The evolving landscape of CAR T cell therapy in children and young adults with B cell acute lymphoblastic leukemia.

Introduction

B cell acute lymphoblastic leukemia (B-ALL) is the most common subtype of childhood ALL, constituting approximately 25% of all pediatric cancers. 1 Despite over 90% cure rates in most children, 1 , 2 , 3 , 4 , 5 patients with relapsed/refractory (r/r) B-ALL face a dismal prognosis, with limited improvement in survival over the last few decades. 6 , 7 , 8 Fortunately, the more recent addition of immune targeted strategies, such as the bispecific T cell engager blinatumomab, the antibody-drug conjugate inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T cell therapy, has had a remarkable impact on remission rates and long-term outcomes. 9 , 10 , 11

The development and success of CAR T cell therapy for the treatment of B-ALL spans several decades. In 1987, Kuwana et al. engineered the first chimeric receptors on T cells by combining the antigen-binding region of an antibody with part of the T cell receptor. 12 Eshhar et al. later developed MHC-independent chimeric receptors in T cells, 13 and in 1993, introduced the first CAR using a single-chain variable fragment (scFv), establishing the foundation for first-generation CARs. 14 Subsequent modifications included the addition of a co-stimulatory domain (e.g., CD28, 4-1BB) to enhance T cell activation, proliferation, and persistence, leading to the development of clinically effective second-generation CAR T cell therapies. 15 , 16 , 17 In 2012, Grupp et al. treated Emily Whitehead, the first patient with pediatric B-ALL to receive CAR T cell therapy. 18 , 19 She was treated with tisagenlecleucel (tisa-cel), an anti-CD19 CAR T cell therapy, and has been in remission for over 10 years. In 2017, tisa-cel became the first approved commercial gene therapy by the Food and Drug Administration (FDA), with an indication for the treatment of r/r B-ALL in children, adolescent, and young adults (CAYAs) based on the results of the ELIANA trial, a global phase 2 registration study. 20

Tisa-cel remains the only FDA-approved CAR T cell product for pediatric patients, indicated for patients up to age 25 years with B-ALL that is refractory or in second or later relapse. 21 It has since been approved by the European Medicines Agency (EMA), Health Canada, Japan, and Swissmedic for similar indications as in the United States, with the exception of age restriction to patients greater than 3 years of age in Canada. 22 In addition, tisa-cel is available in over 30 countries for at least one of its FDA indications. 23 A second product, brexucabtagene autoleucel (brexu-cel), was approved in 2020, 24 and a third product, obetacabtagene autoleucel (obe-cel), was more recently approved in late 2024, 25 both for adults (≥18 years) with r/r B-ALL, each expanding access for adolescent and young (AYA) patients ( Table 1 ).

As immunotherapy and other novel treatments are introduced for B-ALL therapy in both the upfront and salvage settings, the role of CAR T cell therapy will also evolve. Herein, we describe the current usage of CAR T cells for B-ALL, limitations of the currently available therapies, and areas in which we expect to see changes in the future.

How we currently use CAR T cells

Lymphodepleting chemotherapy and CAR T cell infusion

CAR T cell therapy typically begins with lymphodepleting (LD) chemotherapy in order to reduce regulatory T cells and facilitate an immune environment for CAR T cell survival and expansion. 26 LD containing fludarabine has demonstrated improved event-free survival (EFS) compared to regimens of cyclophosphamide alone or with etoposide prior to CAR T cell infusion, 27 , 28 with higher pre-infusion fludarabine exposure linked to a decreased risk of relapse. 29 , 30 The use of cyclophosphamide (500 mg/m 2 intravenously daily for 2 days) and fludarabine (30 mg/m 2 intravenously daily for 4 days) is now considered the standard LD regimen prior to tisa-cel infusion. 20

Per FDA guidance, the dose of tisa-cel is weight dependent: patients weighing ≤ 50 kg should receive 0.2 to 5 × 10 6 CAR-positive viable T cells/kg, while those with >50 kg weight should receive a standard dose of 0.1–2.5 × 10 8 CAR-positive viable T cells. 21 On the day of administration, pre-medication with acetaminophen and an H1-antihistamine such as diphenhydramine are to be given within 30–60 min of cell infusion to prevent infusion-related reactions.

CAR T cell infusion setting

While CAR T cells were initially administered in the inpatient setting, improved recognition of toxicity onset and increasing comfort with management strategies have prompted many centers to shift to an outpatient model, with a low threshold for admission with onset of fever or other post-CAR toxicities. 31 This outpatient management plan is aligned with the product label for tisa-cel, which recommends daily monitoring during the first week following infusion and remaining near a healthcare facility for at least 2 weeks. 32 Furthermore, among hospitalized patients, ICU admission rates have decreased from 47%, initially reported in the ELIANA trial, to 31% in more recent real-world data. 20 , 33

CAR-associated toxicities

Monitoring and management of post-infusion toxicities remain a critical challenge, although growing experience and dedicated analyses have established the unique profile of toxicities associated with CAR T cells in the B-ALL setting. Toxicities are primarily related to inflammation and cytokine release, secondary to CAR T cell expansion and interaction with leukemia, while on-target/off-tumor toxicity has largely been limited to B cell aplasia (BCA).

CRS

Cytokine release syndrome (CRS), the most well-described post-CAR toxicity, refers to a supraphysiologic release of numerous cytokines, particularly interleukin-6 (IL-6), TNF-α, and interferon γ. 34 CRS is characterized by fever and, depending on severity, may be accompanied by hypotension, hypoxia, capillary leak, and end-organ dysfunction. Incidence and severity of CRS following tisa-cel vary and depend largely on the degree of baseline bone marrow disease. 33 Rates of CRS differ across clinical trials and real-world cohorts. In the ELIANA trial, 77% of patients treated with tisa-cel experienced any-grade CRS. 20 In real-world studies, CRS of any grade occurred in 57%–63% of patients receiving tisa-cel and 85% of those treated with brexu-cel. 33 , 35 , 36 CRS has been reported in 69% of those treated with obe-cel. 25 Regarding severe CRS (grade ≥3), while the pivotal ELIANA trial reported grade ≥3 CRS in 47% of patients, 20 real world-studies, including those of the Center for International Blood & Marrow Transplant Research (CIBMTR) and the Pediatric Real World CAR T cell Consortium (PRWCC), have observed markedly lower rates, ranging from 16% to 21%. 33 , 36 , 37 This reduction likely reflects the enrollment of patients with lower disease burden and a shift toward earlier intervention strategies. 38

In 2019, the American Society for Transplantation and Cellular Therapy (ASTCT) established the first consensus guidelines for CRS grading, improving recognition, standardization, and toxicity management. 39 Treatment strategies include supportive care (i.e., acetaminophen, intravenous fluids, and supplemental oxygen), tocilizumab (an antibody against the IL-6 receptor that is approved by the FDA for the treatment of CRS), and steroids, depending on severity. 40

ICANS

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a distinct neurotoxic complication characterized by central nervous system (CNS) inflammation following administration of immune effector cell therapies. The pathophysiology of ICANS is still under active investigation, but it is clear whether elevated intracerebral cytokines play a role. 41 Higher rates of ICANS are also related to baseline bone marrow disease; however, a consistent association with pre-existing CNS disease has not been established. 42 , 43 , 44 ICANS typically manifests around five days after CAR infusion, but it may also occur before, concurrently with, or following CRS. Clinically, it presents with changes in mentation and/or behavior and neurologic function, and, if severe, it can cause seizures or cerebral edema.

Similar to CRS, rates of ICANS differ across clinical trials and real-world cohorts. In the pivotal ELIANA trial, tisa-cel was associated with neurotoxicity of any grade at a rate of 40% (grade ≥ 3.13%) (trial pre-dated the defining of ICANS terminology and grading). 20 Real-world evidence demonstrates a more favorable safety profile for tisa-cel. Incidence rates in the PRWCC and CIBMTR cohorts ranged from 18% to 27% for any-grade ICANS and from 4% to 9% for severe (grade ≥3) ICANS. 33 , 35 , 36 , 37 In contrast, brexu-cel is associated with significantly higher neurotoxicity in the real-world setting, with grade ≥3 ICANS occurring in 35% of young adult patients. 35 Real-world data for rates of ICANS following obe-cel have yet to be reported, but trial data demonstrate that the rates are more in line with those for tisa-cel, with any-grade ICANS in 23% and severe ICANS in 7%. 25 Ultimately, choosing between these CD19-directed CAR T cell therapies requires a careful clinical assessment considering their distinct safety profiles.

As with CRS, consensus guidelines have led to enhanced detection and management of ICANS. 39 Treatment strategies vary but often include high-dose corticosteroids. In refractory cases, additional immunosuppressive agents such as the IL-1 receptor antagonist, anakinra, may be employed. 40 , 45

IEC-HS

Immune effector cell hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) has been identified as a toxicity after both CD19- and CD22-targeted CAR T cell therapy, and it can be associated with potentially life-threatening organ dysfunction. 46 , 47 While our understanding of the mechanism of IEC-HS is still evolving, it is clinically characterized by elevated ferritin, coagulopathy with hypofibrinogenemia, transaminitis, as well as new onset or progressive cytopenias. IEC-HS typically occurs when CRS is resolving or has resolved and is thought to be caused by macrophage activation in a process that is distinct and independent of CRS. The incidence following CD19 CAR T cell therapy in B-ALL has been reported to be around 14%–15%, with higher rates (19%–36%) reported after CD22 CAR T cell therapy. 47 , 48 , 49 , 50 , 51 In a recent study in which multiple definitions of IEC-HS or HLH-like toxicity were applied to a real-world population of patients treated with tisa-cel, the incidence based on retrospective ASTCT consensus grading (14.9%) was consistent with real-time institutional determination of HLH (13%). 52 Consensus grading and management guidelines have recently been developed to aid in recognition and treatment. 49 , 53 Steroids remain the mainstay for the treatment of IEC-HS, with some cases requiring the addition of other agents such as anakinra, emapalumab, and ruxolitinib. 53

ICAHT

CAR T cell-associated cytopenias are the most common toxicity across trials, diseases, and CAR T cell constructs. 54 In pediatric B-ALL patients treated with tisa-cel, grade 3 and 4 neutropenia and thrombocytopenia have been reported to occur in as many as 53% and 41% of patients, respectively. 20

Immune effector cell-associated hematotoxicity (ICAHT) includes neutropenia (N-ICAHT) or thrombocytopenia (T-ICAHT) following CAR T cell infusion. 55 , 56 ICAHT is classified as either early (0–30 days after infusion) or late (>30 days), with classification criteria incorporating both the depth and duration of cytopenias. Severe ICAHT has been reported in approximately 50% of patients across both trial and real-world populations, with 15%–17% of patients experiencing prolonged neutropenia. 57 , 58 , 59 Across these studies, high disease burden pre-infusion is a consistent predictor of prolonged neutropenia.

The underlying pathophysiology of ICAHT is multifactorial, driven by a depleted hematopoietic reserve from prior genotoxic therapies, systemic and localized bone marrow hyperinflammation inherent to CAR T cell-mediated cytokine release, and an imbalance of T and B cells secondary to direct CAR T cell cytotoxicity. 54 , 56 , 60 Standard management includes transfusion support and G-CSF, and although more studies are needed to strengthen the evidence, thrombopoietin (TPO) agonists and stem cell infusions may be considered in refractory cases. 54 , 56

BCA

BCA and subsequent hypogammaglobulinemia are the predicted on-target/off-tumor toxicity of CD19-directed CAR T cell therapy. Supportive care and prevention using intravenous immunoglobulin (IVIG) as well as prophylactic antimicrobials are important and may depend, in part, on a patient’s treatment and infection history. 61 , 62 While there is not a consensus on the prophylactic use of IVIG after CAR T cell therapy, it is commonly used in practice, with replacement suggested for IgG < 400 mg/dL, or, for patients with serious or recurrent infections, IgG levels < 600 mg/dL. 62

Infections

Candidates for CAR T cell therapy are frequently immunocompromised due to extensive prior lines of therapy, and their immune compromise is further exacerbated by CAR-associated hypogammaglobulinemia and neutropenia. 63 , 64 , 65 Consequently, infections continue to be the leading cause of non-relapse mortality. 35 , 66 , 67 Overall, the majority of infections are bacterial and occur within the first 30 days after CAR. 63 , 64 In an analysis of patients who received tisa-cel and had grade 3–4 neutropenia unresolved until day 28, 45% had grade 3–4 infections. 20 Similarly, in another study assessing 38 CAYA patients who also received CD19 CAR, 19 (50%) patients experienced 35 infections, with more than 70% of infections occurring within 30 days of CAR therapy. 64 Data on late-onset infections remain limited, in part due to inconsistent post-treatment follow-up across centers and the short surveillance window, as hematopoietic stem cell transplantation (HSCT) is frequently used as a consolidative strategy after achieving complete response (CR) post-CAR. Prospective studies are needed to optimize and unify antibacterial prophylaxis guidelines as well as post-CAR vaccination strategies, which vary widely across institutions. 62 , 63 , 68 , 69

Current outcomes

The key study that led to FDA approval of tisa-cel was the aforementioned ELIANA trial, a phase 2 multicenter trial, which included 75 CAYA patients. 20 At three months post-infusion, 81% of patients had achieved a measurable residual disease (MRD)-negative remission. At 3-year follow-up, overall survival (OS) was 63%, with an EFS of 44%. 10 Subsequently, reports of the real-world use of tisa-cel have shown similar outcomes, with the CR rate of 85% in the PRWCC study and 86% in a study from CIBMTR consortium. 33 , 36 , 37 Long-term outcomes have also been consistent with ELIANA results, with 12-month OS of 72% and 79.4% for PRWCC and CIBMTR studies, respectively, compared with 77.1% in the ELIANA cohort. 33 , 36

With CR rates surpassing 80% across clinical trials and real-world data, it is clear that tisa-cel has great efficacy in CAYAs with r/r B-ALL. Longer-term outcomes, however, demonstrate that a third of responders will have relapsed by 12 months post-infusion and half of responders will relapse within 3 years. 10 , 33 , 36

Special populations

Although initial studies of tisa-cel excluded certain populations, later phase studies and real-world use following approval have demonstrated favorable efficacy without increased toxicity in infants, children with Down syndrome (DS), and those with isolated and/or combined extramedullary disease.

Infants

Initial early phase studies of tisa-cel excluded patients <3 years of age. However, infants with B-ALL represent an important population that often have aggressive disease with a high incidence of relapse and poor survival, particularly those with KMT2A rearrangements ( KMT2Ar) . 70 Following FDA approval, infants became eligible for tisa-cel under the same indications as older children with r/r B-ALL. A retrospective analysis of 14 infants treated between 2017 and 2020 demonstrated efficacy (64% MRD-negative CR rate) and safety, with only 3 patients having severe (≥ grade 3) CRS and none exhibiting neurotoxicity. 71 Another study of 35 children and infants <3 years of age in Europe demonstrated even better outcomes, with MRD-negative CR reported in 86% of patients infused with measurable disease, 14% severe CRS and only low-grade neurotoxicity, and 12-month OS of 84%. 72 Notably, data do suggest that CD19 CAR T cells (and blinatumomab) may increase the risk of lineage switch (LS) from B-ALL to acute myeloid leukemia (AML) or mixed phenotypic acute leukemia (MPAL), particularly in those with KMT2Ar . 73 , 74 The incidence of LS among infants with KMT2Ar is not yet established but may be up to 7% in children and young adults; accordingly, infants with KMT2Ar should be monitored closely following CD19-targeted therapies for the emergence of LS.

Children with DS

Children with DS are 10–20 times more likely to develop ALL and face increased treatment-related morbidity and mortality than other children. 75 Enrollment on 3 early phase trials of tisa-cel allowed for the inclusion of patients with DS. A pooled analysis of 16 children with DS aged 5–22 years across these trials demonstrated favorable outcomes, similar to children without DS, with a 75% MRD-negative CR rate, and 9 of 14 responders (64%) maintaining a CR from 6 to 48 months post-infusion. 76 Toxicity was manageable, with severe CRS and severe neurotoxicity rates of 44% and 13%, respectively. Real-world analysis has also demonstrated similar findings with good overall responses and the potential to avoid allogeneic HSCT, which comes with significant morbidity in DS. 36

CNS/non-CNS extramedullary disease

While initial studies of tisa-cel excluded patients with CNS disease due to concerns of potentially significant neurotoxicity, real-world data have begun to demonstrate how extramedullary disease (EMD) responds to CAR T cells. 42 , 44 Several studies have included patients with CNS disease, with high remission rates and OS in those with combined medullary and CNS disease as well as those with isolated CNS relapse, highlighting a potential effective strategy in a vulnerable population previously treated with highly toxic therapies. 43 , 77 Importantly, a recent study evaluated the use of CD19 CAR T cells among 43 CAYAs with CNS relapse (39 with first CNS relapse, and 36 with isolated CNS disease), with 98% reaching CNS remission post-infusion and a 100% best overall response rate. 77 Several pooled analyses have reported that EMD responds to CAR T cells, although some reports demonstrate that non-CNS-EMD may not respond or may take longer than bone marrow (BM) to respond. 42 , 44 , 78 , 79 , 80 , 81

Given ongoing concerns about the risk of ICANS with high levels of active CNS disease, many centers have attempted to reduce CNS disease by bridging intrathecal chemotherapy prior to initiation of LD. 43 , 78 However, in a retrospective analysis of 184 patients treated with tisa-cel, severe neurotoxicity was observed in 3 patients with combined CNS and BM disease but not in patients with isolated CNS disease at the time of referral (including 9 patients with active CNS disease at the time of infusion). 44 Furthermore, outcomes and toxicities in this study did not differ based on CNS disease clearance prior to infusion.

Known prognostic factors

Across studies and in the real world, in both the pediatric and adult settings, the presence of high disease burden prior to CAR infusion is associated with inferior survival and increased risk of relapse; high disease burden is generally defined as ≥5% bone marrow blasts but may include CNS or EMD. 25 , 29 , 33 , 82 , 83 , 84 , 85 , 86 To reduce disease burden and improve outcomes, patients often receive bridging therapy before LD. However, bridging strategies are not standardized and depend on multiple factors, including treatment history, comorbidities, drug availability, disease characteristics, and timing of CAR T cell infusion. Conversely, while a sufficient CD19 + antigen load in the bone marrow may contribute to CAR T cell persistence and BCA, real-world data have demonstrated that even patients infused in an MRD-negative CR maintain ongoing BCA until 1 year post-infusion. 33 , 87

Prior therapy may influence the efficacy of subsequent CAR T cell therapy. Retrospective analyses have shown that patients who have received more lines of therapy prior to CAR T cell infusion have inferior outcomes, although it is not clear whether this is related to therapy exposure or disease characteristics, as more lines of therapy also imply a history of a greater number of relapses. 33 , 73 Studies on whether prior blinatumomab exposure affects CD19 CAR T cell outcomes are mixed, with reports of both treatment failure and antigen escape versus no impact on relapse. 85 , 88 , 89 , 90 However, response to blinatumomab has emerged as a key predictor, as blinatumomab non-responders treated with CD19 CAR T cells have exhibited outcomes inferior to those of blinatumomab responders and blinatumomab-naïve patients. 83 , 90 Poor CAR T cell therapy outcomes in blinatumomab non-responders may be due to T cell dysfunction from intrinsic defects, preceding intensive therapy, and/or direct effects of blinatumomab, with a recent study suggesting that blinatumomab can induce T cell dysfunction. 83 , 91 Furthermore, it remains to be seen how upfront use of blinatumomab, as opposed to use in the relapsed setting, impacts subsequent CAR T cell therapy outcomes.

Where we are going?

When is the best time to give CAR?

Although tisa-cel is only indicated for those in second or later relapse or with refractory disease, 21 the approach to the treatment of relapsed B-ALL is ever changing in the era of immune-based therapies. In the Children’s Oncology Group study AALL1331, the addition of blinatumomab was shown to improve OS compared with chemotherapy alone, shifting the treatment paradigm for relapsed B-ALL in CAYAs. 9 More recently, based on promising data from AALL1731 demonstrating improved disease-free survival and OS by adding blinatumomab to the chemotherapy backbone for upfront treatment of B-ALL, the majority of patients will be receiving blinatumomab as part of their initial therapy. 92 The shift of blinatumomab to the front-line setting will necessitate testing novel strategies for first relapse, with one clear choice being CAR T cells.

In contrast to pediatric patients, for adult patients with relapsed ALL, both brexu-cel and obe-cel have been approved for use in first relapse based on favorable clinical trial outcomes. 25 , 93 While tisa-cel is not FDA approved for first relapse, emerging real-world data support its potential use in the first relapse setting in CAYAs. In one retrospective review of 185 CAYAs who received tisa-cel, 36% ( n = 67) received CAR T cell therapy at first relapse, with 85% of evaluable patients achieving a morphologic CR. OS, EFS, and duration of remission in this cohort were not significantly different from those in patients who received therapy for refractory disease or in second or greater relapse, although those treated after first relapse were found to have increased rates of CRS and ICANS. 94 Additionally, although data specific to those in first relapse were not separately reported, a recent real-world analysis by CIBMTR of 768 CAYAs that received tisa-cel reported that 27% were in first relapse. 36 FDA approval for use in first relapse will likely require prospective clinical trials. Notably, ongoing clinical trials are examining the role of tisa-cel among high-risk CAYA patients with B-ALL who are MRD positive at the end of the consolidation phase of standard treatment ( NCT03876769 ) and obe-cel in pediatric patients with r/r disease, including those in first relapse ( NCT06173518 ).

Even if CAR T cells are not used earlier in therapy, there may be benefit to early leukapheresis collection to preserve T cell fitness. While there have been no studies to date to evaluate if there is clinical benefit to early T cell collection in B-ALL, it is known that T cell phenotype at the time of manufacture is important and that prior therapy impacts phenotype. 95 , 96 Increased naive and stem central memory T cells are associated with improved CAR T cell expansion and persistence, likely due to their enhanced proliferative capacity and/or longevity. 96 , 97 , 98 , 99 , 100 Conversely, elevated levels of regulatory T cells before CAR infusion have been linked to poor relapse-free survival (RFS). 101 , 102 One prospective study compared early leukapheresis (at first relapse and before salvage therapy) with standard leukapheresis (at second or greater relapse) in a cohort of patients with diffuse large B cell lymphoma receiving CD19 CAR T cells. 103 They found that the group with earlier apheresis had an increase in naive T cells and in vitro T cell functionality as well as a lower exhaustion profile, with a trend toward better OS and progression-free survival (PFS). Barriers to early collection include procedural risks, the need for central venous access (in most pediatric cases), timing in relation to salvage chemotherapy, and cost when the need for the apheresis product is uncertain. Further prospective clinical trials will be needed to demonstrate if earlier collection indeed has a clinical impact on CAR T cell efficacy.

How do we keep patients safe during CAR T cell therapy?

Toxicity prediction

While the implementation of structured toxicity grading and supportive care protocols has significantly improved patient outcomes following CAR T cell toxicities, the need remains to identify patients at high risk of developing severe toxicities. As potential solutions, efforts have been focused on the development of predictive models, biomarkers, and prognostic tools to enable risk stratification and toxicity mitigation.

The CAR-HEMATOTOX (CAR-HT) score was developed to predict hematotoxicity after CAR T cell therapy in patients with lymphoma and subsequently validated in patients with multiple myeloma. It identifies those at high risk to experience post-CAR prolonged neutropenia (<500/μL for ≥14 days) and severe infections. 104 , 105 , 106 However, in pediatric patients with B-ALL, the CAR-HT has shown limited accuracy and discriminative power. 58 , 107 To address this gap of knowledge, the ALL-Hematotox (ALL-HT) score was recently developed by incorporating baseline bone marrow disease burden. 58 This refined model has demonstrated the ability to predict both hematologic toxicity and severe infections occurring after CD19- and CD22-targeted CAR T cell therapies in CAYA patients with B-ALL. 58 , 67 While these findings require further validation in the commercial CD19 CAR setting, another model, the CytoRisk score, has been validated in children receiving tisa-cel and is able to predict severe neutropenia lasting ≥30 days based on pre-infusion disease burden and CRP and post-infusion ferritin and CRS. 66

Initially validated in adults with lymphoma or B-ALL, the modified endothelial activation and stress index ( m -EASIX) score has also shown a strong predictive value for severe CRS and any grade of ICANS in pediatric and young adult patients with B-ALL treated with CD19 CAR. 108 , 109

In parallel with predictive models, efforts to identify early biomarkers of toxicity are under investigation. Serum cytokines are one biomarker of interest and have been shown to predict severe CRS; however, cytokine analysis can be a challenge to complete in real time, and cytokines are most often measured following infusion, with limited data suggesting utility as a pre-infusion predictor. 110 , 111 Recently, a prospective study showed that increased polymorphic delta activity on electroencephalogram was associated with the development of ICANS prior to clinical symptom onset at a median of 68 h in adults with B-ALL or lymphoma treated with commercial CD19 CAR T cell therapy. 112

Toxicity mitigation

A proactive approach to toxicity mitigation begins even before cell infusion. This includes comprehensive pre-infusion assessments of individual comorbidities, early referral to a specialized CAR T cell center, and pre-treatment strategies aimed at reducing disease burden to minimize the risk of severe inflammatory response. 40 Bridging therapy decisions should be individualized and guided by a systematic assessment of key factors such as disease burden, prior therapies and their side effects, and the anticipated delays between apheresis and infusion. 113 Although the impact of bridging therapy on CAR T cell outcomes remains under investigation, current evidence remains limited to define the optimal first-line regimen. 114 , 115 Lower-intensity approaches are generally preferred, aiming to achieve disease control while minimizing additional toxicities. 115

Historically, the standard approach to CRS and ICANS was reserving the use of tocilizumab and steroids only for severe cases. 40 However, current strategies have shifted toward pre-emptive intervention to prevent escalation of toxicities. In a prospective study of CAYA patients treated with CTL019, pre-emptive tocilizumab given to patients with high disease burden reduced the rates of grade 4 CRS from 50% to 27%, without affecting CAR T cell expansion or efficacy. 116 Similarly, data from the PLAT-02 trial (another CD19 construct) demonstrated a trend toward reduced severe CRS incidence without evidence of reduced anti-leukemic activity with early use of tocilizumab and steroids. 117 Although there remains some concern that elevated free IL-6 following tocilizumab administration may worsen ICANS—in part supported by data from adults with lymphoma receiving axicabtagene ciloleucel, which showed increased incidence of severe ICANS following prophylactic tocilizumab 118 —early use of tocilizumab has not supported this concern in children with B-ALL. 116 , 117

In contrast to CRS, isolated ICANS does not benefit from tocilizumab, as the medication does not cross the blood-brain barrier. 119 , 120 Although emerging data suggest that the prophylactic use of anakinra, an IL-1 receptor antagonist, may reduce the incidence of ICANS in patients with lymphoma receiving CD19 CAR T cell therapy without diminishing therapeutic efficacy, these findings were primarily limited to adult cohorts receiving CD28-based constructs. 121 Evidence in pediatric B-ALL remains scarce, and subsequent studies across different patient populations and CAR T cell designs, including recent real-world assessment and trials with 4-1BB constructs, have reported discrepant results. 122 , 123 , 124 Therefore, the routine implementation of prophylactic anakinra remains a subject of ongoing investigation.

For IEC-HS, prompt recognition and early intervention are critical to enable timely treatment. 53 A pre-emptive approach to IEC-HS management was recently described in the context of CD22 CAR T cells, in which steroids and anakinra are introduced in response to rising ferritin levels, rather than the formal IEC-HS diagnosis, aiming to prevent high-grade IEC-HS and reduce need for prolonged steroid therapy. 51 While steroids and anakinra remain first-line agents for IEC-HS, etoposide has been used in more severe cases, and investigational agents such as emapalumab, an antibody against interferon γ, and ruxolitinib, a JAK/STAT pathway inhibitor, are being evaluated for their therapeutic efficacy. 53

Given the multiple immunosuppressive agents and cytopenias associated with CAR T cell therapy, treatment and prevention of infections are critical. While guidelines established in the setting of HSCT are currently used as a starting point, patients undergoing CAR T cell therapy have a different risk profile, and dedicated studies are needed to establish standard infection prevention strategies.

What happens after the acute post-CAR phase?

Monitoring for residual disease

Determining the optimal strategy to sustain a long-term remission post-CAR T cell infusion remains challenging, making risk stratification and monitoring for relapse imperative. In terms of assessing for disease, MRD, which is a measure of the amount of remaining leukemia cells, is the gold standard for assessing remission status throughout treatment and for assessing relapse. The current standard for assessing MRD is flow cytometry (FC), which has a limit of detection of <1 in 10 4 cells. Positive MRD detected by FC at the end of induction chemotherapy in upfront ALL treatment is a strong prognostic factor for relapse and OS. 125 Relapse after CAR T cell therapy is often defined by the recurrence of FC-detectable MRD. 20 Next-generation sequencing (NGS) offers a more sensitive method of detecting MRD. The increasingly used NGS platform clonoSEQ by Adaptive Biotechnologies allows for the detection of clonal B cell receptor gene sequences, with a sensitivity of <1 in 10 6 cells. 126 , 127 While not yet standard practice for ongoing disease reassessment, studies have shown that patients who have any amount of disease by detectable NGS in the post-CAR setting have a higher risk of relapse. 128 , 129 NGS may demonstrate which patients are at the highest risk of relapse and may benefit from additional disease directed therapies post-CAR infusion, though there are not yet standardized guidelines of when and how to proceed with additional treatment when a patient has NGS-positive disease.

As most centers do not have the ability to detect the presence of CAR T cells in real time, BCA, or low to absent B cell counts measured by FC, has been utilized as a surrogate marker for the ongoing persistence of CAR T cells post-infusion. Studies have shown that earlier loss of BCA within 1 year of CAR infusion is predictive of relapse and inferior outcomes. 128 , 130 BCA is a surrogate marker for the risk of relapse; however, is not perfect, as studies have shown that patients with higher disease burden at the time of CAR infusion have a higher incidence of CD19-negative relapse, and, in some cases, BCA may persist in the setting of CD19-negative relapse, giving a false impression that the patient remains in remission. 86 Another study showed that even patients with CD19-positive relapse had ongoing BCA at the closest time point prior to relapse. 73 Additionally, our group has reported a high incidence of pre-existing BCA even prior to CAR T cell infusion. 131 Currently, NGS is being explored to evaluate BCA, which may be a more sensitive marker of BCA than FC, allowing for earlier intervention when a patient experiences B cell recovery (BCR). 132 While using BCA as a marker for CAR T cell persistence has utility, the optimal treatment strategy when a patient loses BCA remains unclear ( Figure 1 ).

Monitoring for CNS disease following CAR T cell infusion primarily relies on routine assessment of the cerebrospinal fluid (CSF). Frequency of monitoring is not standardized but is important, particularly among patients with a history of CNS disease. Most centers are limited to traditional cell count and cytospin analyses; however, some are beginning to utilize CSF FC at diagnosis and later time points to identify low-level disease, and even differentiate disease from CAR T cell expansion. 133 , 134 , 135 Given the absence of normal B cells in the CNS, BCA has limited application for those receiving CAR T cells for CNS disease. 136 For patients with a history of non-CNS EMD, increased use of surveillance imaging with fluorodeoxyglucose positron emission (FDG PET/CT) may allow for the standardization of post-infusion monitoring to improve risk assessment and guide further treatment strategies. 80 , 137

Post-CAR consolidative strategies

For some patients, surveillance alone may be deemed insufficient based on individual risk factors; in these scenarios, there are three main consolidative management approaches to consider: allogeneic HSCT, CAR reinfusion, and alternative maintenance strategies (i.e., chemotherapy, tyrosine kinase inhibitors [TKIs], and radiation). The role of HSCT following CAR T cell therapy in B-ALL patients remains controversial, with wide practice variations across centers. 138 HSCT can be stratified into two approaches: empirical HSCT, particularly in patients receiving a CAR with a CD28-based co-stimulatory domain, and select HSCT for higher-risk patients, such as those with ≥5% blasts prior to infusion or those with prior failure to blinatumomab. 129 , 138 CAR T cell therapy is frequently used to induce MRD-negative CR for patients with refractory disease, often as a bridge to HSCT and with the aim deeper remission. 129 In a meta-analysis of 758 patients with B-ALL treated with CD19 CAR T cells, consolidative HSCT was associated with a lower relapse rate and improved long-term survival. 139 In the pediatric setting, a separate study showed that patients with primary refractory disease demonstrated improved OS and EFS following HSCT; however, transplant-naïve patients and those who had received multiple prior therapies, including blinatumomab or inotuzumab, or had BM disease ≥5% blasts prior to infusion experienced inferior OS and EFS after HSCT. 140 Nevertheless, a subset of patients achieve a durable CR without further treatment, thereby avoiding the short- and long-term toxicities associated with allogeneic HSCT. 138 Risk stratification to identify patients who should or should not go for HSCT remains challenging, highlighting the importance of the aforementioned disease surveillance strategies to assess risk of relapse post-infusion. Data suggest that there should be particular consideration of consolidative HSCT in patients with high-risk features, including persistent NGS MRD at day +28 and/or 3-month post-infusion, or early loss of BCA prior to six months. 128 An ongoing multicenter trial is evaluating whether NGS monitoring can be used to guide the decision to proceed to HSCT after tisa-cel ( NCT05621291 ).

CAR T cell reinfusion presents an alternative potential strategy to mitigate the risk of post-CAR relapse. Reinfusion of patients at high risk of relapse can be considered, as there have been reports of pediatric patients with early loss of BCA who underwent reinfusion, some of which were able to achieve long-term remission with or without additional therapies. 141 , 142 There is some evidence that a higher dose of CAR T cells or higher doses of LD prior to second infusion are associated with improved CAR T cell expansion and improved response rates. 143 , 144

The third potential option for treatment after CAR includes maintenance strategies, such as maintenance chemotherapy or TKIs. To preserve the function of persistent CAR T cells, chemotherapy after CAR should only be introduced after CAR T cells are no longer detectable, and if patients are thought to be at high risk of relapse. For example, a potential use for maintenance chemotherapy includes those with early loss of BCA. 145 For patients with high-risk genetic factors with targeted treatment options, such as Philadelphia-chromosome positive B-ALL, continuation of a TKI for maintenance post-CAR T cell infusion or post-transplant can be considered as an alternative strategy for long-term maintenance therapy, with limited evidence in adult patients to date. 146 , 147 , 148 For patients with relapse of EMD, radiation could be a potential option for consolidation, either alone or in combination with other treatment options, though current data are limited to use in post-CAR relapse. 149

How can CARs be improved: Novel CAR T cell strategies

Despite the remarkable success of CAR T cell therapy in patients who otherwise would not have any treatment options, both primary non-response and relapse after CAR remain a challenge. Between 10% and 30% of patients exhibit non-response to CD19 CAR T cells, and among those who do respond, about one-third experience relapse by 1 year, with up to 50% experiencing relapse within 3 years. 10 , 33 , 37 , 94 Potential mechanisms of non-response include poor expansion or limited cytotoxicity of CAR T cells, inhibition of CAR T cells by other host immune cells, or limited trafficking of CAR T cells to the sites of EMD. 44 , 80 , 83 , 150 , 151 Relapse may occur due to limited persistence of CAR T cells, antigen escape, or in rare cases, lineage switch. 73 Furthermore, increased use of CD19-targeting immunotherapy will likely change the antigen expression patterns among patients with relapse who require CAR T cells. Ongoing early phase trials and pre-clinical studies seek to address these challenges by designing more potent cell therapies and by targeting novel antigens ( Figure 2 and Table 2 ).

Modifications to enhance CD19-targeted CARs

Numerous modifications to CD19 CAR T cells have been trialed in order to improve upon efficacy, safety, and persistence, including adjustments to the scFv, linker, and co-stimulatory domains. 152 In particular, humanized CAR T cells have emerged as a method to improve persistence by preventing rejection of the mouse-derived scFv that is used in most clinical CARs. 153 A trial in which 74 CAYA patients were treated with humanized CD19-targeting CAR T cells (huCART19) reported 100% initial response in patients who had no prior CAR T cell therapy and 64% in those who had already failed prior CARs. They also reported RFS of 84% in CAR-naïve patients and 74% in CAR-pre-treated patients at 1 year. 154 In addition, a change to the scFv that leads to low-affinity CD19 targeting is another strategy that has led to improved expansion and persistence, with low toxicity in pediatric patients. 155 Comparisons of the two most commonly used co-stimulatory domains, CD28z and 4-1BB, have shown similar clinical efficacy overall, with increased initial expansion in CD28-stimulated cells but improved persistence and a less exhausted T cell phenotype with 4-1BB co-stimulation. 156 , 157 , 158 In one direct comparison in pediatric patients with B-ALL, 4-1BB co-stimulation, which is used in tisa-cel, showed improved efficacy. 159 CD19 CAR T cells may also be modified to include safety switches in case of severe toxicity. This has not been trialed in children, but an adult patient who developed severe ICANS after CD19 CAR T cell therapy has been successfully treated with a pharmacologically controlled switch, an inducible caspase-9 expressed by CAR T cells, which initiates apoptosis when activated by infusion of rimiducid. 160

Alternate antigen targeting

Like CD19, CD22 is a B cell lineage-specific marker expressed on approximately 60%–90% of leukemic blasts in B-ALL. 161 , 162 To address CD19-negative relapse driven by antigen escape, alternative CAR constructs targeting CD22 have been developed as a salvage strategy for patients with CD22-positive B-ALL. 163

In a single-center, phase 1 clinical trial involving the largest cohort reported to date ( n = 58), treatment with CD22-targeted CAR T cells induced a CR in 70% of patients with multiple relapsed B-ALL, including those with CD19-negative disease. 164 Notably, following the implementation of CD4/CD8 T cell selection of the apheresis product, a substantial portion of patients developed IEC-HS, albeit the condition was well tolerated. 164 Similar efficacy of anti-CD22 CAR T cells has been reported in other early-phase investigational trials. A trial at Stanford tested a humanized CD22/4-1BB construct ( n = 16), with a 75% CR rate, while a separate study at University of Pennsylvania tested a fully human CD22/4-1BB construct in a fractionated dosing scheme ( n = 19), with a 74% CR rate. 50 , 165 Although high CR rates were observed in both children and adults in these two trials, remission durability was limited without subsequent HSCT. In contrast to inotuzumab ozogamicin, an approved CD22-targeted antibody-drug conjugate, anti-CD22 CAR T cell therapy has not been associated with the development of sinusoidal obstructive syndrome/veno-occlusive disease, highlighting its potential indication in those with existing liver disease. 166

Preclinical data have revealed several additional B cell antigen targets that may serve as alternatives to CD19 and CD22, some of which are in the early phase of clinical trials. These include thymic stromal lymphopoietin receptor (TSLPR), which is encoded by CRLF2 and is overexpressed in cases of high-risk B-ALL with CRLF2 rearrangements, 167 and B cell-activating factor receptor (BAFF-R). 168

Multi-antigen targeting

For patients who retain CD19, multiantigen targeting and alternative cell types may increase CAR T cell efficacy.

Several methods allow for simultaneous targeting of CD19 and CD22, including co-infusion, co-transduction, or single-vector approaches. 169 Wang et al. tested a 1:1 co-administration strategy across 194 children with a 99% CR rate and 69% EFS at 12m censoring for consolidative HSCT. 170 Pan et al. also demonstrated success using a sequential strategy of CD19, followed by CD22 CAR T cell infusions; 79 of 81 patients received both infusions, and for the 62 who received the target dose, 3-month response rate was 97%, and 18-month EFS was 79%. 171 While co-infusion allows for titration of the amount of each CAR T cell construct to administer, it is time and resource intensive as it requires two vectors and potentially two separate T cell manufacturing runs. Co-transduction, in which multiple vectors are transduced at the same time, has been trialed in two small cohorts of children with good response rates; this strategy is limited by an inability to titrate the amount of anti-CD19 and CD22 CAR T cells that ultimately engraft. 172 , 173

Another approach is using a single vector to allow expression of multiantigen-targeted CARs. This can happen using a single CAR with multiple scFvs (bivalent), which expresses scFvs either sequentially or in a loop structure, or dual CARs (bicistronic), each with their own scFv but undergoing cleavage after transduction to allow for separate expression at the cell surface. Tandem CD19/CD22 constructs have resulted in high initial response rates but poor persistence. 174 , 175 A challenge with this design is avoiding steric hindrance to allow for optimal availability of each binding domain, as evidenced by primarily CD19-driven activity in the bivalent construct. 175 , 176 , 177

Bicistronic CD19/CD22 CAR T cell constructs are an attractive option as they should optimally allow transduced T cells to express separate CD19 and CD22 CARs in equal proportions. The AUTO3 construct was tested across 15 CAYAs with r/r B-ALL, which demonstrated 86% CR and 1-year EFS of 32%. 178 Preliminary results from a bicistronic CD19/CD22 CAR T cell trial in China demonstrated 99.1% CR among 318 pediatric patients, with 12-month EFS of 72.4% among those with isolated or combined hematologic relapse. 179 Early data from a bicistronic construct at our institution demonstrated 100% MRD-negative CR rate among 10 patients, although initial toxicities led to dose de-escalation and stratification by disease burden. 180 This trial is ongoing with improved toxicity profiles and continued CRs at a lower dose level.

Alternate cell types

Allogeneic CARs

The use of allogeneic donor-derived or “off-the-shelf” T cells has the potential to overcome poor T cell fitness and avoid the issues of active disease and low lymphocyte counts at the time of autologous T cell collection. However, use of donor-derived products introduces challenges including graft-versus-host disease (GVHD), immune-mediated rejection, and, consequently, potential need for additional immunosuppression after CAR T cell infusion. 181 To date, a few trials have tested donor-derived allogeneic CAR T cells in pediatric patients with B-ALL relapse after HSCT. 182 In an Italian study of 13 CAYAs who received one of two allogeneic CD19 CAR T cell products (one retroviral and one lentiviral), all achieved MRD-negative CR. 183 Both children and adults were included in a trial of donor-derived CD19 CAR T cells in post-allogeneic HSCT relapse in China, which included 43 patients and resulted in 79% remission. 184 Of note, each of these studies reported post-infusion GVHD in 1 and 2 patients, respectively, and in the latter study, 2 patients died from multiorgan failure and CRS. Gene editing using technologies such as transcription activator-like effector nuclease (TALEN) or CRISPR-Cas9 may allow for off-the-shelf products that do not need to be HLA matched by disrupting the native T cell receptor, which is implicated in the development of GVHD. 182 Gene-edited allogenic CAR T cells, with disruptions of the T cell receptor alpha chain (TRAC) to reduce GVHD risk and disruption of CD52 to protect CAR T cells from alemtuzumab lymphodepletion have been used in a small number of pediatric patients with B-ALL, demonstrating feasibility, safety, and short-term efficacy. 185 , 186 , 187 Further testing of allogeneic strategies is warranted to increase availability of these products.

NK CAR

Natural killer (NK) cells are able to recognize and eliminate malignant cells without prior sensitization and in an antigen-independent manner. 188 , 189 They can be derived from sources including peripheral blood, cord blood, and established cell lines, making them a readily available alternative to T cells. 188 These properties may allow NK cells to overcome known limitations of both autologous and allogenic CAR T cell products, such as the lack of tumor-specific antigens, poor T cell fitness, or T cell-mediated toxicities such as GVHD. While numerous CAR-NK cell trials have been registered in recent years for both solid and hematologic malignancies, further research is needed to assess their safety and efficacy in pediatric patients with B-ALL. 189 , 190 , 191

What else should we be thinking about?

Survivorship

Since the FDA approved the first CAR T cell product in 2017, more than 30,000 patients have received CAR T cells. 192 Given their ability to induce durable remission in many patients with r/r B-ALL, monitoring of late effects in survivors is an essential next step in understanding the long-term impacts of CAR T cells ( Figure 3 ). “Beyond the Storm” was an initial symposium in 2020, in which experts in the field gathered to address the subacute and longer-term toxicities, including neurocognitive outcomes, psychosocial considerations, infection and immune reconstitution, end-organ toxicities, and secondary neoplasms, in children and young adults receiving CAR T cells. 193 Since that time, additional survivorship considerations, such as fertility, have been added to this growing list of long-term outcomes that require further exploration. 194 , 195 Accordingly, two prospective studies have been initiated at St. Jude Children’s Hospital, one looking at delayed effects post-CAR T cell therapy, including longer-term impacts on bone marrow function, immune reconstitution, and neurotoxicity ( NCT06579469 ), and another aiming to comprehensively capture additional long-term effects through multi-day visits in Memphis for clinic evaluations, lab testing, and surveys ( NCT07048535 ). 196

Secondary malignancies

The risk of secondary malignancies, particularly T cell malignancies occurring after genetic T cell modifications, has been a particular concern in CAR T cell development. In November 2023, the FDA reviewed 22 reports of T cell malignancies following B cell maturation antigen (BCMA) CAR T cell therapy in adults. In three of these cases, malignant cells were found to express the CAR transgene, raising concerns about insertional mutagenesis. 192 , 197 As a result, 61 centers across multiple countries treating pediatric, adolescent, and young adult patients with both commercial and early-phase CAR T cells were committed to evaluate the incidence of secondary T cell malignancies after CAR infusion. 198 Among 3,528 infusions, only one patient who was previously treated for a CNS tumor developed a T cell lymphoma, unrelated to CAR T cell therapy.

In pediatric patients with B-ALL, a retrospective analysis of 420 patients reported an incidence of 1.7% ( n = 7) secondary malignancies after CD19 CAR, including 4 solid tumors and 3 myeloid neoplasms. 199 Notably, 6 of them had received prior HSCT and 6 had received radiation, making it impossible to know if it was the CAR T cells or other prior therapy that led to the secondary malignancies. Furthermore, patients with multiple relapsed disease may carry accumulated genetic and epigenetic alterations that increase their risk of developing secondary malignancies. 200 While the current evidence supports a favorable safety profile for CAR T cell therapy, continued surveillance remains essential.

Access

While CAR T cells for r/r ALL are approved in the United States, access is not as straightforward. The cost of commercial CD19 CAR T cell therapy is estimated to be >$400,000. 201 While insurance companies may cover the majority of that cost for insured patients, obtaining authorization can be a prolonged process, leaving those with progressive disease vulnerable as their disease may rapidly progress in the interim prior to apheresis. 202 Furthermore, patients without health insurance may not be able to be treated with commercial CAR T cell therapy and may only be eligible for investigational therapies.

Early phase clinical trials sometimes offer therapy at little to no cost, but trial availability allows limited slots for participation. Partnerships between academic centers and pharmaceutical companies may allow larger and later phase trials to move forward, opening the road to commercialization while providing access in the interim. 203 While tisa-cel was a unique example in which pediatric approval was obtained first, in most cases, CAR T cell products that have been approved since that time remain available only to adults, in whom the cancer incidence and, therefore, product utilization remain higher. Including CAYAs in registration trials will be important to facilitate timely approval of these products.

In addition, novel strategies are required to decrease the cost of CAR T cell manufacturing. Decentralized and shortened manufacturing protocols may decrease costs and allow more centers to participate in CAR T cell production. 203 Even commercial, centrally manufactured CAR T cells can only be given at specialized centers, which may or may not be in geographic proximity to where the patient resides. This may prevent access depending on social circumstances, including caregiver availability and stress, as well as financial burden for lodging as well as other additional costs not covered by insurance. 204 Increasing comfort and education in managing CAR T cell-associated toxicities, as well as the ability to move the majority of care to the outpatient setting, will decrease resource utilization and may expand the number of centers equipped to administer CAR T cells.

Conclusion

Remarkable strides have been made in the treatment of r/r B-ALL with the advent and advancement of CAR T cells. The last decade has demonstrated that tisa-cel has the ability to bring heavily pre-treated and often difficult-to-treat populations into a CR, which, in many cases, is quite durable. The toxicities of CAR T cells are much better understood and anticipated, such that they are largely tolerable. Multiple strategies are being employed to enhance the efficacy and durability of CD19 CAR T cells and to investigate novel constructs that may tackle issues of antigen escape, T cell exhaustion, and product availability.

In the coming years, focus will need to be shifted to several key areas. The first is the potential role of CAR T cell therapy earlier in the B-ALL treatment paradigm. With the upfront incorporation of blinatumomab into initial chemotherapy regimens with excellent outcomes, novel strategies for those in first relapse will be necessary. Utilizing CAR T cells in first relapse, and possibly even earlier in high-risk groups that suffer significant morbidity from chemotherapy (i.e., patients with DS and infants), may aid in reducing the length of treatment and chemotherapy exposure. Furthermore, given the improving persistence of CAR T cells, introducing them earlier may help more patients avoid the morbidity and mortality related to HSCT. Second, the types of CAR T cells available commercially, and particularly to pediatric patients, need to be expanded to offer alternatives for patients who relapse despite CD19-targeted therapy that the majority will receive. Third, it will be critical to improve and standardize post-CAR disease monitoring and maintenance strategies to determine which patients truly require consolidative HSCT versus those who are likely to maintain a long-term response with surveillance and/or an alternative, less toxic therapy. Last, but certainly not least, is the issue of access, a critical factor limiting the global scalability of CAR T cell therapy. With exciting translational work being done across the globe and creative academic, biopharma and non-profit partnerships, the benefits of CAR T cell therapy can reach a broader population.

Acknowledgments

This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Warren Grant Magnuson Clinical Center (ZIA BC 011823, N. Shah).

Author contributions

All authors contributed to the conception and writing of the first draft of this manuscript. No third party was involved in writing or contributed to any part of the study. All authors contributed to reviewing the final manuscript and have agreed to be co-authors.

Declaration of interests

This research was supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

Contributor Information

Alexandra Dreyzin, Email: alexandra.dreyzin@nih.gov.

Sara K. Silbert, Email: sara.silbert@nih.gov.

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