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CAR-T cell therapy for B cell hematological malignancies
CAR-T cell therapy for B cell hematological malignancies. Chimeric antigen receptor (CAR)-T cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin’s lymphoma (NHL) And B-cell acute lymphoblastic leukemia (all).
This treatment is currently being studied in other B-cell tumors, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B cell maturation antigen (BCMA) have become the most popular target antigens for CAR-T cell immunotherapy for these malignant tumors.
This review will discuss the efficacy and toxicity data from key clinical studies of CAR-T cells targeting CD19 and BCMA in the treatment of relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively.
For decades, the treatment of hematological malignancies has been dominated by systemic chemotherapy, radiotherapy and stem cell transplantation. Recently, new insights into the genetic and molecular basis of these malignant tumors have paved the way for the development of targeted therapies, and the increasing understanding of the interaction between the patient’s immune system and cancer cells has led to several innovative immunotherapies.
development of. One of these immunological-based therapeutic strategies that have caused great excitement recently is chimeric antigen receptor (CAR)-T cell therapy . In the treatment of certain types of non-Hodgkin’s lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL), this type of adoptive cell therapy (ACT) has proven to be a real breakthrough and is still Other hematological malignancies evaluated include multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) .
Using the immune system to attack cancer cells is not a new concept. In fact, the development of allogeneic stem cell transplantation (alloSCT) first highlighted the potential of T cells to eliminate cancer cells. In this regard, Kolb et al. Studies have shown that infusion of donor lymphocytes can induce long-term remission in patients with chronic myeloid leukemia (CML) recurrence . Using ACT, immune cells can be collected from patients or donors, then manipulated and/or expanded ex vivo, and then reinjected into the patient .
The success of ACT mainly depends on the existence of a sufficient number of effector cells in the patient, which in turn requires natural anti-tumor recognition capabilities or T cells to be engineered to provide precursors for this recognition ability . Therefore, researchers have developed several strategies to improve the tumor recognition ability of adoptively stimulated cells. The genetic engineering of a new type of receptor (CAR) has led to the development of molecules that can recognize proteins present on the surface of tumor cells and provide T cell activation, proliferation and memory functions .
CAR constructs are hybrid molecules; the extracellular part is based on the structure of monoclonal antibodies and is responsible for surface antigen recognition. This recognition occurs in a major histocompatibility complex (MHC) independent manner. The intracellular part is based on the structure of the T cell receptor (TCR) that binds to one or more costimulatory domains, which can transform antigen recognition into T cell activation .
2. CAR-T cell design
Generally, CAR is composed of three main domains: extracellular domain, transmembrane domain and inner domain. The extracellular domain or extracellular part of CAR usually consists of heavy and light chains derived from antibodies in the form of single-chain variable fragments and a hinge region.
It changes the specificity of the receptor so that it can recognize antigens on the cell surface independently of MHC molecules. For the following reasons, CD19 is most frequently selected as the target antigen of B-NHL, B-ALL and B-CLL: it is frequently expressed at high levels in these malignant tumors, compared to other potential targets (such as CD20), Its expression range is wider, higher or CD22, and it limits the B cell lineage in healthy tissues.
The transmembrane domain of the CAR construct mainly plays a role in stabilizing the CAR, while the intracellular domain provides the necessary signals to activate T cells after antigen recognition .
Over the years, CAR’s design has developed greatly. The design of the first-generation CAR is similar to that of the endogenous TCR complex. In these initial constructs, the intracellular component is usually composed of CD3ζ, which is connected to the extracellular antigen recognition domain, so that it can directly and independently of MHC recognize the antigen on the surface of tumor cells . Importantly, these first-generation designs do not include a costimulatory domain and therefore do not provide a second signal of intact T cell activation.
As a result, these first-generation CAR-T cells are more prone to apoptosis and have limited expansion potential in vivo, resulting in poor cytotoxicity . The addition of costimulatory signal domains (eg, CD28, 4-1BB) to the second-generation CAR results in improved T cell activation, enhanced viability, and more efficient expansion of modified T cells in vivo [4,5]. These second-generation receptors form the basis of currently approved CAR-T cell therapies.
It is becoming increasingly clear that each type of co-stimulatory domain has a specific role in CAR signal transduction. For example, CD28-based CAR-T cells show stronger effector cell functions but have limited persistence, while 4-1BB tends to push CAR-T cells to the central memory phenotype, leading to improved persistence [6,7 ]. The third-generation CAR-T cells combine the signal transduction potential of two costimulatory domains (such as CD28 and 4-1BB). The anti-tumor activity of the fourth-generation CAR includes redirecting T cells for TRUCKs and other genetic modifications, such as the addition of transgenes for cytokine secretion (such as IL-12). ) To further enhance) [8,9].
3. Manufacturing and management of CAR-T cells
Although allogeneic CAR-T cells have been used, the production of CAR-T cells usually starts with the collection of peripheral blood mononuclear cells (PBMC) from the patient (autologous) using high-dose leukocyte separation (Figure 1).
The cells are then transferred to a cell processing facility and loaded with CAR, usually by incubating them with a viral vector encoding CAR, and then importing them into T cells and introducing CAR-RNA (Figure 1).
The CARRNA is then reverse-transcribed into DNA and recombined into the T cell genome, resulting in permanent CAR gene incorporation. Both lentivirus and γ-retroviral vectors have been used for CAR gene transduction of primary T cells (Figure 1) .
Figure 1. Overview of CD19-targeted chimeric antigen receptor (CAR)-T cell therapy in CD19+ non-Hodgkin’s lymphoma (NHL)). T cells are collected from the patient by leukopenia (1), then the CD19 CAR gene is loaded into the T cells by lentivirus or retroviral transduction (2), and then amplified in vitro (3). The resulting CAR-T cells are then returned to the patient via intravenous (i.v.) infusion (4). Lymphatic detoxification chemotherapy is usually performed before CAR-T cell infusion to promote the expansion and persistence of CAR-T cells in the body. Axi-cel, tisa-cel and liso-cel are second-generation CARs whose intracellular part contains T cell receptor zeta chain (CD3ζ) and costimulatory (-CS) domains (CD28 or 4-1BB). The intracellular part is connected to the extracellular part of the CAR through the transmembrane domain (-TM), and the transmembrane domain (-TM) and the extracellular part of the CAR are composed of a hinge and an antigen recognition domain. These three constructs have different hinges (-H), but share the same murine FMC63-derived single-chain variable fragment (scFv) with the antigen-binding domain.
Then the CAR gene-modified T cells are expanded in vitro and made into drug intravenous infusion products. The cells are usually administered as a single infusion. The median time from leukocyte depletion to CAR-T cell administration is 4-5 weeks, and the entire process from referral to infusion may take up to 2 months .
Therefore, doctors often perform bridging chemotherapy to avoid the rapid development of the disease and maintain the patient’s overall condition during the CAR-T cell production period. Before the infusion of CAR-T cells, lymph node dissection (LD) such as fludarabine and cyclophosphamide is usually performed (Figure 1) .
LD chemotherapy reduces the number of T cells in the body, including regulatory T cells, and therefore up-regulates cytokines, such as IL-7 and IL-15 . These cytokines promote T cell expansion and enhance the anti-tumor activity of CAR-T cells.
4. Efficacy and toxicity of CAR-T cell therapy in B cell malignant tumors
In the past few years, CAR-T cell therapy has risen rapidly, and the FDA has approved 5 CAR-T cell drugs. The United States Medicines Agency (FDA) and later the European Medicines Agency (EMA) is responsible for the treatment of certain B-cell NHL types in adults, and relapsed/refractory (r/r) B-ALL in children and young adults. In addition, the potential of CAR T cell therapy is also being explored in other B cell tumors, such as MM and B-CLL [1,8].
4.1 Non-Hodgkin’s Lymphoma
B-cell NHL is the most common hematological malignancy, and diffuse large B-cell lymphoma (DLBCL) is the most common subtype. Despite improvements in treatment, a large proportion of DLBCL patients still develop chemically refractory diseases. Currently, about two-thirds of patients newly diagnosed with DLBCL can be cured by first-line cyclophosphamide, adriamycin, vincristine and prednisolone (CHOP) combined with rituximab .
The second-line treatment standard suitable for patients with r/r DLBCL is rescue chemotherapy followed by autologous SCT (ASCT). Unfortunately, about one-half of patients will remain refractory or relapse after second-line treatment . The prognosis of relapsed/refractory DLBCL is poor. Based on the data from the SCHOLAR-1 study, the study is a multi-cohort retrospective study involving 636 patients. It summarized data from two phase III studies (CORAL and LY.12) and two observational cohorts, where r/ r DLBCL is only 6.3 months (95% CI: 5.9-7.0 months) .
In order to overcome this chemical rupture in DLBCL, several novel treatment strategies have been explored, including CAR-T cell therapy. Several early single-center studies have shown that CD19-directed CAR-T cell therapy for NHL patients has significant anti-lymphoma activity, and laid the foundation for the design of three large-scale multi-center clinical trials [15,16].
The phase II part of the ZUMA-1 trial evaluated axons in patients with refractory high-grade B-cell lymphoma. In this study, bridging therapy was not allowed, and the LD regimen consisted of cyclophosphamide and fludarabine. Patients in the trial are divided into two cohorts: the first cohort-the largest cohort-includes patients with DLBCL, while the second cohort consists of transforming follicular lymphoma (TFL) and primary mediastinal B-cell lymphoma (PMBCL). )
Composition [17,18]. Compared with historical controls, the primary endpoint of ZUMA-1 is the overall response rate (ORR) of patients more than 6 months after receiving axial intravenous injection (SCHOLAR-1 ). A total of 111 patients were recruited, of which 101 received axi-cel. More than two-thirds of patients are ineffective at least to third-line therapy, and 21% of patients relapse within 12 months after ASCT.
In the latest report of the trial, the median follow-up was 27.1 months, the ORR was 83%, and the complete response (CR) rate was 58% . Compared with SCHOLAR-1, this represents a higher CR rate . CR patients have not yet reached the median duration of remission (95% CI: 12.9 months, which cannot be estimated), which highlights the durability of axi-cel . A more detailed overview of the efficacy data in ZUMA-1 is provided in Table 1 [17,18].
The JULIET trial is a phase II multicenter global study of r/r B-cell NHL patients using the anti-CD19 CAR-T cell product tisa-cel [19,20]. JULIET’s main eligibility criteria include aggressive B-cell lymphoma (DLBCL, which accounts for 80% of treated patients, or TFL); about half of patients have refractory disease and have received at least three previous therapies (49% of them Of patients include ASCT). Compared with ZUMA-1, it uses cryopreserved apheresis products and allows patients with rapidly progressive diseases to receive bridging chemotherapy .
Overall, 92% of patients received bridging chemotherapy. LD chemotherapy consists of cyclophosphamide and fludarabine or bendamustine. Similar to the ZUMA-1 trial, the primary endpoint of the trial is the incidence of ORR and CR. A total of 165 patients were enrolled, and 111 patients received tisa-cel infusion. Among 93 patients with evaluable response (at least 3 months follow-up), the reported ORR and CR rates were 52% and 40%, respectively. Table 1 shows more details of efficacy .
Based on the promising results of ZUMA-1 and JULIET, the US FDA approved axi-cel and tisa-cel for certain r/r B cell NHL subtypes in October 2017 and May 2018, respectively. A few months later, both agents also obtained EMA’s approval. With the approval of axi-cel and tisa-cel, people are more and more interested in reporting the efficacy of the therapy in actual clinical practice.
In addition, 55% of people have received bridging therapy, which ZUMA-1 does not allow. Nastoupil et al. , Jacobson et al.  and others  et al. reported “real world” data on the use of axi-cel. . Overall, 43% of patients in the study did not meet the inclusion criteria of ZUMA-1. Of the 294 patients with leukocyte depletion, 274 were actually injected. The best ORR (81%) and CR (57%) ratios are similar to those reported in ZUMA-1 (83% and 58%, respectively).
This fundamentally confirms that the efficacy of axi-cel in r/r B cell NHL (including DLBCL, TFL and PMBCL) can be replicated outside the strict qualification criteria of clinical trials [24-26].
The multicenter TRANSCEND NHL 001 study of liso-cel is the largest CD19 CAR-T cell study ever conducted. Leukocytosis was performed on 344 patients with various r/r B-cell NHL types (including DLBCL, TFL, PMBCL, FL 3b grade and other high-grade B-cell lymphomas) [21-23]. Like in ZUMA-1 and JULIET, DLBCL is the most common histological subtype. Approximately two-thirds of patients are allowed to undergo bridging therapy. A combination of cyclophosphamide and fludarabine is used for lymph node dissection. In the trial, a total of 294 patients received infusions, but 25 patients received substandard products. Among 256 patients with evaluable response, the best ORR and CR rates were 73% and 53%, respectively . The PFS and OS data are shown in Table 1 .
The most common acute toxicity observed after CAR-T cell therapy is CRS and immune effector cell-related neurotoxicity syndrome (ICANS, formerly known as CAR-T cell-related encephalopathy syndrome (CRES)), any of them Either one can be fatal . CRS is caused by the increase of cytokines due to the immune activation of a large number of lymphocytes. The main symptoms include fever, hypotension and hypoxemia .
The median time of occurrence of CUM is 2–3 days, axi-cel [17,18] in ZUMA-1, tisa-cel  in Juliet, and liso-cel 5 days in TRANSCEND . In recent years, guidelines for the uniform classification of CRS have been issued, and the guidelines of the American Society for Transplantation and Cell Therapy (ASTCT) have become the most widely adopted guidelines . The CRS is scored from 1 (mild) to 4 (life threatening) .
In ZUMA-1 (axi-cel) [17,18], JULIET (tisa-cel)  and TRANSCEND (lisocel) , the incidence of CRS at any level is 92%, 58% and 42, respectively. . Respectively% (Table 2). The incidence of CRS ≥3 was 11%, 22%, and 2%, respectively (Table 2). In the actual study by Nastoupil et al., 7% of patients suffered from severe CRS [24,26].
Interleukin 6 (IL-6) is considered to be the main mediator of CRS . This explains why tocilizumab (a therapeutic antibody that blocks IL-6 receptors) has become the drug of choice for the treatment of moderate to severe CRS [28,29]. In most patients, it causes immediate reversal of CRS symptoms. Importantly, in terms of ORR, CR rate or durability of response, tocilizumab does not seem to affect the efficacy of CAR-T cell therapy .
In ZUMA-1 (axi-cel) [17,18], JULIET (tisa-cel)  and TRANSCEND (liso-cel) , the usage rate of tocilizumab was 43% and 14%, respectively And 19% of patients, respectively (Table 2). In the real world, tocilizumab is used more frequently (Nastoupil et al. accounted for 63% of the cases in the study using axi-cel) [24-26]. Until recently, due to concerns about its inhibitory effect on T cell function, corticosteroids were only used in severe CRS cases .
However, it is increasingly clear that corticosteroids can be safely used to treat CAR-T cell-related toxicity without limiting the efficacy. The fact that real-world data on the use of axi-cel in r/r B-cell NHL (ie, similar efficacy in real-world studies by ZUMA-1 and Nastoupil et al., albeit at a higher ratio) further strengthens this statement. Use corticosteroids to treat CRS (55% in ZUMA-1 and 27% in ZUMA-1) [24,26].
Neurotoxicity, called ICANS or CRES, is the second most common serious adverse reaction after CAR-T cell therapy . Affected patients develop toxic encephalopathy with confusion, aphasia, ataxia, seizures, and cerebral edema . The pathophysiology of the etiology of these neurological side effects is still not fully understood. IL-6 does not seem to play an important role in ICANS/CRES; in the mouse model, it is beautifully shown that the anti-IL-6 treatment of tocilizumab has no significant effect on the occurrence and development of ICANS/CRES . Nevertheless, tocilizumab is still used frequently, especially if neurotoxicity occurs at the same time as CRS.
Otherwise, corticosteroids are the treatment of choice, or, if there is an IL-1 receptor blocker, it is the treatment of choice. The severity of ICANS can fluctuate rapidly, so patients need to be closely monitored. This is especially important for very rare but life-threatening cerebral edema, because anti-IL-6 therapy is ineffective . Similar to CRS, the management of ICANS is based on the severity of neurological symptoms.
The 10-point “Immune Effector Cell-Associated Encephalopathy (ICE)” scoring tool has now become the gold standard for screening and grading ICANS . Compared with tisa-cel (21% of JULIET, 12% ≥ 3) and licel-cel (TRANSCEND , 30% and 10% grade ≥ 3), axi-cel (67% of ZUMA-1’s 32 %≥ Grade 3 neurotoxicity) seems to be more common  (Table 2).
4.2 B-cell acute lymphoblastic leukemia
The phase II ELIANA trial investigated the CD19-directed gene-modified autologous T cell product tisa-cel as a single infusion of r/r pediatric and young adult B cell ALL . Of the 107 patients selected, 92 were selected; 17 patients could not be infused due to various reasons: death (N=7), serious adverse events (N=3) or CAR-T cell production failure (N =7). Of the 75 patients who received tisa-cel treatment, 65 (87%) required bridging chemotherapy between enrollment and infusion, and 72 (96%) received LD chemotherapy (mainly fludarabine plus cycloheximide) Phosphoramide).
The patients in this study received the median treatment of 3 previous therapies, 61% of the patients who had previously received alloSCT. The 3-month CR rate was 81%, and the median time of remission was not reached at a median follow-up of 1 year. All patients with treatment response had minimal residual disease (MRD) negative. The 6-month event-free survival rate (EFS) and OS rate were 73% and 90%, respectively, and dropped to 50% and 76% at the 1-year milestone .
Prove the long-term durability in the body. All patients who responded to the treatment had B-cell hypoplasia, and most of the patients in the study received immunoglobulin replacement based on local conditions. Grade 3/4 adverse events (AEs) suspected to be related to tisa-cel occurred in 73% of patients. CRS occurred in 77% of patients, and 48% of patients received tocilizumab treatment.
Neurotoxicity was observed in 40% of patients; all of these events occurred within the first 2 months . Tisa-cel has been approved by the regulatory authorities and can be used to treat refractory B-ALL under the age of 25, relapse after alloSCT or relapse for the second time or later in children and young adults.
4.3 Multiple myeloma
Multiple myeloma is a B-cell tumor characterized by the malignant proliferation of plasma cells in the bone marrow. In the past ten years, we have witnessed tremendous advances in MM, but despite these advances, there is still no cure for the disease. Therefore, new therapeutic drugs need to be developed, and CAR-T cell therapy is considered promising.
B cell maturation antigen (BCMA) is the most widely used target antigen in MMCAR-T cell research [32-34]. BCMA expression is largely restricted to (malignant) plasma cells and some mature B cells [35,36]. BCMA seems to play an important role in promoting the survival and proliferation of MM cells, and it has also been found to be related to the development of drug resistance . Table 3 summarizes all BCMA CAR-T cell clinical trials in MM published as full text on Web of Science/Pubmed (latest search date: January 1, 2020) [38-44].
Due to the early characteristics of most trials, the number of patients infused was small. In most studies, the ORR ranged from 85% to 95%; only two studies, NCT02546167  and NCT02215967 [39,40] reported lower ORR and CR rates. A possible explanation is the insufficient dose of the suboptimal BCMA CAR-T cells used in these trials and the fact that most patients received adequate pretreatment.
The median PFS observed with BCMA CAR-T cell therapy is 1 year [41-44]. As shown in Table 3, most patients develop CRS. CRS grade 3 or higher is observed in 5–41% of patients. Neurotoxicity is a rare event, usually occurring in less than 10% of patients. Only two studies reported the incidence of neurotoxicity as 32% [38%] and 42% .
Although relatively high ORRs have been obtained with BCMA CAR-T cell therapy, the observed therapeutic effects are usually short-lived, and relapses are often observed. Down-regulation or loss of BCMA expression may be an important mechanism of these recurrences . Therefore, targets other than BCMA have been studied in CAR-T cell research, such as CD19 or CD138, but different results have been produced [46,47].
For example, a combination of BCMA and CD19 CAR-T cells to achieve dual antigen targeting is also underway in order to improve the durability of the response . CD19 is an unconventional target antigen in MM, because most of myeloma cells are negative for CD19 as detected by flow cytometry. However, recent more sensitive techniques have shown that CD19 is expressed at ultra-low levels on MM cells, and these levels are sufficient for CD19 CAR T cells to recognize MM cells .
In addition, it seems that CD19+MM cells have the characteristics of cancer stem cells (ie, self-renewal and drug resistance), making them attractive targets for immunotherapy . Another strategy to avoid BCMA negative recurrence involves the use of BCMA CAR-T cells in combination with a gamma secretase inhibitor to prevent BCMA from dividing from the surface of MM cells .
In addition, other studies are also looking for the potential of CAR T cell therapy against other antigens, including CD38, SLAMF7, CD44v6, CD56, GPRC5D, etc. . Currently, no regulatory agency has approved CAR-T cell therapy for MM, but it is expected to receive the first batch of approval in the second half of this year or 2021.
4.4 Chronic lymphocytic leukemia
B-CLL is one of the first diseases to detect CD19 CAR-T cells. Since the first report of the efficacy of second-generation CAR-T cells against CLL in 2011 , the results of CAR-T cell therapy targeting CD19 in a total of 134 CLL patients have been reported . Overall, the prognosis of CLL patients treated with CAR-T cell therapy is particularly poor, and most of them relapse after receiving a lot of treatment.
In these studies, 74 of 108 patients (68.5%) had p53 alterations, and 41 of 70 patients (58.6%) had complex karyotypes . The second observation of different CAR-T cell reports from CLL is that the efficacy of CLL is lower than that of DLBCL or B-ALL: According to the IWCLL criteria, the efficacy of CR is only a minority (20-30%) estimated at 18 months PFS is 25% of patients [54-56]. Interestingly, the response in the lymph nodes seems to be weaker than the response in the bone marrow and blood.
In fact, in some series, a considerable proportion of patients receiving CAR-T cell therapy have no MRD detected in the bone marrow [55,57,58]. For example, in the study of Turtle et al. Including 24 CLL patients who had previously received ibrutinib, four weeks after CAR-T cell infusion, the ORR was 71% (CR 21%), and the bone marrow negative rate was 58%. Among these MRD-negative patients, the PFS and OS rates were almost 100% at a median follow-up of 6.6 months .
The lower efficacy of CAR-T cells in CLL may be partly attributed to the failure of T cells in CLL patients, leading to reduced CAR-T cell function . To overcome this problem, several research groups are studying ways to optimize the CAR structure in CLL.
In addition, ongoing research is exploring the potential of combining CAR-T cell therapy with other anti-CLL therapies. In this regard, data suggests that ibrutinib may improve the prognosis of CLL patients receiving CAR-T cells [57,58]. Based on these observations, a prospective study will further evaluate the maintenance efficacy of ibrutinib when injected with CAR-T cells (NCT03331198).
5. Conclusion and future outlook
CAR-T cell therapy is becoming an important supplement to the treatment of r/r B cell malignancies . In certain aggressive B-cell NHL subtypes (including DLBCL), CAR-T cell therapy targeting CD19 has shown unprecedented clinical activity. The three most advanced CD19 CAR-T cell products used in NHL are axi-cel, tisa-cel and liso-cel. The total CR rate is in the range of 50%. For patients with chemically refractory DLBCL, several previous treatments are ineffective , which is indeed very high.
In addition, the PFS curves of these three drugs showed a steady state in their tails, indicating that a long-lasting response can be observed in approximately 1/3 of NHL patients [17,19]. However, this high efficiency comes at the cost of substantial toxicity. According to the toxicity data in this review (Table 2), it can be concluded that liso-cel has good safety in terms of severe CRS and neurotoxicity , but whether it depends on the product remains to be determined . Among B-ALL, tisa-cel is the only CD19 CAR-T cell product approved by regulatory agencies for the treatment of children and adult young patients with r/r B-ALL under the age of 25.
The toxicity is considerable, but because there are few effective rescue treatments available for these patients, it is generally accepted . r/r MM patients can benefit from CAR-T cell therapy for BCMA. In selected studies, BCMA CAR-T cells are highly active in r/r MM, with an ORR rate of 85-95% (Table 3) and a CR rate as high as 80% . The median PFS is about 12 months, which is also an unprecedented high among MM patients who have undergone a lot of pretreatment. Toxicity is common, with >75% of patients reported to have CRS. The occurrence of neurotoxicity appears to be product-specific (Table 3). Finally, in r/r B-CLL, CD19 CAR-T cells have been tested, but the response rate is disappointing [54-56]. In these patients, it may be necessary to use ibrutinib in combination
(source:internet, reference only)