CAR-T Cell Therapy in Pediatric Non-Hodgkin Lymphoma Treatment

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1		Magdalena Ostojska	--	5215	2023-12-14 11:16:59	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	5215	2023-12-19 02:43:39	\|

This entry is adapted from the peer-reviewed paper 10.3390/jpm13111595

Non-Hodgkin lymphomas (NHL) are a group of cancers that originate in the lymphatic system, especially from progenitor or mature B-cells, T-cells, or natural killer (NK) cells. NHL is the most common hematological malignancy worldwide and also the fourth most frequent type of cancer among pediatric patients. This cancer can occur in children of any age, but it is quite rare under the age of 5 years. In recent decades, available medicines and therapies have significantly improved the prognosis of patients with this cancer. However, some cases of NHL are treatment resistant. For this reason, immunotherapy, as a more targeted and personalized treatment strategy, is becoming increasingly important in the treatment of NHL in pediatric patients.

non-hodgkin lymphoma CAR-T cells

1. Introduction

Non-Hodgkin lymphoma (NHL) is one of the most common childhood malignancies. Its wide occurrence is undoubtedly connected to the heterogeneous nature of NHL. The classification of NHL is most frequently based on immunophenotype (i.e., B-lineage, T-lineage) and molecular biology. The majority of pediatric NHL cases represent three types: lymphoblastic lymphoma, anaplastic large cell lymphoma, as well as aggressive mature B-cell NHL (B-NHL), which primarily includes Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and, less common than the other two subtypes, primary mediastinal B-cell lymphoma. Other NHL types, such as pediatric gray zone lymphoma, marginal zone lymphoma, primary central nervous system (CNS), peripheral T-cell lymphoma lymphoma or cutaneous T-cell lymphoma are much rarer ^[1].

2. The Possibility of Using CAR-T Cells in NHL Therapy

2.1. Mechanism of Action of CAR-T Cells

A CAR construct can bind to target markers through a single-chain variable fragment (scFv) recognition domain. By means of an extracellular link and a transmembrane domain, it is connected to an intracellular molecule called cluster of differentiation (CD)-3 3ζ chain in order to stimulate cell activation ^[2]^[3]. Such a formation forges a first-generation CAR. The T cells used in CAR-T therapy are genetically engineered with a T cell receptor (TCR) and its CD3ζ domain incorporates three immuno-tyrosine activation motifs (ITAMs) ^[4]. Lymphocyte-specific protein tyrosine kinase (Lck)-mediated phosphorylation of ITAMs inaugurates a signal within the cytoplasm.

2.2. CAR-T Cells Anti-CD19

CD19 is a type 1 transmembrane glycoprotein, composed of a cytoplasmic C-terminus, an extracellular N-terminus, and a transmembrane domain in between. It is associated with the immunoglobulin family. CD19 is expressed on the surface of B lymphocytes regardless of their stage of maturation and differentiation. CD19 is also present on cells that have transformed into cancer cells. It is found on cancer cells in B-NHL in more than 95% of cases. Therefore, CD19 has become a suitable target for the treatment of these lymphomas, using CAR technology ^[5]^[6]. To date, the United States Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) have approved four CD19-targeted CAR-T cell drugs for only adult patients with B-NHL.

2.2.1. Axicabtagene Ciloleucel (Other Terms: Axi-Cel, Yescarta, KTE-CD19)

The pivotal multicenter phase 1–2 trial leading to the approval of axi-cel for the treatment of relapsed or refractory (R/R) NHL was ZUMA-1, which included 101 patients aged 23–76 with treatment-resistant lymphoma. The overall response rate (ORR) was 74%, with as many as 54% of patients achieving complete response (CR). In 11 of 33 patients, a partial response (PR) in the first month after infusion converted to CR (usually up to 6 months). The median duration of response (DOR) and the median progression-free survival (PFS) were 11.1 and 5.9 months, respectively. The reduced and less durable response to axi-cel was shown to be associated with higher initial tumor mass, high level of inflammatory markers and lower CAR-T cell expansion in vivo after infusion. Axi-cel was characterized by a manageable long-term safety profile. A median OS exceeded 2 years ^[7]^[8]^[9]. In the primary analysis of the ZUMA-5 study, 104 adult people with R/R indolent NHL were administered a single infusion of axi-cel (2 × 10⁶ CAR-T cells per kg). The ORR was 92% of patients, including 74% with a CR. In the updated study population analysis of 109 people, these values were 94% and 79%, respectively.

2.2.2. Tisagenlecleucel (Other Terms: Tisa-Cel, Kymriah, CTL019)

JULIET was the most important multicenter phase 2 trial that aimed to assess the efficacy and safety of tisa-cel therapy in the treatment of adults with R/R DLBCL, high-grade B-cell lymphoma (HGBCL), or transformed follicular lymphoma (tFL). The study recruited 115 patients aged 22–76 years. The ORR was 52%. And 40% of the trial participants achieved a CR on tisa-cel therapy. Moreover, in approximately 54% patients the initial PR to tisa-cel therapy was finally converted to CR. The effectiveness of tisa-cel treatment did not depend on the patient’s age, gender, initial general condition, tumor size, or previously used treatment methods ^[7]^[8]. The study also examined long-term clinical outcomes of tisagenlecleucel. The median follow-up of 115 adult patients was 40.3 months. After this time, a CR or PR to treatment was observed in 39% and 14% of patients, respectively. Furthermore, research proved that CR to this treatment at 3 or 6 months is a reliable early indicator of long-term survival. A total of 70 of 115 patients died, but the deaths were not related to tisagenlecleucel. Significant differences were not found between short- and long-term analyses of the safety profile of tisa-cel therapy. JULIET demonstrated the durability of response to tisa-cel and its favorable safety profile ^[10].

2.2.3. Brexucabtagene Autoleucel (Other Terms: Tecartus, KTE-X19)

Successful results of the multicenter phase 2 ZUMA-2 trial in 2020 contributed to the registration of KTE-X19 in the treatment of R/R mantle cell lymphoma. Before the single infusion of KTE-X19 (2 × 10⁶ CAR-T cells per kg of body weight), 74 patients aged 38–79 received leukapheresis, bridging therapy (only optional) and conditioning chemotherapy. An objective response was observed in 85% patients and 59% of them had a CR. The median time to obtain an initial response and CR was 1 and 3 months, respectively. A total of 24 of 42 patients with an initial PR or stable disease progressed to a CR. After 12 months of follow-up, OS and PFS were 83% and 61%, in sequence ^[11].

There is also an ongoing study ZUMA-4 on the efficacy and safety of KTE-X19 in pediatric and adolescent participants aged 1–21 with R/R B-precursor ALL or B-NHL. In this clinical trial, patients initially receive conditioning chemotherapy (fludarabine and cyclophosphamide) followed by a single infusion of KTE-X19 at a dose of 2 × 10⁶ or 1 × 10⁶ anti-CD19 CAR-T cells per kg. The primary endpoints are: the overall CRR in ALL patients, the objective response rate in NHL patients, and the percentage of children experiencing adverse events (dose-limiting toxicities, DLT). The duration of patient observation is 2 years. Then, the patients will be transferred to another long-term study whose aim will be to finish/complete the 15-year follow-up assessments ^[12].

2.2.4. Lisocabtagene Maraleucel (Other Terms: Liso-Cel, Breyanzi, JCAR017)

The pivotal study for liso-cel was called TRANSCEND. In its phase 1, researchers assessed liso-cel therapy in 23 patients aged 50–80 with R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients were divided into two groups, depending on dose (50 or 100 × 10⁶ CAR-T cells). Overall response and CR occurred in 82% and 45% of the patients. The safety and efficacy result of liso-cel allowed the study to continue ^[13]. Phase 2 TRANSCEND evaluated the effectiveness of liso-cel in 269 patients aged 18–86 with DLBCL and relapse or progression after ≥2 prior lines of therapy (including prior allogeneic stem cell transplantation or secondary CNS involvement). Patients were divided into three groups depending on the dose of liso-cel (50 or 100 or 150 × 10⁶ CAR-T cells). With the median follow-up of 18.8 months, the ORR was 73%, which included 53% of patients achieving a CR. Those rates did not differ by dose level. The response to treatment was worse among patients with larger tumor diameter or elevated lactate dehydrogenase (LDH). The median time to achieve the first CR or PR was 1 month (range 0.7–8.9 months). A conversion of PR to CR occurred in 28 patients, with a median time of 3 months ^[14]. Basing on TRANSCEND, Patrick et al. used the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) to analyze the population consisting of 181 patients at a mean age of 60.2. The researchers demonstrated that liso-cel (administered as third-line or later treatment) improved health-related quality of life (HRQoL) and symptoms in patients with R/R LBCL. In addition, clinically meaningful improvements of global health status/Quality of Life (QoL) occurred in a higher proportion of treatment responders, compared with nonresponders (72% vs. 41%) ^[15]. The phase 3 TRANSFORM trial compared liso-cel therapy with standard of care (salvage chemotherapy followed by autologous stem cell transplantation) as second-line treatment in patients with R/R LBCL. Each group (depending on the type of therapy) consisted of 92 patients aged 42–67. The median follow-up time was 6.2 months. The ORR and CRR therein were higher in the liso-cel group (86% and 66%), compared to the control group treated with standard therapy (48% and 39%). However, the median time to achieve a CR was shorter in the standard group than in the liso-cel group (14.5 months vs. median not reached). In turn, PFS significantly improved after liso-cel therapy, compared with standard therapy ^[16].

2.2.5. CAR-T Cells in Burkitt Lymphoma after Liver Transplantation

Wang et al. describe the case of a patient aged 2 years 10 months who developed refractory BL (a rare form of post-transplant B-cell lymphoproliferative disorder, PTLD) after liver transplantation (due to decompensated cholestatic cirrhosis). The child received an autologous anti-CD19 CAR-T cells infusion at the total dose of 9.0 × 10⁶ per kg. The child developed a high fever (days 2–5 post-infusion), significant increases in serum inflammatory cytokines (particularly IL-6 on day 4 after infusion) and manageable CRS.

2.3. Other CAR-T Cells against NHL

Despite the impressive efficacy of CD19 CAR-T therapy, progressive disease occurs in a large proportion of patients who receive a CAR T-cell infusion, primarily as a result of a lack of CAR T-cell persistence and tumor cell resistance stemming from antigen loss or reduced antigen expression below the threshold required for CAR T-cell activity ^[17]. Sometimes mutations in the CD19 antigen and the downregulation or disappearance of this antigen from the surface of malignant lymphocytes lead to tumor escape ^[18]. The escape mechanisms associated with antigen loss in B-ALL during CD19 CAR T-cell therapy include alternative splicing of CD19, frameshift mutations, and missense mutations ^[17]. Because of these mechanisms some patients become resistant to CD19-targeted CAR-T treatment. Therefore, alternative markers, such as CD20 and CD22, with a higher expression in B-NHL can be used as targets for T cell therapies ^[18].

2.3.1. Anti-CD20

CD20 is a non-glycosylated membrane phosphoprotein that is highly expressed both in normal B cells and on the surface of malignant B cells ^[18]. Moreover, the overexpression of CD20 could indicate highly progressive disease ^[19]. It is not found on hematopoietic stem cells, making them one of the most promising treatment targets for B-cell malignancies ^[20]. Compared with CD19, CD20 is much more slowly endocytosed following antibody binding and this stability could theoretically positively affect the quality of the immunological synapse, resulting in more robust CAR triggering and T-cell activation ^[21]^[22]. Unfortunately, clinical trial results assessing the efficiency of CD20-targeted CAR-T therapy in pediatric NHL are not available.

2.3.2. Bispecific and Dual Targeting CAR-T Cells

A bispecific receptor consists of two distinguished antigen recognition domains that bind to two separate intracellular domains and are expressed as tandem scFvs in one CAR, or as two different CARs on T cell surface ^[23]. If one of the target molecules is not available to CAR-T cells for reasons such as removal or mutation of the target antigen on malignant cells, a dual-function machine can largely prevent tumor escape. Thus, the bispecific CAR retains the cytolytic property of T cells ^[24].

CD19/CD20

CD19/CD20-bispecific CAR-T cells have been presented as a new synthetic molecule that, after recognition and binding to target tumor antigens on the surface of malignant cells, can establish a synergistic cascade of executive molecules ^[23]. Unfortunately, clinical trial results assessing the efficiency of CD20-targeted CAR-T therapy in pediatric NHL are not available.

CD19/CD22

CD22, a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family, is an inhibitory co-receptor of B-cell receptor that is exclusively expressed on B-cells. CD22 is highly expressed on B-cell lymphomas and leukemias, so it has become a therapeutic target of cell therapy ^[25]. Clinical trials of CD19/CD22 bispecific CAR-T cell therapy have manifested encouraging efficacy in B-cell malignancies in both adults and children.

2.3.3. Sequential CD19/CD20/CD22-Targeted CAR-T Cells

In recent years, most of the research concerned with the use of CAR-T cell therapy in children with NHL was based on sequential administration of different B-cell antigen-targeted CAR T-cells. This strategy is designed to prevent tumor antigen escape and maintain CAR T-cell persistence.

Zhang et al. aimed to examine the efficacy and safety of multitargeted CAR T-cell therapy for pediatric patients with mature B-cell lymphomas. The study enrolled five patients with R/R BL aged 6 to 10 years. Previously they had all failed to show response to multiple courses of intensive chemotherapy and anti-CD20 mAb treatment. A total of 3/5 patients were at stage IV and 2/5 were at stage III, according to the St. Jude staging system. A total of 3/5 children achieved CR after one round of CD19 CAR-T cell therapy. One patient showed a transient response to CD19 CAR-T cell therapy, probably due to CD19 CAR-T cells not expanding adequately, so he received CD22 CAR-T cell therapy as soon as the tumor regrowth was detected. Then, he finally achieved CR. Another patient had no response to the first round of CD19 CAR-T treatment, probably due to delayed expansion of CD19 CAR-T cells, so he also received CD22 CAR-T cells, which seemed to expand adequately. On day 45 post-infusion PET-CT revealed a disappearance of the original tumor, but also an emergence of a new mass, so he was given CD20 CAR-T cells. On day 64 PET-CT confirmed CR. To conclude, CR was observed in all patients between 37 and 77 days post-infusion. The ORR of this multiple CAR-T infusion approach was 100%, including patients who did not respond or progressed after prior CAR-T products, with a median follow-up of 331 days, ranging from 149 to 428 days. All patients remained in CR at the end of the study. The toxicities of the treatment were tolerable. All patients showed myelosuppression, including anemia, thrombocytopenia, and neutropenia, likely attributed to lymphodepleting chemotherapy, which required blood transfusion. All patients showed CRS of different grades, but they fully recovered after active symptomatic and supportive treatment, including an application of corticosteroids in CRS grade 3. This study revealed that targeting different B-cell markers sequentially in CAR-T cell therapy is effective for treating R/R BL in children ^[26].

Du and Zhang described a case of an 8-year-old boy with R/R BL treated with sequentially targeting CD19, CD22, and CD20 with CAR-T cells. He had no discernible response to anti-CD19 CAR-T treatment and exhibited PD, so then he received CD22 CAR-T cells and underwent a PR. Unfortunately, a relapse rapidly occurred, so he was given CD20 CAR-T cells and finally went into CR, which was revealed in PET-CT 65 days post-infusion. By the end of follow-up he achieved 16-month event-free survival (EFS). The toxicities of the treatment were tolerable. The boy experienced mild CRS (grade 1) during administration of the CD19 and CD20 CAR-T cells and CRS grade 3 during the CD22 CAR-T therapy. However, at approximately 6-month follow-up after the end of treatment, the patient’s red blood cells, white blood cells, and platelets based on his routine blood panel, had returned to normal, and his other organs also functioned properly. CAR-T cell therapy targeting multitumor antigens showed a satisfactory effect in the described case ^[27].

2.3.4. General Relevance of Clinical Trials on the Effectiveness and Safety of CAR-T Cell Therapy to the Pediatric Population

The above-mentioned studies involving pediatric patients indicate that CAR-T cell therapy may be effective and safe among children or adolescents with NHL. Also its treatment results are similar to those in adults. This conclusion applies to CD19-targeted CAR-T cell therapies (only tisa-cel and KTE-X19), bispecific targeted CAR-T cell therapies (only CD19/CD22), and sequential CD19/CD20/CD22-targeted CAR-T cell therapies. Unfortunately, no pediatric clinical trial results are available for other types of targeted CAR-T cell therapies. Therefore, their effectiveness and safety in children and adolescents are currently unknown. However, recruiting clinical trials have great potential.

2.4. Recruiting Clinical Trials

The findings of numerous clinical trials conducted on adults, showing the effectiveness of CAR-T cell therapy in NHL treatment, resulted in the commencement of clinical trials on the pediatric population. Currently, 44 recruiting phase 1, 2 or 3 clinical trials are being conducted, testing the possibility, effectiveness and safety of the use of, among others, anti-CD19, -CD20, -CD22, -CD30, -CD5, and -CD7 CAR-T cells in children with both B-cell and T-cell NHL. For more information on currently recruiting clinical trials.

3. The Challenges of CAR-T Cell Therapy

3.1. Aftermath of CAR-T Cell Therapy

Unfortunately, the success of CAR-T cell therapy comes with a price, and occurrence of adverse effects (AEs) is inevitable. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS; previously also referred to as CAR-T-cell-related encephalopathy syndrome or CRES) are in the lead of CAR-T cell therapy AEs and thus remain a crucial element of the aftermath. Likewise, cytopenias, infections or tumor lysis syndrome (TLS) continue to be troublesome ^[28]. Management of CAR-T cell therapy AEs grows in its significance as it is breaking through into the earlier stages of treatment.

3.1.1. Cytokine Release Syndrome

Cytokine release syndrome is the most frequently occurring adverse event of CAR-T cell therapy. The prevalence of CRS is not necessarily affected by cancer type, co-stimulatory domains or trial phase ^[29]. It has been speculated that the development of CRS may correlate with successfulness of CAR-T therapy, but it requires yet further exploration. Its exact mechanism is not yet entirely understood. Nonetheless, it is related to the release of inflammatory cytokines during CAR-T cell administration ^[30].

As it is a systemic inflammatory reaction, fever is the dominant and the earliest symptom of CRS, and it can reach more than 40.5 degrees Celsius in a few days ^[31]. Other symptoms include fatigue, myalgia, arthralgia, rigors or anorexia. Furthermore, these alterations may be followed by tachycardia, hypotension in necessity of vasopressors, tachypnea and hypoxia, or neurological changes ^[32].

CRS appears in the course of 1 to 14 days and its onset tends to settle after approximately 14 to 21 days ^[31]^[33]. Risk factors for severe CRS include, inter alia, a high infusional dose of CAR-T cells or early cytokine elevations, whereas prevention strategies hinge upon pretreatment cytoreduction or prophylactic cytokine therapy ^[31].

CRS can either be self-limited (with the possible support of antipyretics and intravenous fluids) or inevitably call for intervention with anticytokine-directed therapy. The most standard management of CRS, approved by the US FDA consists of tocilizumab, a humanized mAb against IL-6 receptor. Tocilizumab abates CRS promptly, and, even more importantly, it does not interfere with therapeutic effects of CAR-T ^[34]. Interestingly, tocilizumab with a subsequent anti-CD19 CAR-T cell administration was reported to decrease the prevalence and severity of CRS used in prophylaxis, but those trials did not involve children or adolescents ^[35]. In cases of tocilizumab insufficiency, corticosteroids are added to help control CRS, but in high doses, in contrast to tocilizumab, they may damage the desirable effect on CAR-Ts. In the study by Jiang et al., disseminated intravascular coagulation (DIC) is recognized as another CAR-T cell-related event caused by CRS ^[36].

3.1.2. Immune Effector Cell-Associated Neurotoxicity Syndrome

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in a significant number of patients after CAR-T cell administration. However, in comparison to CRS, ICANS occurrence is delayed. Its pathophysiology remains vague, but existing theories claim that it may correspond to CNS T-cell trafficking, increased vascular permeability, and endothelial disruption in the blood–brain barrier (BBB) ^[37].

Clinical signs and symptoms of ICANS are various and wide in their range: from mild headaches through cerebral edema and acute encephalopathy to aphasia, focal deficits, confusion, delirium, seizures or even visual hallucinations ^[38]^[39]. Dysgraphia has been noted as an early indicator of ICANS. ICANS tends to develop after CRS onset.

Thus, the presence of CRS is one of the risk factors for ICANS amongst others, such as pre-existing neurologic dysfunction, elevated LDH and ferritin in laboratory tests, and thrombocytopenia.

Since the immune effector cell-associated encephalopathy (ICE) used to grade ICANS in adults is unadjusted for pediatric patients, Traube et al. adapted the Cornell Assessment of Pediatric Delirium (CAPD) and it is now a screening tool for recognizing delirium in children ^[40]^[41]. CAPD is the most valid in patients under 12 years old. The guidelines suggest assessment at least twice per day ^[40]^[42]. The ICANS grading in pediatric patients combines the ICE (for children ≥12 years olds) and CAPD (for children <12 years old) into overall scale for neurological examination, which includes orientation, naming, following commands, writing and attention (ICE), as well as eye contact with a caregiver, purposeful actions or communicating needs and wants (CAPD).

3.1.3. Other Neurotoxicities

An interesting finding has been presented concerning another form of CAR-T-related neurotoxicity. Ruark et al. published an article on patient-reported neuropsychiatric outcomes ^[43]. Nearly half of the adult patients observed at least one clinically significant negative neuropsychiatric outcome, such as cognitive difficulty, anxiety or depression. As the results suggest, probable risk factors for long-term neuropsychiatric problems are younger age, pre-CAR-T anxiety or depression, and acute neurotoxicity. However, further research is essential to confirm those outcomes. Obviously, it still remains to be determined if those findings apply to children and adolescents.

3.1.4. Infections

Infections are yet another challenge related to CAR-T therapy. The therapy negatively influences a patient’s immune system, principally by causing depletion of B-lymphocytes, with low immunoglobulin rate and prolonged leukopenia. The underlying disease, for which CAR-T cell therapy was used in the first place, high doses of CAR-T cells and past chemotherapy incidents predispose to severe infections. Equally, the presence of the CRS or/and ICANS increase the risk of infections as their management requires even further intervention in the functioning of the patient’s immune system.

3.1.5. Cytopenia

Cytopenias occur fairly commonly in patients after CAR-T cell therapy, of which neutropenia is the most widely spread. Factors such as age, gender or total previous treatment seem to play a role in the prevalence of post-CAR-T therapy cytopenias ^[44]. Early cytopenia generally manifests itself within 28 days after CAR-T cell administration ^[45]. In its nature, CAR-T-related cytopenia may be biphasic, or even triphasic ^[46]. The onset of early cytopenia is associated with the intensity of bridging chemotherapy or pre-administration lymphodepletion chemotherapy, to name a few. Patients with severe CRS or secondary hemophagocytic lymphohistiocytosis (HLH) are in danger of developing stem cell exhaustion as they have a significantly increased level of IFN-ɣ, which causes a suppression of stem cell homeostasis ^[47].

3.1.6. B-Cell Aplasia and Hypogammaglobulinemia

On-target, off-tumor effect of anti-CD19 and anti-CD22 CAR-T cells on normal B-cells generates B-cell aplasia and subsequent hypogammaglobulinemia. BCA might progress into either a manageable depletion and helpful tool to estimate the effectiveness of the applied treatment, or a persistent form leading to hypogammaglobulinemia, eventually resulting in infections.

This AE is to be managed with a use of periodic intravenous immunoglobulin (IVIG) supplementation ^[40]^[42]^[48]. In pediatric patients, IVIG routine replacement is recommended as a standard treatment ^[42]^[45]^[49].

3.1.7. Hemophagocytic Lymphohistiocytosis

This fulminant hyperinflammatory syndrome is likely to arise in patients suffering from serious infection, autoimmune disease or malignancy. Despite its relative rarity (in data gathered in adult patients), this multiorgan failure grows in incidence and, more importantly, has an inglorious high rate of mortality ^[44]^[50]. CRS tendency to progress into or overlap with HLH makes lymphohistiocytosis more challenging in its management. HLH manifests itself mainly with fever, jaundice, organomegaly, as well as gastrointestinal and pulmonary problems ^[50]^[51]. Although diagnostic criteria for carHLH were suggested, such as peak serum ferritin level and development of organ failure (hepatic, renal, pulmonary), the scale is for now recommended for adults only and needs adjustment for pediatric patients ^[52].

3.1.8. Tumor Lysis Syndrome

As a common consequence of anticancer treatment, malignant cells disintegrate. This phenomenon is known as tumor lysis syndrome (TLS). This process is followed by metabolic abnormalities such as hyperkalemia, hyperuricemia, hyperphosphatemia and hypocalcemia. Those may cause arrhythmias and renal failure. Crucial elements of TLS management comprise hyperhydration and allopurinol or rasburicase ^[53]^[54]^[55].

3.1.9. Anaphylaxis and Immunogenicity

Most CAR-T cells contain the addition of non-human elements rendering a risk for allergic reactions. Anaphylaxis is said to happen occasionally but more so in children, as it has been described mostly in cases of repeated CAR-T cell administration ^[56]. Fully humanized CARs are under clinical trials in order to reduce immunogenicity ^[57]^[58]

There continues a lack of data presenting CAR-T cell therapy effect on adult as well as pediatric patients’ experience, or the duration and quality of life and, hence, it is undoubtedly a vast field for future exploration ^[29].

3.2. Limitations of CAR-T Cell Therapy

AEs in CAR-T cell therapy are not the only challenge which present-day medicine is compelled to face. Others include the limitations of CAR-T cell therapy, such as patient selection, resistance to treatment or the tumor microenvironment (TME). Factors like race, ethnicity, gut microbiome and tumor burden (TB) influence response to CAR-T therapy as well.

3.2.1. Patient Selection

As trivial as it may seem, each patient responds to treatment in an individual way. In patient selection, age, fitness, previous therapies, concurrent diseases and organ function, along with practical aspects, such as logistics of administration, must be taken into consideration as they affect the patient’s reaction to CAR-T therapy ^[59]^[60].

Moreover, it is important to have in mind that tisa-cel, axi-cel and liso-cel are different in terms of their composition, manufacturing or toxicity profile and thus, it is essential to choose the most suitable product for the patient, taking into account such specifics as eligibility and timing of CAR-T cell administration ^[61].

3.2.2. Resistance

A multitude of components may contribute to the development of a patient’s resistance to CAR-T cell therapy. Obstacles might occur on different stages of treatment.

Obstacle 1: Achieving CAR-T

Access. Since FDA approval of axi-cel in 2017, the situation has improved as CAR-T cell therapy has become internationally accessible ^[62]. Despite a worldwide range, there is still a question of local accessibility. Treatment centers must have both the capability and the capacity to comply with FDA protocols of manufacturing and administration of CAR-T to the patient, and their number is limited ^[63]. Another question concerns the high expense and its coverage ^[64].

Obstacle 2: Relapse

Relapse subsequent to either anti-CD19 or anti-CD22 therapy is an obvious challenge. It may develop generally in two patterns: early antigen-positive relapse or later relapse with antigen loss (both best explored in patients with pre-B cell ALL) ^[45]^[59].

Antigen-positive relapse. Relapse with antigen-positive disease creates a promising opportunity for re-treatment with CAR T cells. In a study by Turtle et al., poor outcomes subsequent to re-infusion in patients with B-NHL were reported ^[65]. However, fludarabine combined with cyclophosphamide used to intensify lymphodepletion enhanced the re-infusion response, along with initial CAR-T cell expansion and persistence. Other approaches for optimizing re-infusion involve the use of an alternative CAR construct or CAR targeting a different antigen, e.g., CD22.

3.2.3. The Tumor Microenvironment

The TME is an intricate complex, which comprises cells evolving with malignant cells and aiding them in their malignant transformation. In addition, the TME consists of the tumor vasculature, lymphatics and the immune system, along with fibroblasts and adipocytes. All types of cells and molecules present in the TME may take part in tumor development and progression, including promotion of angiogenesis, inducement of drug resistance or immune system suppression ^[66].

As proved in the studies, composition of the TME contributes significantly to the prognosis, for example presence of T-cells and/or NK cells in the TME as well as high expression of programmed death (PD) ligands in malignant cells are predictors for good results ^[67]^[68]. Other findings were presented by Yan et al.; patients with CR displayed low levels of immunosuppressive proteins (CCL2, CXC8, CXCL12, CCL3, -4, -5) affecting the TME, whereas in the group with partial remission (PR) immunosuppressive factors such as CXCL9 were overexpressed ^[69]. Additionally, immunosuppressive cytokines, e.g., IL-10, or tumor-associated fibroblasts (STC1, etc.) were increased in the PR patients, in comparison to CR ones. Consequently, it is speculated that the TME is likely to conceive a milieu to thwart CAR T-cell antitumor activity.

Therefore, augmentation of PD-L1 and PD-L2 expression or increase in the number of recruited and activated local T-cells appear to be a promising method of surpassing the TME limitation in CAR-T cell therapy. Additionally, to advance CAR-T cell therapy in terms of the TME, one requires optimizing the dose and timing, or introducing CAR-T therapy earlier in the disease course, to name a few potential remedies ^[70].

3.2.4. Gut Microbiome

A study by Hu et al. concentrates on a widely discussed subject, i.e., gut microbiome ^[71]. They explore gut microbiome influence on CAR-T cell therapy response and CRS. Their findings include Bifidobacterium correlation with stimulated production of inflammatory cytokines, such as IL-1 and IL-6, and subsequent possible association with CRS severity ^[72].

There is little knowledge on gut microbes’ ways of modulating the host’s immune system. Above all, bacterial communities are said to release intermediary metabolites and, in consequence, affect the host’s defenses ^[73]. Due to the contribution into innate and adaptive immunity of their host, gut microbiota are speculated to have an indirect impact on clinical outcomes of CAR-T cell therapy and grade of CRS ^[74].

3.2.5. Race, Ethnicity and Obesity

In their article, Faruqi et al. observed no meaningful connections of race, ethnicity, or BMI to CAR-T consequences or OS ^[75]. It is only mentioned that Hispanic patients have higher risks for undergoing severe CRS. It is highlighted that CAR-T cell therapy is important for Hispanic and obese patients in particular, as they are more susceptible to the development of chemotherapy-resistant or refractory disease.

3.2.6. Tumor Burden, Inflammation and Attributes of Axi-Cel

Tumor burden (TB) and inflammation have been studied as contributors for outcomes in patients with LBCL ^[76]. In the publication, the authors noted a few correlations, including high TB linked to lower probability of durable response and proinflammatory markers diminishing impact on the ratio of durable response and undermining in vivo expansion.

4. CAR-T Cell Therapy in Hodgkin lymphoma

Although the manuscript analyses CAR-T cell therapy in pediatric NHL, it should be mentioned that there are only a few studies about the use of CAR-T cell therapy in the treatment of Hodgkin lymphoma (HL) which is the most common cancer among adolescent young adult patients (aged 15–19). CAR-T cell therapy may be crucial, because there are still approximately 15% of all patients with R/R HL for whom first-line therapy (high-dose chemotherapy autologous stem cell transplantation) is ineffective. A Ramos’s study conducted among 41 patients aged 17–69 showed that CD30-targeted CAR-T cell therapy may be promising in the NH treatment. The ORR was 72%, with as many as 59% of patients achieving CR. There were also a high rate of durable responses and a good safety profile. Unfortunately, clinical trial results assessing the efficiency of CAR-T therapy in pediatric HL are not available ^[77]^[78].

5. Conclusions

Immunotherapy based on CAR-T cells seems to be a promising strategy for the treatment of non-Hodgkin lymphoma among the pediatric population. Due to the ongoing development of new CAR-T cell drugs that target a wide range of B-cell markers, more individualized treatment strategies are possible, especially for treatment-resistant patients. However, some challenges must also be overcome for the widespread use of CAR-T cells in children and adolescents. Because of the possible adverse events of CAR-T cell therapy, it is necessary to further develop the treatment strategies and inclusion criteria for patients. The significant problem is the long time and costs of producing drugs based on CAR-T cells. In addition, there is also a possibility that the patient may develop resistance to this type of immunotherapy. Additionally, available clinical trial results on the effectiveness and safety of CAR-T cell therapy in the treatment of R/R NHL mainly concern the adult population. However, many studies are currently being conducted on children and adolescents, which may prove to be a breakthrough in the treatment of NHL in this age group.

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