Introduction
Antigen | Expressed on which cells | Effect on the immune system | Tumor Target | The issue of COVID-19 |
---|---|---|---|---|
B-cell leukemia/lymphoma
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CD19* | Most B-cell malignancies and most normal B-cell lineages | • B-cell aplasia contributes to hypogammaglobulinemia and impaired humoral immunity • Neutropenia | B-ALL, DLBCL, FL, MCL | • High risk of severe/critical • Low serological response rate after vaccination (57%) [37]; may have lower serological response rate compared with BCMA-based CAR-T (76.4%) [38] • Longer duration of COVID-19 symptoms [29] • Prone to reinfection and rebound positivity • May be more likely to give rise to multimutational SARS-CoV-2 variants [41] |
CD22 | Most B-cell malignancies and most normal B-cell lineages | B-NHL | ||
CD20 | Most B-cell malignancies and most normal B-cell lineages | B-ALL | ||
Multiple myeloma
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BCMA* | Mainly in plasma blast cells and terminally differentiated plasma cells | • B-cell aplasia contributes to hypogammaglobulinemia and impaired humoral immunity • Neutropenia | MM, PPCL, POEMS, AL | |
GRPC5D | Highly expressed on normal and malignant plasma cells | MM | ||
T-cell leukemia/lymphoma
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CD7 | T cells and natural killer cells and their precursors | • T-cell aplasia contributes to impaired cellular immunity • Neutropenia | T-ALL, T-LBL | • Healthy donor T cells may increase the risk of GVHD after COVID-19 • Delayed viral clearance |
CD5 | All T cells and B1 cell subset | T-ALL | ||
Acute myelogenous leukemia
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CD123 | AML cells; B-ALL cells; HD; hematopoietic stem cells; dendritic cells | • Effect on hematopoiesis • Damage to hematopoietic stem cells | AML | • Delayed recovery of hematopoietic function |
Hodgkin lymphoma
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CD30 | Highly expressed on HD and anaplastic large-cell lymphoma; activated T cells, B cells and NK cells | • Affect the balance of the T-cell subsets • Transient neutropenia | HD | • Delayed viral clearance |
Methods
Assessment and management of patients when preparing CAR-T therapy
Tests | Contents | Patient status |
---|---|---|
General laboratory tests
| ||
CBC, hepatic and renal function, coagulation function, etc. | Hb, WBC, PLT, ALT, AST, ALB, TBIL, LDH, UREA, CREA, BUN, PT, TT, APTT, etc. | For all patients. |
Inflammatory indicators
D-dimer, CRP, procalcitonin, serum ferritin, erythrocyte sedimentation rate, etc. Serum cytokines | IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, INF-γ, etc. | For SARS-CoV-2 confirmed patients to assess the degree of infection. |
Immune indicators
Lymphocyte subsets | total T lymphocytes (CD3+), helper/inducer T lymphocytes (CD3+CD4+), suppressor/cytotoxic T lymphocytes (CD3+CD8+), B lymphocytes (CD3−CD19+), and natural killer cells (CD3−CD16+CD56+), etc. | For all patients to evaluate their immune status. |
Etiological/serological detection
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SARS-CoV-2 | nucleic acid and/or antigen detection | For all patients and repeated if necessary. |
HBV | HBV-DNA, HBsAg, HBsAb, etc. | For all patients. |
Other respiratory viruses | nucleic acid, antigen, or antibody detection (including influenza A or B, RSV, parainfluenza viruses, adenovirus, enterovirus, rhinovirus, etc.) | When a respiratory tract co-infection is suspected. Note: It is difficult to distinguish COVID-19 from other respiratory virus infections based on symptoms alone. |
Sputum cultures | The presence of sputum expectoration. | |
G/GM test | For patients with high-risk factors for fungal infection. | |
mNGS | Optional. An unbiased technology to detect a variety of pathogenic microorganisms. | |
bronchoalveolar lavage fluid through a bronchoscope | SARS-CoV-2 nucleic acid | Advisable if chest CT imaging suggests residual shadow. |
Imaging
| ||
Chest CT scans | For SARS-CoV-2 confirmed patients with pneumonia. | |
Others
| If other infection or organ dysfunction is suspected, the appropriate examinations can be performed. |
1. CAR-T recipients without SARS-CoV-2 infection
Recommendations
-
In areas with localized outbreaks of COVID-19, single-ward living, and laminar-flow beds are recommended during the peri-CAR-T period. (Strong recommendation)
2. CAR-T recipients infected with SARS-CoV-2
Recommendations
-
Whenever SARS-CoV-2 infection occurs (before/after leukapheresis and LD), subsequent treatment should be suspended until the patient becomes asymptomatic and has two negative virus nucleic acid swabs at least 24 h apart. A suspension of 14 days is a minimum duration but should preferably be 21 days, depending on the severity of COVID-19 (i.e., nonsevere, severe, and critical disease) [49, 62]. The suspension can be appropriately extended if the primary condition remains relatively constant to minimize the risk associated with CAR-T therapy. (Strong recommendation)
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In patients who are negative for SARS-CoV-2 nucleic acid/antigen but still have respiratory signs and symptoms, further assessment of pulmonary function is needed to determine whether the patient is suitable for CAR-T therapy initiation. (Strong recommendation)
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For asymptomatic carriers, leukapheresis can be performed, and CAR T-cells can be manufactured. LD and CAR T-cell infusion should be held/suspended for at least 14 days after the date of the first positive test if the patient remains asymptomatic [61]. (Strong recommendation)
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If a patient has persistently positive nucleic acid amplification tests beyond 30 days, additional testing could include digital droplet PCR (polymerase chain reaction), viral genome sequencing to surveil the emergence of new variants of SARS-CoV-2 or attempts to identify replication of the competent virus in conjunction with infectious disease consultation [61]. (Weak or conditional recommendation)
3. CAR-T recipients who have recovered from SARS-CoV-2 infection
Recommendations
-
For patients who have been infection free for at least 14 days, CAR-T therapy can adhere to the standard CAR-T procedure. Otherwise, therapy is typically suspended until 14 days have passed [51]. For patients who have recovered from severe/critical SARS-CoV-2 infection, a suspension of 21 days or longer is preferable, depending on the progression of the primary disease [52, 66]. (Strong recommendation)
Management and treatment strategies for COVID-19 patients post CAR T-cell infusion
Drugs | Key issues to consider | Strength of recommendation |
---|---|---|
Antiviral drugs
| The duration and course of antiviral treatment can be appropriately prolonged. | |
Nirmatrelvir and ritonavir (Paxlovid) (Target: 3CL) | It is essential to monitor for drug-drug interactions, and the dosage should be modified in accordance with renal function. The COVID-19 drug interactions query website is https://covid19-druginteractions.org/checker. | Strong |
Remdesivir* (Target: RdRp) | Remdesivir should not be taken if ALT > 10 ×ULN or if ALT levels are increased and there are symptoms of active hepatitis. | Weak or conditional |
Molnupiravir (Target: RdRp) | No dose adjustment is required for renal or hepatic impairment. | Weak or conditional |
Azvudine (Target: RdRp) | It is not recommended to use during pregnancy or lactation. Patients with moderately to severely impaired liver and kidney function should use it with caution. | Weak or conditional |
Monoclonal antibodies | Patients with major risk factors for disease progression, high viral loads, and rapid disease development (depending upon predominant circulating viral variants). | |
Bebtelovimab* | It is effective against all Omicron subvariant virus strains (including BA.1, BA.1.1, and BA.2). | Weak or conditional |
Tixagevimab/cilgavimab* | It is only recommended for preexposure prophylaxis. | Weak or conditional |
Convalescent plasma | The patient’s individual condition and viral load should be considered while determining whether to administer again. | Weak or conditional |
Human COVID-19 immunoglobulin | Patients with major risk factors for disease progression, high viral loads, and rapid disease development. According to the patient’s condition, it can be infused once again the next day; the total number of infusions should be no more than 5. | Weak or conditional |
Immunoregulatory drugs
| ||
Corticosteroids | Patients with critical and severe conditions that display rapid imaging progression, a body inflammatory response that is aggressive, and a steadily declining oxygenation index. The early use of systemic corticosteroids for severe and critical patients is emphasized. Patients with severe CRS could benefit from high-dose corticosteroid therapy. | |
Dexamethasone | The dosage of dexamethasone should be adjusted to the severity of CRS. The dosage can be appropriately increased to 10 mg/6 h for 1–3 days in patients with ICANS. | Strong |
Methylprednisolone | If ICANS symptoms are still not relieved following the use of dexamethasone, methylprednisolone may be administered. The dosage of methylprednisolone is 1000 mg/day for 3 days, 250 mg × 2/day for 2 days, 125 mg × 2/day for 2 days, and 60 mg × 2/day for 2 days. | Strong |
IL-6 inhibitors
| ||
Tocilizumab | If CRS is exacerbated, combination therapy with IL-6 inhibitor tocilizumab (8 mg/kg) is recommended. Tocilizumab should be used with caution in the case of ICANS. | Strong |
JAK inhibitors
| ||
Baricitinib | Attention should be given to symptoms and warning indications of thromboembolic events, and coagulation indicators should be identified when necessary. | Strong |
Ruxolitinib | Most clinical criteria, symptoms (such as respiratory distress or the need for oxygen), and other clinical indications are used to determine whether to begin the use of ruxolitinib. | Weak or conditional |
IVIGs
| It is recommended for hypogammaglobulinemia (IgG < 4 g/l). | Strong |
1. Short-term infection (< 28 days)
Recommendations
-
Once SARS-CoV-2 infection is confirmed, antiviral therapy must be initiated immediately. Oral antiviral agents, such as paxlovid, remdesivir, and azvudine, are recommended. The choice will depend on the availability of the abovementioned drugs. The duration of antiviral treatment can be appropriately prolonged, which depends on the timing of SARS-CoV-2 nucleic acid/antigen negativity and the patient’s clinical symptoms and immune status. (Strong recommendation)
-
Prophylactic antifungal therapy is not recommended, except for those with grade ≥ 3 CRS, severe/critical SARS-CoV-2, or other high-risk factors for fungal infection [31]. (Strong recommendation)
-
The application of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF, and polyethylene glycol G-CSF is controversial for neutropenia. However, they should still be avoided if CRS occurs. (Weak or conditional recommendation)
-
If CRS occurs, systemic corticosteroids should be used in a timely manner. If CRS is exacerbated, it should be combined with tocilizumab. If CRS still cannot be effectively controlled, it should be combined with or adjusted to the JAK inhibitors baricitinib/ruxolitinib. The oxygen saturation and vital signs of patients should be closely monitored. Laboratory tests, such as those for cytokines, C-reactive protein, and ferritin, should be repeated every 12–24 h. (Weak or conditional recommendation)
-
The principles of treatment for COVID-19-related encephalopathy are consistent with those for ICANS. The ICE score and CARTOX-10 score should be evaluated to guide treatment [125, 126]. Cerebrospinal fluid examination (cell counts, protein levels, inflammatory biomarkers, SARS-CoV-2 nucleic acid, etc.), electroencephalogram and brain MRI are important for differential diagnosis and to exclude alternative diagnoses. Other functional and symptom scales can be evaluated if necessary. (Strong recommendation)
-
Critical patients should be monitored in the hematological ICU or ICU staffed with hematologists. Continuous renal replacement therapy could be considered to eliminate inflammatory cytokines and pathogens [127, 128]. Possible adverse events should be considered with caution. (Weak or conditional recommendation)
2. Medium-term infection (day + 28 to day + 100)
Recommendations
-
Once SARS-CoV-2 infection is confirmed, antiviral treatment should be started as soon as possible. (Strong recommendation)
-
If pneumonia occurs, systemic glucocorticoids should be administered, and the doses and courses of the treatment should be adjusted according to the disease severity. The early use of systemic corticosteroids is critical for severe/critical patients. (Strong recommendation)
-
Immunoglobulin replacement should be administered in patients with hypogammaglobulinemia (IgG < 4 g/l) [31]. (Strong recommendation)
3. Long-term infection (> day + 100)
Recommendations
-
The use of CD20 monoclonal antibodies such as rituximab and obinutuzumab should be suspended during acute episodes of SARS-CoV-2 infection. (Strong recommendation)
-
The use of other agents, such as PD-1/PD-L1 inhibitors, BTK inhibitors and lenalidomide, remains controversial in COVID-19-confirmed CAR-T recipients. (Weak or conditional recommendation)
-
For nonsevere COVID-19 patients, early antiviral intervention is still needed. Monitoring the levels of cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, INF-γ, etc.), C-reactive protein, procalcitonin, and other inflammatory indicators is recommended. If disease exacerbation occurs, systemic corticosteroids, IL-6 and/or JAK inhibitors can be used, as appropriate. (Strong recommendation)
-
For severe/critical patients with SARS-CoV-2, active immunomodulatory therapy is needed. (Strong recommendation)
-
The inappropriate use of antibiotics, especially the use of broad-spectrum antimicrobial agents, should be avoided. (Strong recommendation)
The issue of SARS-CoV-2 vaccination for CAR-T recipients
Recommendations
-
Patients who plan to receive CAR-T therapy should complete their initial SARS-CoV-2 vaccination series at least 2 weeks prior to beginning LD depending on the status of the primary disease [46]. (Strong recommendation)
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The COVID-19 vaccine can be administered after 6 months of CAR-T therapy and as early as 3 months after CAR T-cell infusion in cases of high community transmission rates, at which point immune function gradually recovers and elicits vaccine-induced serological responses [149, 150]. (Strong recommendation)
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Three months after basic immunization, one booster dose is feasible, and the second dose may be considered 6 months later to obtain high antibody titers and a long period of protection [151]. (Strong recommendation)
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Booster vaccination can be performed using homologous or different types of vaccines, such as a homologous inactivated vaccine booster, heterologous inactivated vaccine and subunit vaccine booster, or heterologous mRNA vaccine and adenovirus vaccine booster [137].
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Patients can be revaccinated six months after they have recovered from COVID-19. (Weak or conditional recommendation)
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For unvaccinated individuals, individuals who postpone vaccination and individuals who are at high risk for COVID-19 but unable to mount an adequate immune response following vaccination, long-acting neutralizing antibodies for preexposure prophylaxis can be considered [152, 153]. (Weak or conditional recommendation)
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Health providers, caregivers and household partners should receive the initial immunization and complete booster immunization as early as possible. (Strong recommendation)