Toxicities and Management Strategies

Despite the promising benefits of CAR T-cell therapies in the treatment of certain cancers, clinicians need to be aware of the serious and potentially fatal toxicities that may occur with the use of this newer class of agents. Overall, the most common and unique toxicities associated with CAR T-cell therapies are cytokine release syndrome (CRS) and neurotoxicity, and are entirely distinct from the immune-related adverse events that occur with the use of immune-checkpoint inhibitors. In addition, some toxicities (eg, hypogammaglobulinemia) are a direct result of on-target/off-tumor activity of the CAR T cells, and others (eg, infections) may occur as an indirect consequence of the immunosuppressed state of the patient. Fortunately, CAR T-cell therapy–related toxicities are almost always reversible and can be managed by the judicious use of immunosuppressive medications.

Principles of Patient Monitoring

The NCCN panel has provided recommendations on monitoring patients who receive CAR T-cell therapies based on available evidence and clinical experience, as detailed subsequently and on CART-1 (page 388). For effective toxicity management, clinicians need to closely monitor patients before, during, and after CAR T-cell infusions to ensure the early recognition of and intervention for specific adverse reactions related to treatment. Patients with underlying organ dysfunction may experience additional complications when treated with CAR T-cell therapies; proactive management and multidisciplinary involvement is especially crucial for these patients.

Before and During CAR T-Cell Infusion

Due to the potential cardiac manifestations of CAR T-cell-related toxicities, especially for those with underlying risk,4851 a baseline cardiac assessment (such as an echocardiogram) is recommended. Consultation with cardiology may be warranted for patients with cardiovascular comorbidities at baseline. Central venous access, preferably with double or triple lumen catheter, for intravenous fluid and possible vasopressor use is recommended. Cardiac monitoring should be performed at the onset of clinically significant arrhythmia and additionally as clinically indicated. For patients with large tumor burden and aggressive histologies, standard tumor lysis prophylaxis and monitoring are recommended. Seizure prophylaxis (eg, levetiracetam 500–750 mg orally every 12 hours for 30 days) are often used on the day of infusion, especially for CAR T-cell therapies that are known to cause more severe CAR T-cell–related neurotoxicity (eg, axicabtagene and brexucabtagene). Because of the potential for severe neurotoxicity, all patients should receive baseline neurologic evaluation, including immune effector cell-associated encephalopathy (ICE) scores (for adults) or Cornell Assessment of Pediatric Delirium (CAPD) scores (for children less than 12 years) prior to CAR T-cell therapy. Some centers require baseline brain MRI. Assessment of C-reactive protein (CRP) and serum ferritin levels is recommended at baseline.

Post-CAR T-Cell Infusion

Hospitalization or extremely close outpatient monitoring at centers with CAR T-cell experience is recommended. Close monitoring in the hospital is preferred with current products for adults; however, extremely close outpatient monitoring may be possible at centers with outpatient transplant experience. Hospitalization is warranted for patients at the first sign of CRS or neurotoxicity, including fever, hypotension, or change in mental status. Complete blood count, complete metabolic panel (including magnesium and phosphorus), and coagulation profiles should be monitored daily. CRP and serum ferritin should be rechecked at least 3 times per week for 2 weeks postinfusion. Daily levels can be considered if CRS occurs. Vital signs to allow clinical assessment for CRS should be done at least every 8 hours, or when the patient’s status changes, during the peak window of CRS risk, which is typically the first 1 or 2 weeks postinfusion. The time to onset of fever, and therefore CRS, may be earlier in patients treated with CD28 costimulatory domain-containing products (axicabtagene ciloleucel and brexucabtagene autoleucel) compared with 4-1BB costimulatory domain-containing products (tisagenlecleucel, lisocabtagene maraleucel, and idecabtagene vicleucel). Note that CRS may normalize before the onset of neurotoxicity. Neurotoxicity assessment (as described subsequently) should be done at least twice daily or when the patient’s status changes. This is typically during the first 1 or 2 weeks postinfusion but has been seen with later onset up to a month and very rarely later. If neurologic concern develops, more frequent assessments are recommended. Patients should be monitored for CRS, neurotoxicity, and other toxicities for the duration recommended by the CAR product package insert (at least 4 weeks postinfusion for most patients). Patients should refrain from driving or hazardous activities for at least 8 weeks after infusion.

Management Strategies for Specific CAR T-Cell Therapy-Related Toxicities

An overview of CAR T-cell therapy–related toxicities is shown in the algorithm (see CART-2, page 390). The presentation and the management of specific toxicities related to CAR T-cell therapies are discussed in the following sections. It is critical to recognize that the exact timing, frequency, severity, and optimal management of CAR T-cell-related toxicities vary between products, and are likely to vary further as newer products gain approval. The NCCN Guidelines attempt to provide guidance that is generally applicable, but clinicians must imperatively consult their institutional guidelines and the prescribing information for individual agents for specific management strategies.

CRS

CRS has been reported with all FDA approved CAR T-cell therapies and is one of the most common adverse events that occur with both CD19- and BCMA-directed CAR T cells. Due to the different grading scales used to assess CRS severity in clinical trials, differences in CAR T-cell design and generation, and clinical trial design (including study population, dose regimen, and treatment protocols), a wide range of CRS rates have been reported with different CAR T-cell therapies.5259 Therefore, toxicity rates from trials of different agents may not always be directly comparable.

Presentation and Onset

CRS is defined by the American Society for Transplantation and Cellular Therapy (ASTCT) as a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells (eg, lymphocytes, myeloid cells).60 Specific CRS manifestations may include fever, hypotension, tachycardia, hypoxia, and chills, and may be associated with cardiac, hepatic, and/or renal dysfunction. Serious events that may occur with CRS include hypotension, hypoxia, atrial fibrillation and ventricular tachycardia, cardiac arrest, cardiac failure, renal insufficiency, and capillary leak syndrome. The cardiovascular complications that attend CRS can be severe and even fatal for patients with underlying risk who receive CAR T-cell therapy,48,49 again highlighting the importance of careful patient selection and close monitoring. The typical time to onset for CRS is 2 to 3 days, with a duration of 7 to 8 days, although CRS may occur within hours after CAR T-cell infusion and as late as 10 to 15 days postinfusion.52,5459

Pathophysiology

The overactivation of immune effector cells lead to the release of inflammatory cytokines, which ultimately results in endothelial injury and capillary leak that can present clinically as hemodynamic instability and organ dysfunction.61,62 Multiple cytokines have been implicated in CRS, including IL-6, IL-1, IFN-γ, and TNF-α.6167 IL-6 is considered a central mediator of CRS and is thought to provide an activating signal to CAR T cells.61 In normal conditions, IL-6 binds to membrane-bound IL-6 receptor (IL-6R) on certain immune effector cells and has anti-inflammatory properties; this is referred to as the classic signaling pathway. However, when IL-6 levels are increased (such as during CRS), IL-6 may bind to the soluble form of IL-6R (sIL-6R) and induce a proinflammatory response via activation of a trans signaling pathway.

Risk Factors

Several risk factors for severe CRS have been identified, although these vary across studies and likely across indications.61,62,6871 These generally (but not always) include increased CAR T-cell expansion and higher tumor burden (including high disease burden in bone marrow).61,62,70,71

Grading

The NCCN Guidelines follow the ASTCT Consensus Grading scale for CRS, which used a consensus approach to harmonize the various CRS definitions and grading systems that were previously used in pivotal clinical trials.60 The grades are defined by presence of fever (≥38°C), the severity of hemodynamic compromise, and that of hypoxia. Fever defines the onset of CRS, with a temperature of ≥38°C not attributable to any other cause being the only symptom required for the classification as grade 1 CRS. Other types of organ dysfunction were not included in the ASTCT grading criteria. Laboratory parameters (eg, CRP or specific cytokines) were also not included in the definition or the grading scale for CRS, as it was deemed that there was insufficient evidence to support their use in this context.60 However, these parameters may become more important in the future with additional studies. Refer to CART-3 in the algorithm (page 391) for the adapted definitions of each CRS grade.

Overall Management Strategy for CRS

Management of CRS in patients who received CAR T-cell therapy consists of both direct targeting and nonspecific immunosuppressive strategies to counter the overactive immune cells and increased cytokine levels. Generally, patients are administered a combination of tocilizumab and corticosteroids, in addition to receiving supportive care.

Anti-IL-6 Therapy

Tocilizumab is a humanized, IgG1κ anti-IL-6R antibody that was approved by the FDA in 2017 for the treatment of severe or life-threatening CAR T cell–induced CRS in adults and pediatric patients aged 2 years and older.72,73 Tocilizumab binds to both soluble and membrane-bound IL-6R and is hypothesized to block the downstream signal transduction pathways implicated in CRS.74 Tocilizumab is currently the only anti-IL-6 therapy approved by the FDA for the treatment of CRS.

This approval was based on a retrospective study of patients with hematologic malignancies who developed severe or life-threatening CRS and received tocilizumab after treatment with tisagenlecleucel (n=45) or axicabtagene ciloleucel (n=15) in prospective trials.72,73 CRS was resolved within 14 days of the first tocilizumab dose in 69% and 53% of patients in the tisagenlecleucel and axicabtagene ciloleucel cohorts, respectively. No adverse reactions were reported in this study, although infections, cytopenias, elevated liver enzymes, and lipid dysregulation have been reported with tocilizumab use in clinical trials for other conditions.72,73

Although it is approved for severe or life-threatening cases, many centers and the prescribing information for individual agents advise using tocilizumab at lower grades of CRS.69,75 For example, the prescribing information for axicabtagene ciloleucel states that tocilizumab can be considered for grade 1 CRS if CRS symptoms persist for more than 24 hours.6 This is supported by data from an exploratory safety management cohort of the ZUMA-1 trial, which demonstrated that patients who received earlier intervention with tocilizumab and/or corticosteroids for CRS (as early as grade 1) had numerically lower rates of grade 3 or greater CRS (2%) compared with patients who received intervention at later CRS grades (12%).76

A proposed alternative to tocilizumab is siltuximab, an anti-IL6 antibody that is approved for the treatment of Castleman’s disease.77 By targeting the same pathway as tocilizumab, siltuximab would theoretically also be a viable treatment option for CRS. An additional potential advantage of siltuximab over tocilizumab is that the latter targets the receptor for IL-6 without sufficient central nervous system (CNS) penetration. This causes a transient rise in serum IL-6 levels, which some have postulated may worsen neurotoxicity by increasing cerebrospinal fluid IL-6 levels.65,78 This potential increase in the neurotoxicity is an important concern in general with the use of tocilizumab for CRS and may support the more frequent use of corticosteroids in conjunction with tocilizumab in more recent management guidelines. For persistent refractory CRS after 1 or 2 doses of tocilizumab, the guideline recommends considering the addition of corticosteroids. Despite the theoretical advantage of the IL-6-targeting siltuximab, there is limited data in the formal clinical trial setting supporting the use of this agent for CRS.78,79 Anakinra, an IL-1Ra antagonist currently approved for the treatment of several inflammatory conditions,80 is considered another potential alternative to tocilizumab for the treatment of CRS following CAR T-cell therapy. The rationale for targeting IL-1 is primarily based on evidence from two preclinical studies, which demonstrated that IL-1 blockade protected against CRS in mouse models without impacting the antitumor activity of the CAR T-cells.65,66 While there are some reports in patients that suggest anakinra may be effective for managing CAR T-cell therapy–associated CRS,81,82 there is also limited data supporting use of anakinra in this setting. Data from ongoing clinical trials will shed light on whether siltuximab and anakinra are viable alternatives to tocilizumab for the treatment of CRS.

Corticosteroids

Corticosteroids play an important role in CRS management in addition to anti-IL-6 therapy. Although the use of corticosteroids may alleviate the symptoms of CRS, there is theoretical concern that the use of higher doses of steroids could suppress CAR T-cell expansion and persistence, and therefore reduce the antitumor benefit of CAR T-cells.83 However, this concern has not been supported in most studies, and corticosteroids are a cornerstone of CRS management. Furthermore, in the context of axicabtagene, the use of corticosteroids, either with milder CRS (or even prophylactically) appear to be associated with preserved efficacy, lower risk of severe CRS, and lower cumulative use of steroids.76,84,85 The most commonly used corticosteroids are dexamethasone and methylprednisolone. For patients with neurologic symptoms, dexamethasone may be preferred due to better penetration of the blood–brain barrier.86 If steroids are used for the management of CRS, a rapid taper should be used when symptoms begin to improve.

Options for Steroid-Refractory CRS

If CRS does not improve after tocilizumab and steroids, workup for infections need to be considered and managed as appropriate. In addition to siltuximab and anakinra, other agents can be considered for patients who are refractory to both tocilizumab and corticosteroids, including the Janus associated kinase (JAK) 1/2 inhibitor ruxolitinib, cyclophosphamide, extracorporeal cytokine adsorption with continuous renal replacement therapy, intravenous IgG (IVIG), and antithymocyte globulin; however, data supporting the use of these agents are mostly anecdotal or from small case series.6,8792 This will likely change in the future as results from ongoing clinical trials mature.

NCCN Recommendations for CRS

Urgent intervention is required to prevent the progression of CRS; however, other potential causes of inflammatory response, including infections and malignancy progression, should be ruled out. Empirical treatment for infections is warranted in patients who are febrile and neutropenic. Organ toxicities associated with CRS may be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, but clinicians should be aware that these do not influence CRS grading under the ASTCT system. Organ toxicities should receive a thorough workup and appropriate management. Fever is defined as a temperature that is above 38°C that is not attributable to any other cause. For patients with CRS who receive antipyretics or anticytokine therapy, such as tocilizumab or steroids, fever is not required to grade subsequent CRS severity. For these cases, hypotension or hypoxia will determine CRS grading. See subsequent sections (and CART-3 and CART-3A [pages 391 and 392]) for detailed treatment recommendations for CRS by grade.

In general, after each dose of anti-IL-6 therapy or corticosteroids, the need for subsequent dosing should be assessed. As per the prescribing information for axicabtagene ciloleucel, consider the use of prophylactic corticosteroids in patients after weighing the potential benefits and risks. Steroid prophylaxis for axicabtagene ciloleucel is dexamethasone 10 mg orally once daily for 3 days, with the first dose starting before CAR T-cell infusion; however, use of dexamethasone in this setting may increase the risk of grade 4 and prolonged neurologic toxicities. Additionally, antifungal prophylaxis should be strongly considered in patients receiving steroids for the treatment of CRS and/or neurotoxicity.

Grade 1 (fever ≥38°C): For prolonged CRS (longer than 3 days) in patients or those with significant symptoms, comorbidities, and/or are elderly, 1 dose of tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg) can be considered. For patients treated with axicabtagene ciloleucel or brexucabtagene autoleucel, tocilizumab can be considered if CRS symptoms persist for >24 hours. For patients treated with lisocabtagene maraleucel, consider tocilizumab for grade 1 CRS that develops <72 hours after infusion, and consider adding 1 dose of dexamethasone 10 mg; for CRS that develops ≥72 hours after infusion, treat symptomatically. For patients who received idecabtagene or lisocabtagene, consider administering dexamethasone 10 mg intravenously every 24 hours for early-onset CRS (<72 hours after infusion). Additional supportive care for grade 1 CRS includes sepsis screen and empirical broad spectrum antibiotics (especially in neutropenic patients), judicious use of intravenous fluids, electrolyte repletion, and management of specific organ toxicities.

For grade 2 (fever with hypotension not requiring vasopressors and/or hypoxia requiring low-flow nasal cannula or blow-by), tocilizumab 8 mg/kg intravenous over 1 hour (not to exceed 800 mg/dose) is recommended and can be repeated in 8 hours if no improvement is observed. No more than 3 doses should be administered in 24 hours, with a maximum of 4 doses total. Dexamethasone 10 mg intravenous every 12 to 24 hours (or equivalent) can be considered (depending on the product) for persistent refractory hypotension after 1 or 2 doses of an anti-IL-6 therapy. Note that some centers and manufacturer recommendations suggest the use of corticosteroids routinely for grade 2 CRS. Cardiac monitoring should be performed at least at the onset of grade 2 CRS until resolution to grade 1 or less. Additional supportive care for grade 2 CRS includes intravenous fluid bolus as needed, management as per grade 3 if no improvement is seen within 24 hours of starting anti-IL6 therapy, and symptomatic management of organ toxicities. For those with persistent refractory hypotension after 2 fluid boluses and anti-IL-6 therapy, clinicians should start vasopressors, transfer the patient to an ICU, consider an echocardiogram, and initiate more thorough methods of hemodynamic monitoring. Telemetry and electrocardiogram, along with assessment of troponin and brain natriuretic peptide should be performed if tachycardia persists.

For grade 3 (fever with hypotension requiring a vasopressor with or without vasopressin or hypoxia requiring high-flow cannula, face mask, nonrebreather mask, or Venturi mask), anti-IL-6 therapy as per grade 2 is recommended, if the maximum dose is not reached within a 24-hour period. Dexamethasone 10 mg intravenous (or equivalent) should be administered every 6 hours. Patient can be managed as grade 4 if refractory to this treatment. Additional supportive care for grade 3 CRS includes the transfer of the patient to the ICU, an echocardiogram, hemodynamic monitoring, supplemental oxygen, intravenous fluid bolus and vasopressors as needed, and symptomatic management of organ toxicities.

For grade 4 (fever with hypotension requiring multiple vasopressors, excluding vasopressin, and/or hypoxia requiring positive pressure [eg, continuous positive airway pressure, bilevel positive airway pressure, intubation, mechanical ventilation]), anti-IL-6 therapy as per grade 2 is recommended, if the maximum dose is not reached within a 24-hour period. Dexamethasone 10 mg intravenous (or equivalent) should be administered every 6 hours. If refractory, 3 doses of methylprednisolone 1000 mg/day intravenous can be considered; dosing every 12 hours can also be considered. For example, methylprednisolone intravenous 1,000 mg/day can be administered for 3 days, followed by a rapid taper at 250 mg every 12 hours for 2 days, 125 mg every 12 hours for 2 days, and 60 mg every 12 hours for 2 days. Other agents such as anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG, antithymocyte globulin, or extracorporeal cytokine adsorption with continuous renal replacement therapy might also be considered.

Tocilizumab availability may be limited due to the FDA Emergency Use Authorization for hospitalized patients with severe COVID-19.93 Under these conditions, the NCCN panel recommends that the use of tocilizumab be limited to a maximum of 2 doses during a CRS episode. Clinicians should also consider using steroids more aggressively (eg, with the first or second dose of tocilizumab). If necessary, replacement of the second dose of tocilizumab with siltuximab or anakinra can be considered, although again there is limited evidence to support this approach and neither of these agents have received FDA approval for the treatment of CRS.

Neurotoxicity

Neurotoxicity is another adverse event that commonly occurs with CAR T-cell therapies. As with CRS rates, neurotoxicity incidence rates after CAR T-cell therapy reported in clinical trials vary widely. This is due to many factors, including differences in grading scales, CAR design and development, and clinical trial design. The rates of CAR T -cell–related neurotoxicity can vary across products, and clinicians should familiarize themselves with their frequency for the product(s) they are using.

Presentation and Onset

The neurotoxicity that occurs with CAR T-cell therapies has been termed immune effector cell-associated neurotoxicity syndrome (ICANS) by the ASTCT, and it is defined as a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.60

Occasionally, neurologic adverse events may occur in the context of CRS, especially headaches. Neurologic symptoms due to CRS typically happen earlier than ICANS and lack the more generalized encephalopathy and frequent language disturbances of the latter. It is very important to remember that ICANS, unlike CRS, is generally unresponsive to tocilizumab, which is unable to cross the blood–brain barrier when administered intravenously.64,94,95 Data from a preclinical study showed that prophylactic treatment with tocilizumab did not prevent CAR T cell–induced neurotoxicity in a mouse model.65 Similarly, data from a small study in 43 patients who received CD19-directed CAR T-cell therapy suggested that early intervention therapy with tocilizumab did not have an impact on overall neurotoxicity rates or in preventing severe neurotoxicity events.96 Other studies have also found that tocilizumab did not alleviate neurologic toxicities in patients treated with CD19-directed CAR T-cell therapies.47,94

Transient neurologic symptoms reported to occur with CAR T-cell therapies can be heterogeneous and include encephalopathy, delirium, aphasia, lethargy, headache, tremor, myoclonus, dizziness, motor dysfunction, ataxia, sleep disorder (eg, insomnia), anxiety, agitation, and signs of psychosis. Serious events, such as seizures, depressed level of consciousness, and fatal and serious cases of cerebral edema, have also occurred. Despite similarities with other encephalopathies, the neurotoxicity associated with CAR T-cell therapy has distinct common features, including language disturbances, encephalopathy, and motor dysfunction, which are captured in the ASTCT consensus grading criteria for ICANS.60,64,94,97 Headache alone is not considered a useful diagnostic symptom for ICANS, as it is very common and frequently co-occurs with fever. The ASTCT consensus guidelines include intracranial pressure and edema as domains for ICANS grading, but cerebral edema is very rare and it is unclear if it arises from a distinct pathophysiology.60

The typical time to onset of neurotoxicity is 4 to 10 days after receiving CAR T-cell therapy, with a duration of 14 to 17 days.52,5457,64,94,98 The duration may be slightly shorter with BCMA-directed CAR T-cell therapies.59,99

Pathophysiology

Although the pathophysiology is not yet fully understood, CAR T-cell-related neurotoxicity is thought to occur as a result of endothelium cell activation and leak in the central nervous system, leading to elevated inflammatory cytokines in the cerebrospinal fluid (CSF).61,64,86,94,100,101 Several cytokines are implicated in the pathophysiology of CAR T-cell related neurotoxicity, including IL-6, IFNγ, and TNFα.

Risk factors

CRS is considered a strong risk factor for ICANS, with the severity of CRS correlating with that of ICANS.58,64,94,97,101 Other possible ICANS risk factors may include higher disease burden, high baseline inflammatory state, pre-existing neurologic comorbidities, and higher CAR T-cell dose.64,86,94 High-grade ICANS is more common with CD19-directed CAR than BCMA-directed CAR.5259,99 As with CRS, reported risk factors and incidence vary across studies.64,94,98,102

Grading

The NCCN panel recommends following the ASTCT ICANS Consensus grading scale, which consists of an ICE score as a standardized assessment for encephalopathy, as well as the following 4 neurologic domains: level of consciousness, seizure, motor findings, and elevated intracranial pressure/cerebral edema (see CART-4, page 393).60 The pediatric version incorporated the CAPD score in place of ICE assessment in children younger than 12 years or those with developmental delay.60 The overall ICANS grade is the most severe symptom in any of the 5 domains.

By including only the most common and specific neurotoxicity symptoms that would trigger specific interventions, the ASTCT ICANS consensus grading scale improves the ease of grading compared with the method used by earlier trials, which was to grade by CTCAE multiple individual and often overlapping terms (such as encephalopathy and delirium). For seizures, the ASTCT ICANS grading scale considers any single clinical or subclinical electrographic seizure of any type to be a grade 3 event, with prolonged or repetitive clinical or subclinical seizures without a return to baseline in between to be grade 4.

The ICE component of the ASTCT ICANS grading scale is derived from a 10-point screening tool that enables the objective grading of overlapping encephalopathy terms.60 ICE is a modified version of the CARTOX-10 screening tool, and evaluates the following abilities: (1) orientation, (2) naming, (3) command following, (4) writing, and (5) attention (see CART-4, page 393). In addition to contributing to the grade of ICANS, the ICE assessment can be used daily or every shift as a screen for the onset of ICANS during the at-risk period.

Please refer to CART-4 (page 393) for additional details on use of the ICE screening tool and the ASTCT ICANS grading scale.

Management of ICANS/Neurotoxicities Related to CAR T-cell Therapy

Corticosteroids form the cornerstone of ICANS management, in addition to careful monitoring and supportive care. Tocilizumab is not recommended by the NCCN Panel to treat neurotoxicity in patients treated with CAR T-cell therapies, unless there is concurrent CRS. It may be preferable to use corticosteroids alone in the patient with grade 1 CRS (fever alone) and higher grade ICANS due to the possibility that tocilizumab may exacerbate ICANS.

NCCN Recommendations

The panel recommends that clinicians use the ASTCT ICANS Consensus Grading Scale for Adults to grade any CAR T-cell–related neurotoxicity (see CART-4, page 393). The ICANS grade is determined by the most severe event (ie, ICE score, level of consciousness, seizure, motor findings, raised intracranial pressure/cerebral edema) that is not attributable to any other cause (eg, sedating medication). The ICE score should be derived from the ICE Assessment Tool. This tool can be used to track a patient’s status over time; however, clinical judgement is still necessary when using the ICE assessment. Other signs and symptoms such as headache, tremor, myoclonus, asterixis, and hallucinations may occur and could be attributable to immune effector-cell engaging therapies. Although they are not included in this grading scale, careful attention and directed therapy may be warranted.

Neurology consultation is recommended at the first sign of neurotoxicity. On a neurotoxicity diagnosis, neurologic assessment and grading should be performed at least twice a day to include cognitive assessment and motor weakness. MRI of the brain with and without contrast (or brain CT, if MRI is not feasible) is recommended for those with neurotoxicity that is grade 2 or higher. An electroencephalogram for seizure activity should also be conducted for those patients. Clinicians should be cautious when prescribing medications that can cause CNS depression (excluding those needed for seizure prophylaxis or treatment). If dexamethasone is used for prophylaxis of CRS, there may be an increased risk of grade 4 and prolonged neurologic toxicities.6,85

Treatment for neurotoxicity is based on ICANS grade (see CART-5, page 394). Supportive care alone is recommended for grade 1 neurotoxicity. If ICANS develops within 72 hours after infusion of either lisocabtagene maraleucel or idecabtagene vicleucel, consider administering dexamethasone 10 mg intravenously every 12 to 24 hours for 2 doses and reassess.

For grade 2 neurotoxicity, patients should receive supportive care and a dose of dexamethasone 10 mg intravenous, followed by reassessment. Dexamethasone may be repeated every 6 to 12 hours, if there is no improvement.

Dexamethasone 10 mg intravenous every 6 hours or methylprednisolone (1 mg/kg intravenous every 12 hours) is recommended for grade 3 neurotoxicity; for patients who received axicabtagene ciloleucel or brexucabtagene autoleucel, methylprednisolone 1 gram daily for 3 to 5 days may be preferable. High-dose corticosteroids are the recommended treatment option for grade 4 neurotoxicity. For example, methylprednisolone IV 1,000 mg/day (may consider twice a day) for 3 days, followed by rapid taper at 250 mg every 12 hours for 2 days, 125 mg every 12 hours for 2 days, and 60 mg every 12 hours for 2 days. Convulsive status epilepticus should be treated as per institutional guidelines.

Patients with grade 3 neurotoxicity or higher should receive ICU care. Clinicians should consider repeating neuroimaging (CT or MRI) every 2 or 3 days if the patient has persistent neurotoxicity that is grade 3 or higher. Patients should also undergo assessment for papilledema or other signs of elevated intracranial pressure. If elevated intracranial pressure is excluded, a diagnostic lumbar puncture may be considered for patients with grade 3 or 4 neurotoxicity. Antifungal prophylaxis should be strongly considered in patients receiving steroids for the treatment of CRS or neurotoxicity. If steroids are given for the management of ICANS, a fast taper should be used when there is improvement.

Tocilizumab can be used for the treatment of CRS in patients with neurotoxicity and CRS occurring concurrently. It may be preferable to use corticosteroids alone in the patient with grade 1 CRS (fever alone) and concurrent higher grade neurotoxicity due to the possibility that tocilizumab may exacerbate neurotoxicity. Consider transferring the patient to the ICU if the neurotoxicity is associated with CRS that is grade 2 or higher.

Hemophagocytic Lymphohistiocytosis/Macrophage-Activation Syndrome

Hemophagocytic lymphohistiocytosis/macrophage-activation syndrome (HLH/MAS) can be described as severe immunologic syndromes caused by uncontrolled immune activation. This is thought to be the result of hyperactivation of macrophages and lymphocytes, increased production of proinflammatory cytokines, infiltration of lymphocytes and histiocytes in tissues and organs, and immune-mediated multiorgan failure.75,103105 Unlike HLH/MAS that occurs due to underlying genetic mutations (referred to as primary HLH/MAS), CAR T-cell therapy–induced HLH/MAS is considered a secondary HLH/MAS, as it is caused by an immune trigger.104,106 One recent study estimated that HLH/MAS occurs in 3.5% of patients treated with CAR T-cell therapy.107 However, the true incidence of HLH/MAS has been debated, in part due to the close overlap in CRS and HLH/MAS symptoms.75,106,108

A clear diagnosis of HLH/MAS after CAR T-cell therapy can be difficult, because the clinical features and laboratory abnormalities can have substantial overlap with CRS (eg, high fevers, increased ferritin levels).60,63,75,109,110 Most patients with moderate to severe CRS have laboratory abnormalities that meet the classic criteria for HLH, such as elevated CRP, hyperferritinemia, cytopenias, hypofibrinogenemia, coagulopathy, and elevated levels of several serum cytokines, including IL-6, INFγ, sIL-2Ra, and granulocyte macrophage colony-stimulating factor.63,104 Clinical features associated with CAR T cell–induced HLH include fever, multiorgan dysfunction, and CNS issues (eg, headaches, vision disturbances, and issues related to walking), but patients may not have hepatosplenomegaly or evidence of hemophagocytosis.60,75,103

Because HLH/MAS symptoms resolve with the clinical management and resolution of CRS in most cases (and therefore there is no need to directly treat HLH/MAS), an expert panel convened by the ASTCT decided to exclude HLH/MAS from the definition of CRS.60 Furthermore, a separate grading scale for HLH/MAS was not established, due to the degree of similarity with CRS and the lack of available CTCAE terms. Clinical management of HLH/MAS mirrors the strategies used for managing CRS, which consists of anti-IL-6 therapy and aggressive use of corticosteroids; the overall goal of this strategy is to suppress the overactive immune cells responsible for the symptoms.75 A high mortality rate has been linked with refractory HLH/MAS,111,112 and therefore prompt treatment is required. Some cases of late-onset HLH/MAS-like pathology may occur, which may be tocilizumab refractory. For these cases, corticosteroids and anakinra should be considered. There have been anecdotal reports of the resolution of HLH with anakinra administration.107,113,114 As a last resort, etoposide may be an option for HLH/MAS that shows no improvement with these measures; this is primarily based on clinical experience with non–CAR T cell–associated HLH.75,104,105,111,115 In general, this approach is not recommended due to etoposide’s toxicity to T lymphocytes and lack of data in the CAR T-cell setting. Intrathecal cytarabine is another potential option for patients with HLH-associated neurotoxicity,75 however, data supporting use of this agent in this setting is lacking.

NCCN Recommendations

The NCCN Panel recommends the following criteria for when there is clinical concern for HLH/MAS: (1) Rapidly rising and high ferritin (>5000 ng/mL) with cytopenias in the context of fever, especially if accompanied by any of the following: grade ≥3 increase in serum bilirubin, aspartate aminotransferase, alanine transaminase; grade ≥3 oliguria or increase in serum creatinine; or grade ≥3 pulmonary edema; (2) presence of hemophagocytosis in bone marrow or organs based on histopathologic assessment of cell morphology and/or CD68 immunohistochemistry.

For HLH/MAS, treat as per CRS with tocilizumab and steroids, although the suspicion of HLH/MAS should prompt consideration of higher doses of steroids at a given CRS grade. If no improvement is observed within 48 hours, consider addition of anakinra to corticosteroids. Etoposide or intrathecal cytarabine can be considered as a last resort for HLH with CNS involvement.

Hypogammaglobulinemia

Hypogammaglobulinemia is another potential risk associated with CAR T-cell therapy, and has been reported in up to 53% of patients who received CAR T-cell therapy in registrational clinical trials.610

Characterized by low antibody levels in the blood and an increased risk of infection,116 hypogammaglobulinemia is a consequence of extremely low B-cell or plasma cell counts, referred to as B-cell or plasma cell aplasia, respectively. These types of aplasia are an expected result of the on-target/off-tumor activity associated with the successful use of CAR T-cell therapy, due to the presence of the targeted antigens on nonmalignant B cells or plasma cells.1,106

Long-term hypogammaglobulinemia can occur, even in patients with a complete remission after CAR T-cell therapy infusion. Hypogammaglobulinemia may be treated with the infusion of IVIG, a fractionated blood product derived from the plasma of thousands of individuals and contains antibodies against a wide range of pathogens.117,118 However, at present there is no compelling data for the use of IVIG after CAR T-cell infusion in patients who do not experience frequent or severe infections with hypogammaglobulinemia, and institutional practices vary.

NCCN Recommendations

After anti-CD19 CAR T-cell therapy, consider monthly 400–500 mg/kg IVIG replacement for select patients with hypogammaglobulinemia (those with serum IgG levels <400–600 mg/dL and serious or recurrent infections [particularly bacterial]). IVIG should be continued until serum IgG levels normalize and infections are resolved. The optimal IgG threshold to use may depend on patient characteristics and infection frequency or severity.

Hematologic Toxicities

Patients who receive CAR T-cell therapy are also at risk for hematologic toxicities, including prolonged cytopenia, such as neutropenia, thrombocytopenia, anemia, and/or leukopenia.

Acute cytopenia is common in patients treated with CAR T-cell therapy; however, grade 3 or higher prolonged cytopenia that remained unresolved weeks or months after infusion are reported frequently in patients treated with CAR T-cell therapies.610 Clinicians should be aware that cytopenia may occur in the weeks to months after lymphodepleting chemotherapy and CAR T-cell therapy infusion.

Factors that may contribute to prolonged cytopenias include CRS and ICANS severity, disease burden, the number of prior therapies, baseline blood cell counts, peak CRP and ferritin levels, and CAR construct.62,119,120 Although lymphodepletion may be a contributing factor, the pathophysiology of prolonged cytopenia after CAR T-cell infusion remains unclear.121

Cytopenias are generally managed with transfusion or growth factor support, if the possibility of myelodysplastic syndrome has been ruled out.103,122,123 Growth factors may be considered for persistent cytopenias. The guidelines do not provide specific recommendations on the management of CAR T-cell therapy–associated cytopenia in the current version of the guidelines.

Infections

Infections after CAR T-cell therapy are common and have been reported in up to 70% of patients who received CAR T-cell therapy in registrational clinical trials for approved agents.610 Bacterial, viral, and fungal infections have all been reported with use of CAR T-cell therapy.124,125 Most infections occur soon after infusion and may occur for a number of reasons, including lymphodeleting or antecedent chemotherapy, CAR T cell–mediated B-cell or plasma cell depletion, prolonged cytopenias, corticosteroid treatment, or as a consequence of the malignancy itself.103,126 The severity of CRS may also be associated with an increased risk of acute infections.124126 Other potential risk factors for severe infections within the first 30 days include ICANS, tocilizumab, and corticosteroid use.121 Patients remain at increased risk of complications for weeks to months after infusion.58,124,127,128 Infections are generally managed using agents that target the source of infection. Additionally, prophylaxis against vesicular stomatitis virus/herpes simplex virus reactivation and Pneumocystis jirovecii pneumonia infections is generally used for patients undergoing CAR T-cell therapy and for several months after. The decision to administer antibacterial or antifungal prophylaxis should be risk-adjusted based on patient characteristics, such as prior lines of suppressive therapy, infection history, etc.129 IVIG replacement therapy may be used for select patients. The guidelines recommend IVIG replacement for certain patients treated with anti-CD19 CAR T-cell therapy who experience serious or recurrent infections (particularly bacterial) concurrently with hypogammaglobulinemia. For additional guidance on infections and vaccinations, see NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections (available at NCCN.org).

Summary

CAR T-cell therapies are a novel and revolutionary class of cancer therapies that have shown efficacy against several types of cancers. However, data from clinical trials have shown that all approved CAR T-cell therapies are associated with unique adverse reactions, including CRS and neurologic toxicities. Patient monitoring before, during, and after CAR T-cell therapy is critical for early recognition of potential toxicities and timely intervention. CAR T cell–related toxicities can generally be reversed through the use of appropriate management strategies, such as immunosuppressive agents. Due to the changing therapeutic landscape, recommendations for management of CAR T-cell toxicities will continue to evolve as data emerge from clinical trials evaluating novel treatment options.

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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

The complete NCCN Guidelines for Management of Immunotherapy-Related Toxicities are not printed in this issue of JNCCN but can be accessed online at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2022. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Disclosures for the NCCN Management of Immunotherapy-Related Toxicities

At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.

Individual disclosures for the NCCN Management of Immunotherapy-Related Toxicities members can be found on page 405. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)

The complete and most recent version of these guidelines is available free of charge at NCCN.org.

Individual Dislcosures for the NCCN Management of Immunotherapy-Related Toxicities Panel
Individual Dislcosures for the NCCN Management of Immunotherapy-Related Toxicities Panel

  • View in gallery

    (Top) For the full activation and proliferation of T cells, 2 signals are required. Signal 1 results from the interaction between the peptide antigen expressed on the antigen presenting cell (APC) and the T-cell receptor. Signal 2 results from the interaction between a costimulatory receptor (such as CD28 or 4-1BB) expressed on T cells and its corresponding ligand expressed on APCs. (Bottom) Chimeric antigen receptors (CARs) are modular structures comprised of an antigen recognition domain, a hinge domain, a transmembrane domain, and at least 1 intracellular domain. Intracellular domains of currently available CAR T cells include a costimulatory domain (derived from CD28 or 4-1BB) and a T-cell activation domain. Incorporation of both types of intracellular domains in a single construct is thought to enable CARs to transduce both signal 1 and signal 2 on binding to the tumor antigen, thereby enhancing the activation and proliferation of CAR T cells.

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