A Review of CAR-T Therapy in Pediatric and Young Adult B-Lineage Acute Leukemia: Clinical Perspectives in Singapore

Introduction

A range of mechanisms are used by the immune system to suppress cancer cells and many of these mechanisms are inactivated during the development of the cancer, allowing cancer cells to spread. Cancer immunotherapy is based on the notion that the immune response can be harnessed or reprogrammed to effectively eradicate cancer cells. As T cells play a crucial role in the adaptive immunity involved in tumor surveillance and pathogen clearance, they have been studied for their role in anti-cancer therapy.1,2 In the 1970s, stem cell transplantation provided the first biological evidence that adoptive T cells from an MHC-compatible healthy donor could exert a powerful graft-versus-leukemia effect, leading to long-term eradication of chemo-refractory leukemias. The use of tumor-infiltrating lymphocytes by Rosenberg in 1986 to cure a subset of patients with advanced cancers3 further supported the potential of adoptive T cell therapies. These early salvage therapies provided the foundation for the subsequent major advancements in T cell-based therapies.

Sequential seminal innovations over the last 30 years contributed to the modular development of a clinically effective CAR-T construct. The first synthesis of a chimeric immunoglobulin/T-cell receptor (TCR) molecule, now known as the chimeric antigen receptor (CAR), led to the scientific plausibility that T-cells could be engineered with antibody type-specificity for therapy against specific targets.4 Subsequently the first generation of effector T-cells expressing a CAR was conceived around 1989–1993 by Israeli immunologists Zelig Eshhar and Gideon Gross.5,6 Around this time, Irving and Weiss showed that following extracellular antigen-binding, signal transduction through a transmembrane CD8 and intracellular TCR CD3ζ domain present in a CAR could independently mediate T-cell activation.7 A significant boost to this field occurred when Michel Sadelain developed retroviral vectors as a method to introduce genes into T-cells, enabling large-scale modification of their cytotoxicity and specificity for cancer cells.8 The first-generation synthetic CAR that is expressed from the T cells reprograms lymphocyte function and specificity by the coupling of the intracellular T-cell signaling domains and the antigen-binding single chain Fv domain (scFv), bypassing the need for native major histocompatibility complex (MHC)-restricted T-cell activation. This worked modestly but lacked the proliferation, persistence and potency needed for effective cancer killing. This was primarily due to the lack of a second signal for T-cell activation, the co-stimulatory signal. These limitations were overcome in the second-generation construct which linked the antigen-binding activation of intracellular T-cell signaling (Signal 1) to a single co-stimulatory signal (Signal 2), either a 41BBz or CD28 module; this ingenious modification formed the basis of the first clinically effective CAR-T therapies.9,10 More than a decade later, chimeric antigen receptor T-cell (CAR-T) therapy is now a breakthrough treatment of patients with hematologic cancers, especially with chimeric antigen receptors (CARs) targeting CD19 in B-cell malignancies. Third-generation CARs which include multiple and/or new co-stimulatory signaling modules to enhance their function are currently being studied.11–15

In 2011, anti-CD19 directed CAR-T cells produced complete remissions in multiply relapsed pediatric acute lymphoblastic lymphoma and adult chronic lymphocytic leukemias at around the same time, resulting in the landmark success in the clinical application of CAR-T therapies.16,17 It is notable that the initial applications of CAR-T therapy began simultaneously in pediatric and adult patients, with the pivotal trial results leading to the breakthrough designation of tisagenlecleucel reported in pediatrics. This stood in contrast to many other small molecule therapies and drugs that were traditionally established in adult trials first before being extended to pediatric cohorts. To date, there has been just one FDA and EMA approved CAR-T for pediatric and young adult patients, tisagenlecleucel (Kymriah™, Novartis) up to 25 years of age with B-cell ALL that is refractory or in second relapse.18,19 In this review, we focus on the burden of relapsed/refractory paediatric B-ALL, the limitations of current strategies, the emerging paradigms for the role of CAR-T in r/r B-ALL, our local perspectives on the health economics and future direction of CAR-T therapies in pediatric patients.

The Burden and Unmet Needs of Pediatric Acute Lymphoblastic Leukemia (ALL)

Pediatric acute lymphoblastic leukemia is the commonest childhood cancer, accounting for approximately 25% of all childhood cancers. Thirty-seven per 1,000,000 children are diagnosed with acute lymphoblastic leukemia each year in the United States.20 In Singapore, about 30 children are diagnosed each year with paediatric leukemia, two-thirds of whom are acute lymphoblastic leukemia. Paediatric ALL is classified into B-ALL and T-ALL with B-ALL accounting for 85% of the cases and T-ALL accounting for 15% (Singapore childhood cancer registry, unpublished data, 2022).

Poor Survival of Relapsed/Refractory B-ALL

Although the 5-year overall survival (OS) rate for pediatric B-ALL has improved to approximately 85–90%,21,22 prognosis remains poor in patients defined as high risk at diagnosis and in relapsed/refractory patients.23

Relapsed/refractory disease accounts for 10–15% of B-ALL in children and 18% in patients with T-ALL23,24. As a group, relapsed/refractory pediatric B-ALL is the fourth commonest childhood cancer.25 Event-free survival (EFS) for high-risk pediatric B-ALL remains at about 50–67% across most protocols (Singapore childhood cancer registry 2022, National Registry of Diseases Office, personal communication, 2022).26–28 At first relapse, 3-year survival probabilities can vary from 20–70% depending on the time to relapse and effectiveness of reinduction.29,30 Survival after a second disease relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is dismal.

Since the early 2000s, a risk-adapted, MRD-guided pediatric chemotherapy protocol (MASPORE) has been the standard treatment regimen. In the MASPORE 2003 and 2010 study cohorts,28,31 15% of all B-ALL patients were defined as high risk (n=126 of 823 patients) based on high-risk genetics, clinical features or poor disease response. High-risk patients had an inferior event-free survival of 51.8% ± 10% compared with 92.3% ± 4.1% in the standard-risk patients and 83.6 ± 4.9% in the intermediate-risk patients.28

KK Women’s and Children’s hospital-based registry data showed 48 out of 235 B-ALL (20%) treated on contemporary protocols from 2003 to 2021 had relapsed/refractory disease. Despite excellent overall survival across all groups of B-ALL (Figure 1A), the 5-year OS in the high-risk B-ALL group was 62.9% (Figure 1B) while relapsed B-ALL had a 5-year OS of <50% (Figure 1C).

Figure 1 Five-year and 10-year Overall Survival of Pediatric and Adolescent B-ALL in (A) All groups. (B) High-risk B-ALL. (C) Relapsed B-ALL.

Notes: SCCR 2021 data, unpublished, with permission from KK Women’s and Children’s Hospital, KKH.

Late Effects of Irradiation, Transplant and Treatment Intensification for High-Risk Patients

Forty-two of 186 survivors of pediatric B-ALL, diagnosed between 1985–2012, seen in our pediatric long-term follow-up clinic had received radiotherapy as part of curative treatment including stem cell transplant; 50% had received radiation as part of relapse treatment, 44% received this within the primary treatment and 6% both during primary treatment and as part of relapse. A significant 32/42 (76%) suffered from at least one significant adverse late effect, predominantly metabolic complications, endocrinopathies and second neoplasms/cancers (LTFU registry), illustrating the cost of cure. Besides the late effects of irradiation, long-term complications of HSCT include chronic graft-versus-host disease, infertility, organ impairment, late infectious complications and cardiomyopathy.

Acute Treatment Toxicities of Pediatric-Inspired Protocols in Adolescents and Young Adults

Adolescent and young adult (AYA) B-ALL, diagnosed at age <40 years, have better outcomes when treated using pediatric-inspired chemotherapy regimens, but experience much higher toxicities compared with the children. In a retrospective review of 116 AYA B-ALL patients32 from the registries of three tertiary hospitals (Singapore General Hospital, National University Hospital and Tan Tock Seng Hospital), 25% were treated with a pediatric-inspired MASPORE protocol28 and 75% were treated with a HyperCVAD protocol. A higher rate of adverse events was observed for patients treated on the MASPORE arm; these events included severe pancreatitis (13.8 vs 0.0%, p < 0.001), avascular necrosis (13.8 vs 2.2%, p = 0.016), cerebral venous thrombosis (13.8 vs 1.1%, p = 0.004) and other thrombosis (27.6 vs 5.7%, p = 0.0043) deaths due to treatment-related toxicities. Although 5-year OS and progression-free survival could be improved (5-year OS 86% vs 60%) using a pediatric-inspired protocol, this comes at the cost of higher treatment-related toxicities. Furthermore, 40% of AYA patients eventually required consolidation with a hematopoietic stem cell transplant (13.8% on the MASPORE protocol and 49.4% on HyperCVAD). As current therapies in young adults and children are insufficient and lead to significant morbidities, there is an urgent need to improve quality-adjusted life years in survival.

Current Therapies, State of the Art and Limitations

Treatment options for pediatric and young adults who have r/r B-ALL include immunotherapies such as blinatumomab (BLN) and inotuzumab and salvage chemotherapy regimens (SCR) (Table 1). These treatments have sub-optimal outcomes and are used to bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT), which also has sub-optimal outcomes (Wang et al, 2022). There are at least 21 published trials on novel therapies besides CAR-T, for relapsed/ refractory pediatric leukemia (13) and lymphoma (8) since the early 2000s, excluding CAR-T.33 We further elaborate on the success and limitations of salvage chemo-intensifications and immunotherapies as a means to allogeneic hematopoietic stem cell transplantation (HSCT) and CAR-T therapies in B-ALL.

Table 1 Recent Clinical Trials for R/R Pediatric B-ALL Other Than CAR-T Therapies

Total body irradiation (TBI)-based hematopoietic stem cell transplantation (HSCT) is the current standard of care for relapsed/refractory B-lineage acute lymphoblastic leukemia. The best outcomes are achieved if the patient is transplanted in deep remission, when there is no longer any measurable residual disease (MRD) in the bone marrow (“MRD negative”).30 Many genetically high-risk and relapsed/refractory patients are inherently refractory to chemotherapy.34 Achieving MRD negativity prior to transplant requires intensification of chemotherapy traditionally, with high acute treatment-related mortality due to infectious complications. Total body irradiation-based allogeneic hematopoietic stem cell transplant (HSCT) can be curative but is associated with high incidence of acute toxicities and chronic health conditions.35

The last FDA approved drugs for relapsed/refractory pediatric B-ALL was clofarabine in 2004 and nelarabine for pediatric T-ALL and T-LBL in 2005,36,37 indicating the gradual move away from salvage chemotherapies to targeted approaches. In the very high risk (VHR) group of pediatric B-ALL, chemotherapy intensification approaches with newer drugs such as clofarabine are associated with significant toxicities.38

More recently, commercial antibody-based immunotherapies such as inotuzumab (an anti-CD22 antibody-drug conjugate) and blinatumomab (a bispecific CD3-CD19 T-cell engager or BiTE) have become the new standard of bridging therapy to HSCT in first relapse or in refractory disease, improving initial complete remission rates to 39% (blinatumomab) and 58% (inotuzumab) in chemo-refractory pediatric patients. Immunotherapies in general have reduced significantly the toxicities of intensive chemotherapy regimens with higher rates of leukemia response and greater likelihood of proceeding to HSCT.29,39,40 Despite the improved CR rates, overall survival outcomes are variable, with suboptimal outcomes in second or greater relapses and high leukemia burden at the time of antibody salvage (Table 1).

In a randomized phase III study COG AALL1331, Brown et al studied if substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL. In first relapse, 2-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39–0.98]; one-sided P = 0.02). However, blinatumomab did not appear to improve overall survival in second or later relapses, including post-transplant relapses.41,42

Inotuzumab ozogamicin (InO) is an anti-CD22 drug-antibody conjugate that has been well established in adult r/r B-ALL in the INO-VATE ALL trial43 to produce a higher rate (80.7% vs 29.4%, P<0.001) and deeper (MRD negative 78.4% vs 28.1%, P<0.001) complete remissions than with standard therapy. The Children’s Oncology Group trial AALL1621 concluded that InO was effective and well tolerated in heavily pre-treated children and adolescents with R/R CD22-positive B-ALL with a CR/CRi rate of 58.3%; 90% CI, 46.5–69.3). In both adults and children, sinusoidal obstructive syndrome (SOS) of the liver after hematopoietic stem-cell transplantation and prolonged cytopenias were notable.

In conclusion, while there are gains made in effective and less toxic regimens other than chemotherapy for relapsed/refractory B-ALL, the major limitations of antibody therapies are the short half-life and the inability to cross the blood–brain barrier to treat or prevent central nervous system (CNS) leukemia. Complete remission after these antibody therapies is not durable in the absence of a stem cell transplant. Therefore, total body irradiation-based stem cell transplant still cannot be avoided for long-term cure in younger patients.

CAR-T Therapy for Relapsed/Refractory Pediatric B-ALL

Finding a curative salvage therapy with fewer long-term toxicities would translate to improved quality-adjusted life years in these children and young adults. Chimeric antigen receptor (CAR)-T cell therapy is one such promising therapy. Briefly, the patient undergoes a leukapheresis for lymphocytes prior to chemotherapy intensification, the lymphocytes are sent to a cell and gene therapy facility (either local or overseas) where CAR-T is produced by ex vivo lentiviral vector transduction of T cells to express the chimeric antigen receptor (CAR) that will provide a T-cell activation signal and a 4–1BB domain to provide a costimulatory signal (Maude et al, 2018b). These patients receive lymphodepletion, typically fludarabine 120 mg/m2 given over 4 days and cyclophosphamide 1000 mg/m2 over 2 days, followed by a single infusion of CAR-T.

In 2016, autologous anti-CD19 CAR-T cell therapy resulted in unprecedented 12-month overall survival (OS) rates of 77.2% in chemo-refractory B-ALL patients,44 leading to an FDA breakthrough therapy designation as tisagenlecleucel (Tisa-cel). Notably, only 9% in the pivotal study44 and 16.1% in a subsequent real-world analysis45 underwent a consolidative HSCT while in remission, strengthening the value of “living” cell therapy as an alternative to a HSCT.

Clinical Trials in CAR-T Therapies in Paediatric r/r B-ALL

The success of anti-CD19 CAR-T therapies including the pivotal ELIANA trial has been amply summarized in literature. Here, we describe the current clinical evidence that is relevant specifically to pediatric B-ALL and the clinical considerations for CAR-T in the treatment of r/r pediatric B-ALL.

Tisagenlecleucel (Other Names: CTL019, Tisa-Cel, CART-19, Trade Name: Kymriah)®

The first pediatric application of Tisa-cel, previously known as CTL019, was reported in a case report of two children with relapsed/refractory B-ALL. CTL019 resulted in the remarkable induction of remission of relapsed and refractory leukemia in the first two patients treated on this protocol. Remission has been sustained in one patient and was accompanied by relapse due to the emergence of CD19-blasts in the other patient.16 CTL019 contains a lentiviral transduced anti-CD19 CAR, with the scFv derived from the recombinant monoclonal murine antibody clone FMC63, a CD8-alpha hinge, a 4–1BB costimulatory domain and CD3z intracellular signaling domain. Table 2 summarizes the clinical trials for tisagenlecleucel in pediatric and young adult R/R B-ALL patients leading to marketing approval.

Table 2 Clinical Trials for Tisagenlecleucel in Pediatric and Young Adult R/R B-ALL Patients

The first phase I/II trial investigating CTL019 in pediatric CD19+ R/R B-ALL was a single-arm, phase II, open-label study (B2101J, NCT01626495) conducted at the Children’s Hospital of Philadelphia (CHOP). A total of 30 r/r ALL patients were enrolled and treated with CTL019, including 25 patients between the ages of 5 and 22 years and 5 other patients between the ages of 26 and 60 years. After 1 month of infusion 27 patients were in complete remission. The event-free survival and overall survival rates at 6 months were 67% and 78%, respectively. The probability that CTL019 would persist at 6 months was 68% and sustained remissions were observed up to 2 years.46 A longer follow-up of the same study included 59 patients with r/r B-ALL pediatric and young adults of whom 93% (55/59) achieved CR/CRi 1 month post infusion, with 52/55 in MRD negative remission. Five patients (8% of all responders) proceeded to HSCT consolidation, and 17 patients (31%) received reinfusions due to loss of B cell aplasia or MRD recurrence. CTL019 was subsequently studied across 13 US study sites (ENSIGN, NCT02228096) in a multicenter, single-arm, phase II trial for r/r B-ALL pediatric and young adult patients aged 3–21 years. The number of enrolled patients was 73 and 58 of those patients were infused. The overall remission rate was 69% with 64% being in CR and 5% in CRi. Relapse-free survival rate was 71% and 61% for 6 and 12 months. In responding patients CTL019 could be detected for up to 764 days.47 ELIANA was the global pivotal registration trial for tisagenlecleucel (NCT02435849l) which included a total of 92 patients, of whom 75 received CTL019. The overall remission rate after 3 months of follow-up was 81%. From the 75 patients who received CTL019 infusion, they had an overall rate of survival of 90% after 6 months and 76% at 12 months after infusion.47 In a managed access Phase IIIb trial (B2001X, NCT03123939), tisagenlecleucel was studied in a multi-center global study to provide access to patients with r/r ALL including prior anti-CD19 therapy after enrolment ended in the pivotal ELIANA (NCT02435849) study with a focus in post-blinatumomab and post-inotuzumab outcomes. The efficacy and safety of tisagenlecleucel in the B2001X study remain consistent with outcomes in ELIANA. In patients with prior BLINA or INO as bridging therapy, a trend toward suboptimal outcomes was observed. Since the post-marketing approval of Tisa-cel as a salvage treatment, real-world experience has been reported with the largest cohort from the prospective multi-center observational CIBMTR study conducted across North America. Overall response rate was comparable with ELIANA at 86% with 16% proceeding to pre-emptive consolidative HSCT. The minority of patients who had received blinatumomab (15%) and inotuzumab (11%) prior to CAR-T infusion had a complete remission rate of 78% and 65%, respectively, although a not insignificant proportion of patients eventually experienced treatment failure, relapse or died from ALL during a median of 10.9 months.45

The published Tisa-cel evidence to date indicates that in pediatric r/r B-ALL, there is a subset of patients cured by a single infusion of CAR-T despite multiple lines of previous salvage and without any post-infusion interventions. Secondly, the median marrow blasts at infusion was about 2% in the real-world study and much higher in the original ELIANA cohort. With this in mind, the goal of bridging to CAR-T should not be to render the patient with no disease prior to CAR-T infusion, but to maintain disease control until infusion. The use of blinatumomab and inotuzumab bridging, while discouraged if disease can be controlled with a light-handed chemotherapy approach, may still be the only means to safely infuse a patient with high disease burden, and should not preclude a patient from using CAR-T to achieve long-term remission. The question of which patient and when to consolidate with a HSCT continues to be studied. In the real-world analysis, about 10–15% of patients who responded to CAR-T later received pre-emptive consolidative HSCT while in remission due to a lack of CAR-T persistence of early loss of B cell aplasia. A smaller subset of patients received repeated infusions of Tisa-cel. In a separate analysis of anti-CD19 CAR-T infusion across three different clinical trials of anti-CD19 CAR-T, an overall response rate in 7/18 (38.9%) to the second infusion was reported, hampered by poor CAR-T expansion and antigen modulation, which could potentially be overcome by intensification of lymphodepletion.48

Other Anti-CD19 CAR-T Therapies for Pediatric B-Lineage Leukemias

Other variations of anti-CD19 CAR-T products with a 4–1BB costimulatory domain and with a CD28 co-stimulatory domain have been developed by other groups since, all reporting similar success in the r/r pediatric B-ALL. The main difference between the second-generation CAR designs is the costimulatory domain. The 4–1BB domain has been shown to improve CAR-T persistence through amelioration of T-cell exhaustion.49

In the PLAT-02 Phase I trials (NCT02028455), the Seattle group infused lentiviral transduced CD19 (GCM63) CAR-T in a defined 1:1 CD4+: CD8+ ratio. The rate of MRD-negative CR at 1 month was 93%, with a median duration of B cell aplasia of 3 months. The 12-month EFS was 50% and OS 66%. Factors favoring persistence of B-cell aplasia (BCA), defined in this trial as peripheral B cells <1% of lymphocytes, were pre-infusion CD19+ antigen load of >15% and the use of lymphodepletion. Point-of-care CAR-T treatments using an anti-CD19 41BB lentiviral vector are currently in clinical trials across various countries, including Barcelona, Russia, Germany, including the authors’ institutions in Singapore.50,51

The Memorial Sloan Kettering Cancer Centre (USA), National Cancer Institute (USA) and Sheba Medical Centre (Israel) have developed CD28z second generation anti-CD19 CAR-T cells generated with gamma-retrovirus. In a phase I study of KTE-C19, which contains a CD28 domain and based on the NCI CAR-T, involving 21 children and young adults, CAR-T cells were not detected beyond 68 days;47,52,53 therefore, KTE-C19 and similarly, other CD28 CAR-T serve as a bridge to allogeneic transplantation for most patients who receive it. The CD28z CAR-T patients in all three centres were consolidated with HSCT in remission due to the recognized shorter persistence of the CD28z CAR-T. Results from all centres were comparable with this approach with CR rates at 28 days ranging from 70–90% and long-term EFS between 53–73%.54–56

Lambel et al extensively characterized pre-infusion risk factors associated with the development of each relapse pattern via a multicenter, retrospective review of children and young adults with r/r B-ALL treated with a murine-based CD19-CAR construct. Of 420 CAR-treated patients, 166 (39.5%) relapsed, including 83 (50%) CD19 positive, 68 (41%) CD19 negative and 12 (7.2%) lineage switch (LS) relapses. A greater cumulative number of prior complete remissions was associated with CD19 positive relapses, whereas high pre-infusion disease burden (defined as >5% marrow blasts), prior blinatumomab non-response, older age, and 4–1BB CAR construct were associated with CD19 negative relapses. The presence of a KMT2A rearrangement was the only pre-infusion risk factor associated with lineage switch.57

CAR-T Toxicities

Toxicities such as cytokine release syndrome (CRS) and neurotoxicity are common complications that occur after CAR-T-cell infusion.58 Scoring and management algorithms are well summarized in guidelines and beyond the scope of this review.59,60 With increasing experience with the early use of tocilizumab and steroids, the management of these potentially fatal toxicities is now anticipatory.

Cost-Effectiveness

Thielen et al (2020) found that Tisa-cel is cost-effective with a willingness-to-pay (WTP) threshold of 80,000 EUR per QALY gained for the treatment of children and young adults with r/r ALL in the Netherlands. This favorable result is because of the survival gains from Tisa-cel treatment compared with other treatments with a total of 14.01 life years.61 Cost-effectiveness analysis conducted by Wang et al (2022) reveals that at a unit price of S$500k for commercial CAR-T treatment for children and young adults with r/r ALL, it is a cost-effective treatment when compared with salvage chemotherapy and blinatumomab from Singapore’s healthcare system perspective. The studies suggest that CAR-T is cost-effective because of the avoidance of higher drug administration, hospitalization cost, and the following allo-HSCT cost. Cost effectiveness of CAR-T cells is also seen with treatment of other hematological malignancies such as lymphoma (Wang XJ et al, J Med Econ 2021. DOI: 10.1080/13696998.2021.1922066). With the establishment of point-of-care CAR-T, we anticipate an even larger cost-effective margin, with the reduction of centralized manufacturing costs, cryopreservation and long-distance courier and economy of scale due to relative affordability. The initial cost incurred would include several years of capital-intensive infrastructure building, technology transfer and talent development, as well as maintenance of the good manufacturing practice (GMP) licensure of the cell therapy facilities. Patient-related outcomes are significant, in terms of gains in quality-adjusted life years (QALYs) and reduction of acute and long-term toxicities from high-dose chemotherapy and total body irradiation. A cost-effective analysis is not yet available in the Singapore healthcare setting.

Future Directions of CAR-T R/R Pediatric B-ALL

Tisa-cel, as of September 2022, is the only CAR-T approved for r/r pediatric B-ALL in the primary refractory state, in post-transplant relapse or in second or later relapses. In the latter cases, the opportunity to minimize long-term toxicities and improve quality-adjusted life years from prolonged hospitalization and treatment complications has already been missed. Many centers, including ours, are actively investigating the role of a long-acting CAR-T in high-risk or very high-risk patients, extending the definitions of “refractory” to the context of high MRD after first induction or consolidation with the aim to replace treatment intensification approaches including hematopoietic stem cell transplant in these children (NCT03876769, NCT05429905, NCT05038696). Antigen escape-mediated relapse is one of the major limitations of single-targeting CAR-T therapies, particularly with the 41BBz-CAR-T which exerts a sustained immune pressure on a single antigen. To reduce this relapse, targeting multiple antigens such as CD20 and CD22 by using dual CAR constructs is an important approach to investigate62,63 and beyond the scope of this review. Improving manufacturing capacities by shortening the manufacturing time is an important future direction which will shorten the waiting time for a patient to receive CAR-T, reducing the risk of disease progression which would compromise eligibility and safety.

Other Relapsed/Refractory Pediatric Diseases

CAR-T therapy has shown a tremendous success in the treatment of hematological malignancies. Novel CAR-T therapies to r/r T-cell ALL and AML are currently in phase I/II clinical trials. Unlike B-cell aplasia which can be supported with immunoglobulin infusions, profound T-cell aplasia and marrow aplasia results in opportunistic, fatal infections, as such, T-ALL and AML-directed CAR-T treatment will need to be followed by a stem cell transplant in chemo-refractory patients unless CARs to leukemia specific antigens are developed.

Future translational efforts will be focused on developing a successful CAR-T for relapsed/refractory pediatric solid tumors with the primary barriers in homing, persistence in a hostile microenvironment, antigen heterogeneity and on-tumor, off-target toxicities.64,65 Preclinical and early phase I trials of CAR-T targeting GD2, Glypican 3, B7-H3, HER2 and CD47 are some of the therapeutic candidate targets and will include biomarkers for success.66

Conclusion

Relapsed/refractory acute lymphoblastic leukemia has a dismal prognosis and standard-of-care salvage therapies involve intensive alkylator-based chemotherapy and irradiation-based allogeneic stem cell transplant. The challenge of acute toxicities, cumulative long-term morbidities and late mortality are particularly important in pediatric and young adult survivors, taking into account the person-years of follow-up and the non-plateauing trajectory of mortality due to adverse late effects.67 In Singapore, where healthcare is advanced and salvage treatments pursued intently, CAR-T therapy has demonstrated improved survival with a low risk of long-term side effects with significant improvements in quality-adjusted life years. CAR-T as salvage for multiply-relapsed, incurable pediatric B-ALL was a pivotal moment in 2016.44 The full potential of CAR-T, in our opinion, would be to realize the curative, toxicity-sparing potential of engineered T-cells earlier on in treatment, allowing one to depart from treatment intensification approaches and the need for irradiation-based hematopoietic stem cell transplants in a pre-defined group of patients. Newer clinical paradigms and innovations need to be investigated: Moving CAR-T therapies front-line for high-risk patients; loosening the definitions of “refractory” to include poor MRD-response and those with high-risk genetics; incorporating strategies for persistence and overcoming antigen escape-mediated relapse with dual-targeting approaches.

Several studies have shown CAR-T cell therapy to be a cost-effective treatment option with limited budget implications in the treatment of r/r ALL patients who have failed at least two lines of prior therapies. Studies in adult patients with diffuse large B-cell lymphoma also show similar cost-effectiveness.68 Equitable and sustainable access to CAR-T therapy in this part of the world, regardless of socioeconomic status, remains an area of clinicians’ and patients’ advocacy.

Clinical trials, point-of-care CAR-T manufacturing capabilities, and industry-academic collaborations are important avenues for generation of new paradigms, improving access and advancing innovations in CAR-T therapies. Anti-CD19 CAR-T has provided a valuable and evolving framework for this. While CAR-T cell therapy has expanded to include multiple myeloma in adults and T-cell leukemias in both adults and children, clinical applications appear to be limited to hematological malignancies at present due to the ability to target cell surface determinants on blood cells (which can be transiently or permanently eradicated without major consequence) without significant deleterious effects on major organs. Future translational efforts are focused on developing a successful CAR-T for relapsed/refractory pediatric solid tumors, where a large unmet need resides and where there are even greater barriers to overcome such as persistence in a hostile microenvironment, antigen heterogeneity, and on-tumor, off-target toxicities.64,65 Advances in T-cell receptor therapy could expand the role of cellular immunotherapy in patients with solid tumor.69

Acknowledgments

Ms. Jillian Teo and Ms. Germaine Liew provided data and figures from the Singapore Childhood Cancer Registry.

Disclosure

Professor William YK Hwang reports Honorarium for talk from Novartis, outside the submitted work. The authors report no other conflicts of interest in this work.

References

1. Sadelain M, Rivière I, Riddell S. Therapeutic T cell engineering. Nature. 2017;545(7655):423–431. doi:10.1038/nature22395

2. Sadelain M, Rivière I, Brentjens R. Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer. 2003;3(1):35–45. doi:10.1038/nrc971

3. Rosenberg SA, Terry WD. Passive immunotherapy of cancer in animals and man. In Klein G, Weinhouse S editors, Advances in Cancer Research. Vol. 25. Academic Press; 1977:323–388. doi:10.1016/S0065-230X(08)60637-5

4. Kuwana Y, Asakura Y, Utsunomiya N, et al. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun. 1987;149(3):960–968. doi:10.1016/0006-291x(87)90502-x

5. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A. 1989;86(24):10024–10028. doi:10.1073/pnas.86.24.10024

6. Gross G, Eshhar Z. Endowing T cells with antibody specificity using chimeric T cell receptors. FASEB J off Publ Fed Am Soc Exp Biol. 1992;6(15):3370–3378. doi:10.1096/fasebj.6.15.1464371

7. Weiss A, Irving BA, Tan LK, Koretzky GA. Signal transduction by the T cell antigen receptor. Semin Immunol. 1991;3(5):313–324.

8. Sadelain M. Methods for retrovirus-mediated gene transfer into primary T-lymphocytes. In: Robbins PD, editor. Gene Therapy Protocols. Methods in Molecular Medicine. Humana Press; 1997:241–248. doi:10.1385/0-89603-484-4

9. Imai C, Mihara K, Andreansky M, et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia. 2004;18(4):676–684. doi:10.1038/sj.leu.2403302

10. Krause A, Guo HF, Latouche JB, Tan C, Cheung NKV, Sadelain M. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med. 1998;188(4):619–626. doi:10.1084/jem.188.4.619

11. Feins S, Kong W, Williams EF, Milone MC, Fraietta JA. An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am J Hematol. 2019;94(S1):S3–S9. doi:10.1002/ajh.25418

12. Roselli E, Boucher JC, Li G, et al. 4-1BB and optimized CD28 co-stimulation enhances function of human mono-specific and bi-specific third-generation CAR T cells. J Immunother Cancer. 2021;9(10):e003354. doi:10.1136/jitc-2021-003354

13. Roselli E, Faramand R, Davila ML. Insight into next-generation CAR therapeutics: designing CAR T cells to improve clinical outcomes. J Clin Invest. 2021;131:2. doi:10.1172/JCI142030

14. Schubert ML, Schmitt A, Neuber B, et al. Third-generation CAR T cells targeting CD19 are associated with an excellent safety profile and might improve persistence of CAR T cells in treated patients. Blood. 2019;134(Supplement_1):51. doi:10.1182/blood-2019-125423

15. Carpenito C, Milone MC, Hassan R, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A. 2009;106(9):3360–3365. doi:10.1073/pnas.0813101106

16. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–1518. doi:10.1056/NEJMoa1215134

17. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–733. doi:10.1056/NEJMoa1103849

18. Clinical Cancer Research. FDA approval summary: tisagenlecleucel for treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Available from: https://clincancerres.aacrjournals.org/content/25/4/1142.long. Accessed November6, 2020.

19. Ali S, Kjeken R, Niederlaender C, et al. The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Oncologist. 2020;25(2):e321–e327. doi:10.1634/theoncologist.2019-0233

20. National childhood cancer registry explorer (NCCR*Explorer). Available from: https://nccrexplorer.ccdi.cancer.gov/. Accessed September9, 2022.

21. Pui CH, Yang JJ, Bhakta N, Rodriguez-Galindo C. Global efforts toward the cure of childhood acute lymphoblastic leukemia. Lancet Child Adolesc Health. 2018;2(6):440–454. doi:10.1016/S2352-4642(18)30066-X

22. Hodby KA, Marks DI. Recent advances in the management of acute lymphoblastic leukaemia. Curr Treat Options Oncol. 2020;21(3):23. doi:10.1007/s11864-020-0712-8

23. Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol. 2012;30(14):1663–1669. doi:10.1200/JCO.2011.37.8018

24. Gibson A, Trabal A, McCall D, et al. Venetoclax for children and adolescents with acute lymphoblastic leukemia and lymphoblastic lymphoma. Cancers. 2022;14(1). doi:10.3390/cancers14010150

25. Locatelli F, Schrappe M, Bernardo ME, Rutella S. How I treat relapsed childhood acute lymphoblastic leukemia. Blood. 2012;120(14):2807–2816. doi:10.1182/blood-2012-02-265884

26. Marshall GM, Dalla Pozza L, Sutton R, et al. High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation. Leukemia. 2013;27(7):1497–1503. doi:10.1038/leu.2013.44

27. Eckert C, Parker C, Moorman AV, et al. Risk factors and outcomes in children with high-risk B-cell precursor and T-cell relapsed acute lymphoblastic leukaemia: combined analysis of ALLR3 and ALL-REZ BFM 2002 clinical trials. Eur J Cancer. 2021;151:175–189. doi:10.1016/j.ejca.2021.03.034

28. Yeoh AEJ, Ariffin H, Chai ELL, et al. Minimal residual disease–guided treatment deintensification for children with acute lymphoblastic leukemia: results from the Malaysia-Singapore acute lymphoblastic leukemia 2003 study. J Clin Oncol. 2012;30(19):2384–2392. doi:10.1200/JCO.2011.40.5936

29. Gore L, Locatelli F, Zugmaier G, et al. Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood Cancer J. 2018;8(9):1–7. doi:10.1038/s41408-018-0117-0

30. Campana D, Leung W. Clinical significance of minimal residual disease in patients with acute leukaemia undergoing haematopoietic stem cell transplantation. Br J Haematol. 2013;162(2):147–161. doi:10.1111/bjh.12358

31. Yeoh AEJ, Lu Y, Chin WHN, et al. Intensifying treatment of childhood B-lymphoblastic leukemia with IKZF1 deletion reduces relapse and improves overall survival: results of Malaysia-Singapore all 2010 study. J Clin Oncol. 2018;36(26):2726–2735. doi:10.1200/JCO.2018.78.3050

32. Wann SL Clinical outcomes of Adults and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL): a Multicenter Analysis of Pediatric-Inspired Protocol (MASPORE) Vs Hyper-CVAD in Singapore. ASH; 2021. Available from: https://ash.confex.com/ash/2021/webprogram/Paper150615.html. Accessed March13, 2022.

33. Brivio E, Baruchel A, Beishuizen A, et al. Targeted inhibitors and antibody immunotherapies: novel therapies for paediatric leukaemia and lymphoma. Eur J Cancer. 2022;164:1–17. doi:10.1016/j.ejca.2021.12.029

34. Goto H. Childhood relapsed acute lymphoblastic leukemia: biology and recent treatment progress. Pediatr Int. 2015;57(6):1059–1066. doi:10.1111/ped.12837

35. Pui CH, Cheng C, Leung W, et al. Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med. 2003;349(7):640–649. doi:10.1056/NEJMoa035091

36. Pui CH, Jeha S. Clofarabine. Nat Rev Drug Discov. 2005;4:S12–S13. doi:10.1038/nrd1724

37. Cohen MH, Johnson JR, Justice R, Pazdur R. FDA drug approval summary: nelarabine (Arranon) for the treatment of T-cell lymphoblastic leukemia/lymphoma. Oncologist. 2008;13(6):709–714. doi:10.1634/theoncologist.2006-0017

38. Salzer WL, Burke MJ, Devidas M, et al. Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic leukemia: a report from the Children’s Oncology Group study AALL1131. Cancer. 2018;124(6):1150–1159. doi:10.1002/cncr.31099

39. von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/Phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol off J Am Soc Clin Oncol. 2016;34(36):4381–4389. doi:10.1200/JCO.2016.67.3301

40. O’Brien MM, Ji L, Shah NN, et al. Phase II trial of inotuzumab ozogamicin in children and adolescents with relapsed or refractory B-cell acute lymphoblastic leukemia: children’s oncology group protocol AALL1621. J Clin Oncol. 2022;40(9):956–967. doi:10.1200/JCO.21.01693

41. Brown PA, Ji L, Xu X, et al. Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children, adolescents, and young adults with first relapse of B-cell acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 2021;325(9):833–842. doi:10.1001/jama.2021.0669

42. Brown PA, Ji L, Xu X, et al. A randomized phase 3 trial of blinatumomab vs. chemotherapy as post-reinduction therapy in high and intermediate risk (HR/IR) first relapse of B-acute lymphoblastic leukemia (B-ALL) in children and adolescents/young adults (AYAs) demonstrates superior efficacy and tolerability of blinatumomab: a report from children’s oncology group study AALL1331. Blood. 2019;134(Supplement_2):LBA–1. doi:10.1182/blood-2019-132435

43. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740–753. doi:10.1056/NEJMoa1509277

44. Maude SL, Teachey DT, Rheingold SR, et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL. J Clin Oncol. 2016;34(15_suppl):3011. doi:10.1200/JCO.2016.34.15_suppl.3011

45. Pasquini MC, Hu ZH, Curran K, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4(21):5414–5424. doi:10.1182/bloodadvances.2020003092

46. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–1517. doi:10.1056/NEJMoa1407222

47. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–448. doi:10.1056/NEJMoa1709866

48. Holland EM, Molina JC, Dede K, et al. Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation. J Immunother Cancer. 2022;10(5):e004483. doi:10.1136/jitc-2021-004483

49. Long AH, Haso WM, Shern JF, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21(6):581–590. doi:10.1038/nm.3838

50. Maschan M, Caimi PF, Reese-Koc J, et al. Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients. Nat Commun. 2021;12(1):7200. doi:10.1038/s41467-021-27312-6

51. Castella M, Caballero-Baños M, Ortiz-Maldonado V, et al. Point-of-care CAR T-cell production (ARI-0001) using a closed semi-automatic bioreactor: experience from an academic phase I clinical trial. Front Immunol. 2020;11:482.

52. Ruella M, Locke FL. Beat pediatric ALL MRD: CD28 CAR T and transplant. Blood. 2019;134(26):2333–2335. doi:10.1182/blood.2019003821

53. Lee DW, Wayne AS, Huynh V, et al. ZUMA-4 preliminary results: phase 1 study of KTE-C19 chimeric antigen receptor T cell therapy in pediatric and adolescent patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL). Ann Oncol. 2017;28:v360–v361. doi:10.1093/annonc/mdx373.014

54. Curran KJ, Margossian SP, Kernan NA, et al. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL. Blood. 2019;134(26):2361–2368. doi:10.1182/blood.2019001641

55. Shah NN, Lee DW, Yates B, et al. Long-term follow-up of CD19-CAR T-cell therapy in children and young adults with B-ALL. J Clin Oncol off J Am Soc Clin Oncol. 2021;39(15):1650–1659. doi:10.1200/JCO.20.02262

56. Jacoby E, Ghorashian S, Vormoor B, et al. CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study. Leukemia. 2022;36(6):1525–1532. doi:10.1038/s41375-022-01546-9

57. Lamble A, Myers RM, Taraseviciute A, et al. Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells. Blood Adv. 2022:2022007423. doi:10.1182/bloodadvances.2022007423

58. Yakoub-Agha I, Chabannon C, Bader P, et al. Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2020;105(2):297–316. doi:10.3324/haematol.2019.229781

59. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62. doi:10.1038/nrclinonc.2017.148

60. Mahadeo KM, Khazal SJ, Abdel-Azim H, et al. Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy. Nat Rev Clin Oncol. 2019;16(1):45–63. doi:10.1038/s41571-018-0075-2

61. Thielen FW, van Dongen-Leunis A, Arons AMM, Ladestein JR, Hoogerbrugge PM. Cost-effectiveness of Anti-CD19 chimeric antigen receptor T-Cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. A societal view. Eur J Haematol. 2020;105(2):203–215. doi:10.1111/ejh.13427

62. Spiegel JY, Patel S, Muffly L, et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med. 2021;27(8):1419–1431. doi:10.1038/s41591-021-01436-0

63. Cordoba S, Onuoha S, Thomas S, et al. CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. Nat Med. 2021;27(10):1797–1805. doi:10.1038/s41591-021-01497-1

64. Ma S, Li X, Wang X, et al. Current progress in CAR-T cell therapy for solid tumors. Int J Biol Sci. 2019;15(12):2548–2560. doi:10.7150/ijbs.34213

65. DeRenzo C, Krenciute G, Gottschalk S. The landscape of CAR T cells beyond acute lymphoblastic leukemia for pediatric solid tumors. Am Soc Clin Oncol Educ Book. 2018. doi:10.1200/EDBK_200773

66. Gupta A, Cripe TP. Immunotherapies for pediatric solid tumors: a targeted update. Paediatr Drugs. 2022;24(1):1–12. doi:10.1007/s40272-021-00482-y

67. Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol off J Am Soc Clin Oncol. 2009;27(14):2328–2338. doi:10.1200/JCO.2008.21.1425

68. Wang XJ, Wang YH, Ong MJC, Gkitzia C, Soh SY, Hwang WYK. Cost-effectiveness and budget impact analyses of tisagenlecleucel in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia from the Singapore healthcare system perspective. Clin Outcomes Res. 2022;14:333–355. doi:10.2147/CEOR.S355557

69. Tan AT, Yang N, Lee Krishnamoorthy T, et al. Use of expression profiles of HBV-DNA integrated into genomes of hepatocellular carcinoma cells to select T cells for immunotherapy. Gastroenterology. 2019;156(6):1862–1876.e9. doi:10.1053/j.gastro.2019.01.251

70. Ko RH, Ji L, Barnette P, et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. J Clin Oncol off J Am Soc Clin Oncol. 2010;28(4):648–654. doi:10.1200/JCO.2009.22.2950

71. Parker C, Waters R, Leighton C, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010;376(9757):2009–2017. doi:10.1016/S0140-6736(10)62002-8

留言 (0)

沒有登入
gif