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Liu, Q.;  Liu, Z.;  Wan, R.;  Huang, W. Clinical Strategies of CAR-T-Cell Therapy for Hematological Malignancies. Encyclopedia. Available online: https://encyclopedia.pub/entry/27941 (accessed on 09 July 2025).
Liu Q,  Liu Z,  Wan R,  Huang W. Clinical Strategies of CAR-T-Cell Therapy for Hematological Malignancies. Encyclopedia. Available at: https://encyclopedia.pub/entry/27941. Accessed July 09, 2025.
Liu, Qianzhen, Zengping Liu, Rongxue Wan, Wenhua Huang. "Clinical Strategies of CAR-T-Cell Therapy for Hematological Malignancies" Encyclopedia, https://encyclopedia.pub/entry/27941 (accessed July 09, 2025).
Liu, Q.,  Liu, Z.,  Wan, R., & Huang, W. (2022, September 29). Clinical Strategies of CAR-T-Cell Therapy for Hematological Malignancies. In Encyclopedia. https://encyclopedia.pub/entry/27941
Liu, Qianzhen, et al. "Clinical Strategies of CAR-T-Cell Therapy for Hematological Malignancies." Encyclopedia. Web. 29 September, 2022.
Clinical Strategies of CAR-T-Cell Therapy for Hematological Malignancies
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This entry is adapted from the peer-reviewed paper 10.3390/cancers14184452

Chimeric antigen receptor (CAR) T cells have been successfully used for hematological malignancies, especially for relapsed/refractory B-cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. Patients who have undergone conventional chemo-immunotherapy and have relapsed can achieve complete remission for several months with the infusion of CAR T-cells. However, side effects and short duration of response are still major barriers to further CAR T-cell therapy. To improve the efficacy, multiple targets, the discovery of new target antigens, and CAR T-cell optimization have been extensively studied.

immunotherapy CAR T-cell efficacy clinical strategies acute lymphoblastic leukemia

1. Introduction

Cellular immunotherapy of hematological malignancy has achieved remarkable progress in the last decade, especially that based on chimeric antigen receptor (CAR) T cells. CAR T-cells have experienced four generations. First-generation CAR T-cells were found to lack persistence and expansion in pre-clinical studies, while second-generation cells overcame these limitations by containing intracellular costimulatory domain (e.g., CD28 or 4-1BB), later fused to CD3zeta. Third-generation cells with two costimulatory domains of CD28 and 4-1BB showed promising results in persistence and anti-tumor activity [1], while fourth-generation CAR T-cells additionally achieved specific cytokine release through gene editing following T cell activation [2]. CD19-directed CAR T-cells as representative second-generation CAR T-cells have led to unprecedented development in the treatment of B-cell hematological malignancies, with over 90% overall survival [3][4]. It is worth mentioning that Melenhorst et al. of the University of Pennsylvania found that after infusion of second-generation CAR T-cells (CTL019) in two CLL patients, stable cloned CAR T-cells could be continuously detected in vivo, and sustained remission for 10 years was achieved, which is encouraging [5]. For patients with chemotherapy resistance and difficulty in matching hematopoietic stem cells, CAR T-cell therapy may be the salvage regimen. Several commercial products (e.g., axicabtagene ciloleucel, lisocabtagene maraleucel, tisagenlecleucel, brexucabtagene autoleucel) have been approved by the US Food and Drug Administration (FDA) for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) and other relapsed or refractory (R/R) large B-cell lymphomas [4][6][7].
However, this emerging cellular immunotherapy faces multiple challenges in the treatment of malignancies. On the one hand, most of the patients treated with CAR T-cells suffer from cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematological toxicity, and grade 3/4 side effects that can threaten the life of patients [8][9][10]; on the other hand, short persistence of CAR T-cells in vivo is related with poor efficacy [11]. Therefore, some optimization schemes for CAR T-cells, such as multiple target treatment, discovery of new targets, and CAR construct optimization, have been widely studied to reduce adverse events and improve CAR T-cell efficacy [12][13][14][15][16]. However, the clinical application strategies of CAR T-cells, which have an essential role in the overall treatment process, have rarely been discussed. After determining that a patient is suitable for CAR T-cell therapy, it is necessary to determine the lymphatic clearance scheme and dosing strategy according to the patient’s basic condition, to help the patient obtain the best blood environment and maximize the utilization of CAR T-cells [17]. Furthermore, for refractory and relapsed hematological malignancies, the combined application of multiple treatments may lead to longer event-free survival for patients [18][19]. The implementation of combined strategies to increase the persistence or antitumor activity of CAR T-cells has become a research hotspot. In addition, the safe and effective implementation of a strategy is inseparable from the supervision of the disease and careful comprehensive management, which will promote patients obtaining complete remission (CR) and disease-free survival.

2. Lymphodepletion Regimen

After infusing into the blood, CAR T-cells specifically recognize the target antigen through the single-chain variable fragment (scFv) binding domain, which requires a suitable immunomodulatory environment for T cell survival and proliferation [20][21][22]. Lymphodepletion followed by CAR T-cell infusion remodels the immune environment for creating enough T cell pool, decreasing immunosuppressive cell populations, increasing the availability of cytokines and thus promoting lymphocyte proliferation and survival, and increasing tumor antigen presentation by inducing cell death [23][24][25]. Cyclophosphamide (Cy) and fludarabine (Flu) are two major lymphodepletion compositions, known as potent immunosuppressive agents. In one case, the overall response rate (ORR) without lymphodepletion was only 25%, while ORR rose to 58% after lymphodepletion that had made changes in cytokine profiles and had increased CAR T-cell durability [26][27]. However, how the lymphodepletion regimen impacts CAR T-cell efficacy is still unclear.
Generally, lymphodepletion with cyclophosphamide and/or fludarabine is implemented on -5, -4, and -3 days before CAR T-cell injection to create an immunosuppressive environment that provides CAR T-cell expansion in vivo [28][29]. Moreover, the chemotherapy pretreatment regimen adopted in most trials is a dose of fludarabine generally maintained at about 30 mg/m2·d or 25 mg/m2·d; the dose of cyclophosphamide is 200 to 3000 mg/m2·d [7][11][30][31][32], which is considered to be a relatively safe dose. The co-administration of cyclophosphamide and fludarabine is viewed as adequate lymphodepletion. Studies have shown that a low incidence of CR and high rate of relapse may be associated with inadequate CAR T-cell persistence and expansion in vivo and cell-mediated immunosurveillance [17][33][34]. Cyclophosphamide and fludarabine-mediated lymphodepletion reshape the blood environment, prolong CAR T-cell survival time, regulate the release of activating cytokines, and improve the event-free survival time of patients [33][35][36].
Studies have shown that the effect of lymphodepletion and the reactivity of subsequent CAR T-cell therapy is dose-dependent [11]. A total of 17 patients received high-dose cyclophosphamide of 3 g/m2·day (HD-Cy), while 8 patients received low-dose cyclophosphamide at 1.5 g/m2·day (LD-Cy), with fludarabine at 25 mg/m2·day for 3 days. Results manifested that CAR T-cell expansion in the HD-Cy group was remarkably higher than that in the LD-Cy group. The disease response rate of the former was 94%, while the latter was only 38% [11]. This indicates that deeper lymphodepletion leads to higher clinical response due to thoroughly eliminating immunosuppression and reducing cytokine rejection of CAR T-cells. In addition, high-dose Cy increased the level of IL-7 and MCP-1 and was associated with CR and/or progression-free survival (PFS) [35][37]. However, the mechanism through which HD-Cy leads to a favorable cytokine profile has yet to be determined [11][38]. Nevertheless, in a previous study targeting diffuse large B-cell lymphoma (DLBCL), patients who received modulated chemotherapy with low a dose of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) had a higher level of cytokines, particularly IL-5 and IL-15, which are critical for T cell proliferative cytokines [29][39].
The addition of fludarabine to cyclophosphamide as a lymphodepleting regimen before CD19-directed CAR T-cell therapy significantly improved outcomes in patients treated with CAR T-cells [40]. Over 90% of patients who received fludarabine-containing lymphodepletion achieved CR and had no relapse, while 58% of patients without fludarabine suffered a relapse. In patients with CD19+ relapse, a loss of CAR T-cell in blood was detected by PCR analysis [33]. Incorporation of fludarabine into the lymphodepletion regimen, lower concentration of LDH, and higher platelet count before the lymphodepletion regimen containing fludarabine may lead to minimal residual disease-negative complete remission (MRD- CR) [26]. Compared with the lower cumulative fludarabine exposure during lymphodepletion, patients in the higher group had an 11-month improvement in leukemia-free survival, and the CD19+ recurrence rate within 1 year decreased from 100% to 27.4% [41]. However, when the disease burden is high, the effect is weakened, so the dose of fludarabine should be formulated according to the patient’s disease burden and designed individually [42]. Interestingly, for DLBCL patients who relapsed after CAR T-cell therapy, pre-existing CAR T-cells were revitalized after the second lymphatic clearance containing fludarabine and created an anti-tumor effect with a predominant grade 2 CRS [43]. This case indicates that CAR T-cells could be reactivated under circumstances by disturbing the immune equilibrium. CAR T-cell activation and cytotoxicity depend on the immune homeostasis of the blood environment, and the blood environment after lymphatic clearance seems merely to maintain for a period time, which may be one of the reasons why patients can only achieve short-term remission. At the same time, to obtain satisfactory clinical efficacy, the degree of lymphatic clearance needs to be proportional to the patient’s disease burden; thus, a universal single dosage is not suitable [11][33].

3. Dosing Regimen of CAR T-Cells

Before lymphocytes are removed, T cells will be isolated from the peripheral blood mononuclear cells (PBMC) of patients as raw materials for subsequent manufacturing of CAR T-cells [44]. The preparation of CAR T-cells is about 13 days, including T cells expanding for 9 days; another study shortens the preparation time to 7 days with similar effectiveness [45][46]. Surprisingly, Gracell Bio in China has developed a fabrication technique of FasTCAR, which shortens the preparation time of CAR T-cells to 1 day [47]. FasTCAR technology transforms the activation, transduction, and expansion steps into a single “concurrent activation-transduction” step, eliminating the time for in vitro expansion of CAR T-cells [48]. After obtaining CAR T-cells and achieving the standards of identity, potency, sterility, and adventitious agents, the infusion strategy of CAR T-cells can be determined by clinicians and manufacturers based on phase I clinical trials identifying the maximally tolerated dose (MTD) [49].
In CD19-directed CAR T-cell products (axicabtagene ciloleucel, lisocabtagene maraleucel, tisagenlecleucel, brexucabtagene autoleucel) that have been proved by FDA, the single infusion dose is about 1–3 × 106/kg, except that tisagenlecleucel is 0.1–6×108 viable cells, of which 5×108 viable cells are more suitable for DLBL and relapsed or refractory follicular lymphoma (FL) [3][4][6][7][28][29][50][51][52]. In adults, some CD19-targeted products in the treatment of different diseases in the dose range of 2 × 106/kg showed higher ORR and CR and lower incidence of high-grade CRS and neurological event (NE) side effects. Determination of a safe/efficacious dose range is based on understanding dose-response/exposure/safety analyses. A dose-escalation test showed that 1 × 106/kg is the highest single-injection tolerated dose for R/R ALL and non-Hodgkin’s lymphoma (NHL) patients; in this condition, all toxicities, including grade 4 CRS, are reversible [53]. Moreover, a lower CAR T-cell dosage of 1 × 105/kg is effective and safe for treating r/r B-ALL [54]. It can be seen that the clinical results cannot intuitively find the relationship between the dose and the efficacy of CAR T-cells, except that high doses show dose-dependent toxicity. This may be due to the initial CAR T-cell viability and different immunosuppressive gene expression of the tumor microenvironment [55].
A single injection of low-dose CAR T-cells is considered safe and effective, but not with durable remission. Some researchers have studied one-time injection or segmental injection of low-dose or high-dose CAR T-cells [32][38]. A single-arm, open-label study verified the difference between these two strategies in efficacy. The trial is divided into a high-dose single infusion (5 × 108/kg), low-dose single/fractionated infusion (5 × 107/kg), and high-dose fractionated infusion (5 × 108/kg); the numbers of patients were 6, 9, and 20, respectively [56]. The high-dose fractionated group showed the best effect, with a complete remission rate of 90% and a two-year overall survival rate of 73%, while in the high-dose single infusion group, patients suffered from refractory CRS complicated with culture-positive sepsis [56]. The low rate of adverse events of the high-dose fractionated group indicates that fractionated infusion of a high dose may alleviate immune response. Characteristics including age, disease phenotype, chemotherapy regimen received before infusion, and whether to undergo stem cell transplantation are all related to dosage selection, indicating that it is difficult to set the dosing interval to enable long-term complete remission [57]. Before receiving CAR T-cell therapy, these patients had experienced more than two lines of systemic therapy; however, at the same therapeutic dose, there were differences in the patients’ physical condition, immune homeostasis of the blood environment, disease burden, and cytokine pool after lymphatic depletion. A scoring system is set up to determine various aspects of the patient’s physical state, thereby determining the corresponding dose standard within a certain scoring range. The dosing regimen of CAR T-cells is individualized. However, studies of the clinical response of patients to CAR T-cells could provide clinicians with data for developing a personalized dosage strategy.

4. Combination Strategies

Anti-CD19 CAR T-cells show a strong short-term CR in the treatment of refractory and relapsed B-cell diseases. Its limitations include the inability to achieve long-term disease-free survival and risk of recurrence due to a lack of sustained expansion of CAR T-cells [55], and patients with a high tumor burden treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) could not achieve complete remission [58]. CAR T-cells or allo-HSCT achieved considerable short-term efficiency when used alone; researchers can explore combination to achieve long-term disease-free survival.
Allo-HSCT, as a kind of consolidation strategy, has shown a powerful capability for R/R B-cell lymphoma [58][59][60][61][62][63]. With a quick bridge to allo-HSCT after CAR T-cell therapy, the one-year event-free survival (EFS) was up to 73% compared with 50% for CAR T-cells alone, and the rate of severe grade 2–4 acute graft-versus-host disease (aGVHD) was less than 23.1% compared with 41.6% of allo-HSCT alone [7][64][65][66]. Moreover, the timing of allo-HSCT treatment affects patient prognosis. It was shown that the period within three months after treatment is considered to be a suitable time window for consolidation therapy [65]. MRD- CR patients receiving allo-HSCT showed detectable CAR T-cells for 21 months. Jiang H et al. [66] found that allo-HSCT was an independent prognostic factor for EFS and relapse-free survival (RFS) in MRD- CR patients. For patients with CD19-negative relapse, allo-HSCT may be desirable as a consolidated method because of immune reconstitution [54]. From another point of view, CAR T-cell therapy has obtained a larger range of patients for allo-HSCT [66]. In addition, CAR T-cells can be used as maintenance therapy after allo-HSCT therapy. Shi et al. found that CAR T-cells combined with lenalidomide maintenance therapy significantly prolonged PFS in patients with multiple myeloma. Lenalidomide increased the antitumor activity and persistence of CAR T-cells, which might be due to the fact that lenalidomide can maintain the long-term immune surveillance of CAR T-cells in remission, and this combined strategy promotes T cells toward the less terminally differentiated phenotype [67]. RNA sequencing and assays for transposase-accessible chromatin indicated that lenalidominde can alter T-helper response, cytokine production, T cell activation, cell-cycle control, and cytoskeletal remodeling [68][69].
CAR T-cells combined with ibrutinib, a kind of bruton’s tyrosine kinase inhibitor, improved CAR T-cells engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia [70]. Ibrutinib is a crucial component of a first-line treatment option for chronic lymphocytic leukemia (CLL), and it showed superior PFS and CR in progressive CLL patients who were too frail to receive aggressive therapy [71]. Continuous use of ibrutinib leads to tolerance and tumor recurrence, and fortunately, CAR T-cells show obvious therapeutic efficacy and durability after ibrutinib failure [72]. Therefore, the combination of these two therapies may create an advance for r/r CLL patients. Compared with CLL patients treated with CAR T-cells without ibrutinib, CLL patients treated with CAR T-cells combined with ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines, which is consistent with pre-clinical results [73]. Moreover, one-year overall survival and PFS probabilities of a combination of CAR T-cells with ibrutinib were 86% and 59%, respectively, while anti-CD19 CAR T-cell therapy was only 38% and 50% [74]. After more than 1 year of ibrutinib therapy, the efficiency of CAR T-cell engraftment, tumor clearance, and survival were improved [70].
CAR T-cell therapy with immune checkpoint inhibitors has now moved to the clinical stage. A pre-clinical study demonstrated that CAR T-cell therapy combined with PD-1 blockade showed better tumor control, and the persistence of CAR T-cells was up to 21 days in mice [75]. Furthermore, neuroblastoma and metastatic melanoma with CAR T-cell therapy combined with PD-1 blockade indicated that PD-1 blockade can enhance cytokine production and reduce activation-induced cell death (AICD) of CAR T-cells after repeated antigen stimulation [17][76].
Moreover, the effect of the first-line chemotherapy for CLL patients can be strengthened by combining it with CAR T-cell therapy. After regular chemotherapy treatment with pentostatin, cyclophosphamide, and rituximab, patients who received CAR T-cells ranging from 3 × 106 to 3 × 107 CAR T-cells/kg were observed to have more than 28 months CR and modest CRS neurotoxicity [34]. In addition, the above methods combined with CAR T-cell therapy are moving to the clinical stage, and other molecular medicines such as immunomodulatory drugs, utomilumab, hypomethylating agents, Phosphoinositide 3-kinase (PI3K) inhibition, γ-secretase inhibitors, and fas blockade, are part of widely ongoing pre-clinical studies [77]. These combination strategies represent a new treatment paradigm that leverages the ability of genetically modified T cells to target and destroy tumor cells.

5. Occurrence and Management of Side Effects

Anti-CD19 CAR T-cell therapy led to cytokine release syndrome, hematological toxicity, and ICANS attributed to inflammatory cytokines and chemokines released by immune cells, which are the main obstacles after CAR T-cells were administrated into the blood system via intravenous injection [78]. The average onset time of CRS is 3 days after injection, and it lasts for about 7 days [79]. When the neurological event occurs, it is generally within 8 weeks and lasts for 28 days [79]. Blood events such as thrombocytopenia and neutropenia may exist throughout the whole disease event. The incidence of CRS in the milestone trial is as high as 77%, the average incidence of neurological events is more than 30%, and blood events are more than 40% [7]. Although corresponding support and drug treatments were performed during the treatment process, the final mortality rate of patients is more than 40%, accompanied by disease progression and aggravating effects of side effects [6][7][80]. Therefore, it is meaningful to review the occurrence and management of side effects. Moreover, early detection and timely control of adverse events also play important roles in the treatment of disease.
Generally, grade 1/2 CRS, mainly including fever, fatigue, nausea, mild hypoxia, or headache, is not life-threatening and is relieved after symptomatic and supportive treatments performed with close monitoring of the functional status of various organs and the level of cytokines in the blood. Grade 3/4 CRS is life-threatening to patients and is closely related to the subsequent neurotoxic events [10]. Grade 3/4 CRS is accompanied by more severe hypoxia, which requires ventilator support if necessary, and ICU care is needed in some severe cases [81]. In 2020, Pierre Sesques et al. [76][79] did a retrospective study on commercial products such as axicabtagene ciloleucel and tisagenlecleucel and found that grade 3/4 CRS and neurological events were reduced to 8% and 10% compared with the key trial in 2017, which is 11% and 32%, respectively. The lower rate of grade 3/4 side effects is due to earlier and more systematic interventions.
When CRS occurs, the levels of IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ in the blood are significantly increased; in particular, IL-6 is parallel to the severity of CRS. Compared with grade 1/2 CRS, grade 3/4 CRS showed a rapid increase in IL-6 in the early stage, and the patients’ fever was high and lasted for a significant period. These clinical symptoms can be used as an early prediction of severe CRS and can provide treatment strategies for adequate treatment in the later period [10][82][83]. On the other hand, the rapid expansion of infused CAR T-cells is also related to CRS [9]. At the same time, the concentration of the above cytokines also significantly increased with the expansion of CAR T-cells, which is associated with not only injection protocol but also the kind of costimulatory domain of CAR T-cells [16][31]. The IL-6 antagonist tocilizumab is the first-line treatment for CRS; however, it is usually used when supportive treatment does not work. If necessary, it can be used in combination with the immunosuppressant dexamethasone. Generally, it can provide relief after one week of treatment. However, when the tumor burden and the number of recurrences in the past are high, severe CRS requires hemodialysis or plasma exchange to overcome difficulties [10][29].
In addition, grade 3/4 CRS is related to the increased risk of subsequent infections, especially bloodstream infections that are difficult to distinguish from grade 3/4 CRS. Bloodstream infections are similar to CRS symptoms, but the treatment methods for the two are different. Researchers can determine the infection through imaging methods and laboratory tests, such as computed tomography, bacterial examination, magnetic resonance imaging, C-reactive protein (CRP), procalcitonin, etc. When it is impossible to distinguish, clinicians should use antibiotics based on their experience [84][85]. Moreover, the incidence of disseminated intravascular coagulation (DIC) increases in patients with grade 3/4 CRS. As a result, early and proper interventions targeted to CRS-related coagulopathy greatly contribute to the control of side effects in CAR T-cell therapy [82].
Neurotoxic events occurred in the study as compared with the high incidence of CRS, but with the optimization of CAR T-cells, the incidence of CRS and neurological events decreased [32][86]. ICANS often occurs with grade 3/4 CRS. ICANS includes encephalopathy, confusion, delirium, tremor, restlessness, lethargy, and epilepsy in severe patients (Grade 3) [7]. There is no specific treatment method, other than relying on supportive treatment. Specific antibodies targeting cytokines related to neurotoxic events may be found in the future. Studies have shown that neurotoxicity is related to CAR T-cells crossing the blood–brain barrier and triggering an immune response in the brain. IFN-γ and IL-6 in the cerebrospinal fluid are nearly 40 times higher than those in the serum [87]. At the same time, the qPCR of the CAR expression indicates that it is in the cerebrospinal fluid, and the CAR copy number is three times higher [87]. Thus, the detection of components in cerebrospinal fluid can be used as a method to predict neurotoxicity [83][85][87]. Due to individual differences, CRS, hematological toxicity, and neurotoxicity may occur in patients at any time after CAR T-cell treatment. Identifying the characteristics of side effects and determining the treatment may be helpful for the positive progress of CAR T-cell therapy.

References

  1. Enblad, G.; Karlsson, H.; Gammelgård, G.; Wenthe, J.; Lövgren, T.; Amini, R.M.; Wikstrom, K.I.; Essand, M.; Savoldo, B.; Hallböök, H.; et al. A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia. Clin. Cancer Res. 2018, 24, 6185–6194.
  2. Duan, D.; Wang, K.; Wei, C.; Feng, D.; Liu, Y.; He, Q.; Xu, X.; Wang, C.; Zhao, S.; Lv, L.; et al. The BCMA-Targeted Fourth-Generation CAR-T Cells Secreting IL-7 and CCL19 for Therapy of Refractory/Recurrent Multiple Myeloma. Front. Immunol. 2021, 12, 609421.
  3. Abramson, J.S.; Palomba, M.L.; Gordon, L.I.; Lunning, M.A.; Wang, M.; Arnason, J.; Mehta, A.; Purev, E.; Maloney, D.G.; Andreadis, C.; et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet 2020, 396, 839–852.
  4. Schuster, S.J.; Bishop, M.R.; Tam, C.S.; Waller, E.K.; Borchmann, P.; McGuirk, J.P.; Jäger, U.; Jaglowski, S.; Andreadis, C.; Westin, J.R.; et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N. Engl. J. Med. 2019, 380, 45–56.
  5. Melenhorst, J.J.; Chen, G.M.; Wang, M.; Porter, D.L.; Chen, C.; Collins, M.A.; Gao, P.; Bandyopadhyay, S.; Sun, H.; Zhao, Z.; et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature 2022, 602, 503–509.
  6. Locke, F.L.; Ghobadi, A.; Jacobson, C.A.; Miklos, D.B.; Lekakis, L.J.; Oluwole, O.O.; Lin, Y.; Braunschweig, I.; Hill, B.T.; Timmerman, J.M.; et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019, 20, 31–42.
  7. Maude, S.L.; Laetsch, T.W.; Buechner, J.; Rives, S.; Boyer, M.; Bittencourt, H.; Bader, P.; Verneris, M.R.; Stefanski, H.E.; Myers, G.D.; et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 439–448.
  8. Cordeiro, A.; Bezerra, E.D.; Hirayama, A.V.; Hill, J.A.; Wu, Q.V.; Voutsinas, J.; Sorror, M.L.; Turtle, C.J.; Maloney, D.G.; Bar, M. Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells. Biol. Blood Marrow Transplant. 2020, 26, 26–33.
  9. Bao, F.; Wan, W.; He, T.; Qi, F.; Liu, G.; Hu, K.; Lu, X.-A.; Yang, P.; Dong, F.; Wang, J.; et al. Autologous CD19-directed chimeric antigen receptor-T cell is an effective and safe treatment to refractory or relapsed diffuse large B-cell lymphoma. Cancer Gene Ther. 2019, 26, 248–255.
  10. Heng, G.; Jia, J.; Li, S.; Fu, G.; Wang, M.; Qin, D.; Li, Y.; Pei, L.; Tian, X.; Zhang, J.; et al. Sustained Therapeutic Efficacy of Humanized Anti-CD19 Chimeric Antigen Receptor T Cells in Relapsed/Refractory Acute Lymphoblastic Leukemia. Clin. Cancer Res. 2020, 26, 1606–1615.
  11. Curran, K.J.; Margossian, S.P.; Kernan, N.A.; Silverman, L.B.; Williams, D.A.; Shukla, N.; Kobos, R.; Forlenza, C.J.; Steinherz, P.; Prockop, S.; et al. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL. Blood 2019, 134, 2361–2368.
  12. Yan, Z.; Cao, J.; Cheng, H.; Qiao, J.; Zhang, H.; Wang, Y.; Shi, M.; Lan, J.; Fei, X.; Jin, L.; et al. A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: A single-arm, phase 2 trial. Lancet Haematol. 2019, 6, e521–e529.
  13. Pan, J.; Zuo, S.; Wang, Z. Sequential CD19-22 CAR T therapy induces sustained remission in children with r/r B-ALL. Blood 2020, 135, 387–391.
  14. Shah, N.N.; Johnson, B.D.; Schneider, D.; Zhu, F.; Szabo, A.; Keever-Taylor, C.A.; Krueger, W.; Worden, A.A.; Kadan, M.J.; Yim, S.; et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: A phase 1 dose escalation and expansion trial. Nat. Med. 2020, 26, 1569–1575.
  15. Rafiq, S.; Yeku, O.O.; Jackson, H.J.; Purdon, T.J.; Van Leeuwen, D.G.; Drakes, D.J.; Song, M.; Miele, M.M.; Li, Z.; Wang, P.; et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 2018, 36, 847–856.
  16. Weng, J.; Lai, P.; Qin, L.; Lai, Y.; Jiang, Z.; Luo, C.; Huang, X.; Wu, S.; Shao, D.; Deng, C.; et al. A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia. J. Hematol. Oncol. 2018, 11, 25.
  17. Heczey, A.; Louis, C.U.; Savoldo, B.; Dakhova, O.; Durett, A.; Grilley, B.; Liu, H.; Wu, M.F.; Mei, Z.; Gee, A.; et al. CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Mol. Ther. 2017, 25, 2214–2224.
  18. Adusumilli, P.S.; Zauderer, M.G.; Rivière, I.; Solomon, S.B.; Rusch, V.W.; O’Cearbhaill, R.E.; Zhu, A.; Cheema, W.; Chintala, N.K.; Halton, E.; et al. A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti–PD-1 Agent Pembrolizumab. Cancer Discov. 2021, 11, 2748–2763.
  19. Wei, J.; Xiao, M.; Mao, Z.; Na Wang, N.; Cao, Y.; Xiao, Y.; Meng, F.; Sun, W.; Wang, Y.; Yang, X.; et al. Outcome of aggressive B-cell lymphoma with TP53 alterations administered with CAR T-cell cocktail alone or in combination with ASCT. Signal Transduct. Target. Ther. 2022, 7, 101.
  20. Mackall, C.L.; Hakim, F.T.; Gress, R.E. Restoration of T-cell homeostasis after T-cell depletion. Semin. Immunol. 1997, 9, 339–346.
  21. Klebanoff, C.; Khong, H.T.; Antony, P.A.; Palmer, D.C.; Restifo, N.P. Sinks, suppressors and antigen presenters: How lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005, 26, 111–117.
  22. Dummer, W.; Niethammer, A.G.; Baccala, R.; Lawson, B.R.; Wagner, N.; Reisfeld, R.A.; Theofilopoulos, A.N. T cell homeostatic proliferation elicits effective antitumor autoimmunity. J. Clin. Investig. 2002, 110, 185–192.
  23. Muranski, P.; Boni, A.; Wrzesinski, C.; Citrin, D.; Rosenberg, S.A.; Childs, R.W.; Restifo, N.P. Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go? Nat. Clin. Pract. Oncol. 2006, 3, 668–681.
  24. Wrzesinski, C.; Restifo, N.P. Less is more: Lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. Curr. Opin. Immunol. 2005, 17, 195–201.
  25. Gattinoni, L.; Finkelstein, S.E.; Klebanoff, C.; Antony, P.A.; Palmer, D.; Spiess, P.J.; Hwang, L.N.; Yu, Z.; Wrzesinski, C.; Heimann, D.M.; et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 2005, 202, 907–912.
  26. Hay, K.A.; Gauthier, J.; Hirayama, A.V.; Voutsinas, J.M.; Wu, Q.; Li, D.; Gooley, T.A.; Cherian, S.; Chen, X.; Pender, B.S.; et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood 2019, 133, 1652–1663.
  27. Vitale, C.; Strati, P. CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Clinical Trials and Real-World Experiences. Front. Oncol. 2020, 10, 849.
  28. Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; Lin, Y.; et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N. Engl. J. Med. 2017, 377, 2531–2544.
  29. Locke, F.L.; Neelapu, S.S.; Bartlett, N.L.; Siddiqi, T.; Chavez, J.C.; Hosing, C.M.; Ghobadi, A.; Budde, L.E.; Bot, A.; Rossi, J.M.; et al. Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma. Mol. Ther. 2017, 25, 285–295.
  30. Tang, X.-Y.; Sun, Y.; Zhang, A.; Hu, G.-L.; Cao, W.; Wang, D.-H.; Zhang, B.; Chen, H. Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: A non-randomised, open-label phase I trial protocol. BMJ Open 2016, 6, e013904.
  31. Li, S.; Zhang, J.; Wang, M.; Fu, G.; Li, Y.; Pei, L.; Xiong, Z.; Qin, D.; Zhang, R.; Tian, X.; et al. Treatment of acute lymphoblastic leukaemia with the second generation of CD19 CAR-T containing either CD28 or 4-1BB. Br. J. Haematol. 2018, 181, 360–371.
  32. Ying, Z.; Huang, X.F.; Xiang, X.; Liu, Y.; Kang, X.; Song, Y.; Guo, X.; Liu, H.; Ding, N.; Zhang, T.; et al. A safe and potent anti-CD19 CAR T cell therapy. Nat. Med. 2019, 25, 947–953.
  33. Turtle, C.J.; Hanafi, L.-A.; Berger, C.; Gooley, T.A.; Cherian, S.; Hudecek, M.; Sommermeyer, D.; Melville, K.; Pender, B.; Budiarto, T.M.; et al. CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Investig. 2016, 126, 2123–2138.
  34. Geyer, M.B.; Rivière, I.; Sénéchal, B.; Wang, X.; Wang, Y.; Purdon, T.J.; Hsu, M.; Devlin, S.M.; Halton, E.; Lamanna, N.; et al. Autologous CD19-Targeted CAR T Cells in Patients with Residual CLL following Initial Purine Analog-Based Therapy. Mol. Ther. 2018, 26, 1896–1905.
  35. Turtle, C.J.; Hanafi, L.-A.; Berger, C.; Hudecek, M.; Pender, B.; Robinson, E.; Hawkins, R.; Chaney, C.; Cherian, S.; Chen, X.; et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 + and CD4 + CD19-specific chimeric antigen receptor–modified T cells. Sci. Transl. Med. 2016, 8, 355ra116.
  36. Geyer, M.B.; Rivière, I.; Sénéchal, B.; Wang, X.; Wang, Y.; Purdon, T.J.; Hsu, M.; Devlin, S.M.; Palomba, M.L.; Halton, E.; et al. Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. JCI Insight 2019, 4, e122627.
  37. Hirayama, A.V.; Gauthier, J.; Hay, K.A.; Voutsinas, J.M.; Wu, Q.; Gooley, T.; Li, D.; Cherian, S.; Chen, X.; Pender, B.S.; et al. The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. Blood 2019, 133, 1876–1887.
  38. Zhao, H.; Wei, J.; Wei, G.; Luo, Y.; Shi, J.; Cui, Q.; Zhao, M.; Liang, A.; Zhang, Q.; Yang, J.; et al. Pre-transplant MRD negativity predicts favorable outcomes of CAR-T therapy followed by haploidentical HSCT for relapsed/refractory acute lymphoblastic leukemia: A multi-center retrospective study. J. Hematol. Oncol. 2020, 13, 42.
  39. Kochenderfer, J.N.; Somerville, R.P.; Lu, T.; Shi, V.; Bot, A.; Rossi, J.; Xue, A.; Goff, S.L.; Yang, J.C.; Sherry, R.M.; et al. Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated with High Serum Interleukin-15 Levels. J. Clin. Oncol. 2017, 35, 1803–1813.
  40. Fabrizio, V.A.; Boelens, J.J.; Mauguen, A.; Baggott, C.; Prabhu, S.; Egeler, E.; Mavroukakis, S.; Pacenta, H.L.; Phillips, C.L.; Rossoff, J.; et al. Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy. Blood Adv. 2022, 6, 1961–1968.
  41. Dekker, L.; Calkoen, F.G.; Jiang, Y.; Blok, H.; Veldkamp, S.R.; De Koning, C.C.H.; Spoon, M.; Admiraal, R.; Hoogerbrugge, P.; Vormoor, B.J.; et al. Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. Blood Adv. 2022, 6, 1969–1976.
  42. Dourthe, M.-E.; Rabian, F.; Yakouben, K.; Chevillon, F.; Cabannes-Hamy, A.; Méchinaud, F.; Grain, A.; Chaillou, D.; Rahal, I.; Caillat-Zucman, S.; et al. Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia 2021, 35, 3383–3393.
  43. Liang, Z.; Zhang, H.; Shao, M.; Cui, Q.; Wu, Z.; Xiao, L.; Huang, H.; Hu, Y. Lymphodepletion chemotherapy revitalizes chimeric antigen receptor T cells contributing to regression of relapsed B-cell lymphoma: A case report. Medicine 2020, 99, e22510.
  44. Sadelain, M.; Rivière, I.; Riddell, S. Therapeutic T cell engineering. Nature 2017, 545, 423–431.
  45. Tu, S.; Huang, R.; Guo, Z.; Deng, L.; Song, C.; Zhou, X.; Yue, C.; Zhang, L.; He, Y.; Yang, J.; et al. Shortening the ex vivo culture of CD19-specific CAR T-cells retains potent efficacy against acute lymphoblastic leukemia without CAR T-cell-related encephalopathy syndrome or severe cytokine release syndrome. Am. J. Hematol. 2019, 94, E322–E325.
  46. Tumaini, B.; Lee, D.W.; Lin, T.; Castiello, L.; Stroncek, D.F.; Mackall, C.; Wayne, A.; Sabatino, M. Simplified process for the production of anti–CD19-CAR–engineered T cells. Cytotherapy 2013, 15, 1406–1415.
  47. Zhang, C.; He, J.; Liu, L.; Wang, J.; Wang, S.; Liu, L.; Ge, J.; Gao, L.; Kong, P.; Liu, Y.; et al. Novel CD19 chimeric antigen receptor T cells manufactured next-day for acute lymphoblastic leukemia. Blood Cancer J. 2022, 12, 96.
  48. Hong, M.; Clubb, J.D.; Chen, Y.Y. Engineering CAR-T Cells for Next-Generation Cancer Therapy. Cancer Cell 2020, 38, 473–488.
  49. Li, D.H.; Whitmore, J.B.; Guo, W.; Ji, Y. Toxicity and Efficacy Probability Interval Design for Phase I Adoptive Cell Therapy Dose-Finding Clinical Trials. Clin. Cancer Res. 2017, 23, 13–20.
  50. Jacobson, C.A.; Chavez, J.C.; Sehgal, A.R.; William, B.M.; Munoz, J.; Salles, G.; Munshi, P.N.; Casulo, C.; Maloney, D.G.; de Vos, S.; et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): A single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022, 23, 91–103.
  51. Fowler, N.H.; Dickinson, M.; Dreyling, M.; Martinez-Lopez, J.; Kolstad, A.; Butler, J.; Ghosh, M.; Popplewell, L.; Chavez, J.C.; Bachy, E.; et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: The phase 2 ELARA trial. Nat. Med. 2022, 28, 325–332.
  52. Shah, B.D.; Ghobadi, A.; Oluwole, O.O.; Logan, A.C.; Boissel, N.; Cassaday, R.D.; Leguay, T.; Bishop, M.R.; Topp, M.S.; Tzachanis, D.; et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: Phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet 2021, 398, 491–502.
  53. Lee, D.W.; Kochenderfer, J.N.; Stetler-Stevenson, M.; Cui, Y.K.; Delbrook, C.; Feldman, S.A.; Fry, T.J.; Orentas, R.; Sabatino, M.; Shah, N.N.; et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. Lancet 2015, 385, 517–528.
  54. Pan, J.; Yang, J.F.; Deng, B.P.; Zhao, X.J.; Zhang, X.; Lin, Y.H.; Wu, Y.N.; Deng, Z.L.; Zhang, Y.L.; Liu, S.H.; et al. High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients. Leukemia 2017, 31, 2587–2593.
  55. Yan, Z.-X.; Li, L.; Wang, W.; OuYang, B.-S.; Cheng, S.; Wang, L.; Wu, W.; Xu, P.-P.; Muftuoglu, M.; Hao, M.; et al. Clinical Efficacy and Tumor Microenvironment Influence in a Dose-Escalation Study of Anti-CD19 Chimeric Antigen Receptor T Cells in Refractory B-Cell Non-Hodgkin’s Lymphoma. Clin. Cancer Res. 2019, 25, 6995–7003.
  56. Frey, N.V.; Shaw, P.A.; Hexner, E.O.; Pequignot, E.; Gill, S.; Luger, S.M.; Mangan, J.K.; Loren, A.W.; Perl, A.E.; Maude, S.L.; et al. Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults with Acute Lymphoblastic Leukemia. J. Clin. Oncol. 2020, 38, 415–422.
  57. Anagnostou, T.; Riaz, I.B.; Hashmi, S.K.; Murad, M.H.; Kenderian, S.S. Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: A systematic review and meta-analysis. Lancet Haematol. 2020, 7, e816–e826.
  58. Ma, Y.; Zhang, S.; Fang, H.; Yu, K.; Jiang, S. A phase I study of CAR-T bridging HSCT in patients with acute CD19+ relapse/refractory B-cell leukemia. Oncol. Lett. 2020, 20, 20.
  59. Li, Q.; Mu, J.; Yuan, J.; Yang, Z.; Wang, J.; Deng, Q. Low Level Donor Chimerism of CD19 CAR-T Cells Returned to Complete Donor Chimerism in Patients with Relapse After Allo-Hematopoietic Stem Cell Transplant. OncoTargets Ther. 2020, 13, 11471–11484.
  60. Wen, S.; Niu, Z.; Xing, L.; Wang, Y.; Li, H.; Kuang, N.; Luo, J.; Zhang, X.; Wang, F. CAR-T bridging to allo-HSCT as a treatment strategy for relapsed adult acute B-lymphoblastic leukemia: A case report. BMC Cancer 2018, 18, 1143.
  61. Hua, J.; Zhang, J.; Wu, X.; Zhou, L.; Bao, X.; Han, Y.; Miao, M.; Li, C.; Fu, Z.; Wu, D.; et al. Allogeneic Donor-Derived Anti-CD19 CAR T Cell Is a Promising Therapy for Relapsed/Refractory B-ALL After Allogeneic Hematopoietic Stem-Cell Transplantation. Clin. Lymphoma Myeloma Leuk. 2020, 20, 610–616.
  62. Hua, J.; Zhang, J.; Zhang, X.; Wu, X.; Zhou, L.; Bao, X.; Han, Y.; Miao, M.; Li, C.; Fu, C.; et al. Donor-derived anti-CD19 CAR T cells compared with donor lymphocyte infusion for recurrent B-ALL after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2021, 56, 1056–1064.
  63. González-Barca, E.; Boumendil, A.; Blaise, D.; Trněný, M.; Masszi, T.; Finel, H.; Michieli, M.; Bittenbring, J.T.; Gritti, G.; Snowden, J.A.; et al. Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2020, 55, 393–399.
  64. Styczynski, J.; Tallamy, B.; Waxman, I.; Van De Ven, C.; Milone, M.C.; Shaw, L.M.; Harrison, L.; Morris, E.; Satwani, P.; Bhatia, M.; et al. A pilot study of reduced toxicity conditioning with BU, fludarabine and alemtuzumab before the allogeneic hematopoietic SCT in children and adolescents. Bone Marrow Transplant. 2011, 46, 790–799.
  65. Zhang, Y.; Chen, H.; Song, Y.; Tan, X.; Zhao, Y.; Liu, X.; Li, Z.; Yang, F.; Jiang, M.; Gao, Z.; et al. Chimeric antigen receptor T-cell therapy as a bridge to haematopoietic stem cell transplantation for refractory/relapsed B-cell acute lymphoblastic leukemia. Br. J. Haematol. 2020, 189, 146–152.
  66. Jiang, H.; Li, C.; Yin, P.; Guo, T.; Liu, L.; Xia, L.; Wu, Y.; Zhou, F.; Ai, L.; Shi, W.; et al. Anti-CD19 chimeric antigen receptor-modified T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia: An open-label pragmatic clinical trial. Am. J. Hematol. 2019, 94, 1113–1122.
  67. Shi, X.; Yan, L.; Shang, J.; Kang, L.; Yan, Z.; Jin, S.; Zhu, M.; Chang, H.; Gong, F.; Zhou, J.; et al. Anti-CD19 and anti-BCMA CAR T cell therapy followed by lenalidomide maintenance after autologous stem-cell transplantation for high-risk newly diagnosed multiple myeloma. Am. J. Hematol. 2022, 97, 537–547.
  68. Otáhal, P.; Prukova, D.; Král, V.; Fabry, M.; Vočková, P.; Latečková, L.; Trneny, M.; Klener, P. Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells. OncoImmunology 2016, 5, e1115940.
  69. Works, M.; Soni, N.; Hauskins, C.; Sierra, C.; Baturevych, A.; Jones, J.C.; Curtis, W.; Carlson, P.; Johnstone, T.G.; Kugler, D.; et al. Anti–B-cell Maturation Antigen Chimeric Antigen Receptor T cell Function against Multiple Myeloma Is Enhanced in the Presence of Lenalidomide. Mol. Cancer Ther. 2019, 18, 2246–2257.
  70. Fraietta, J.A.; Beckwith, K.A.; Patel, P.R.; Ruella, M.; Zheng, Z.; Barrett, D.M.; Lacey, S.F.; Melenhorst, J.J.; McGettigan, S.E.; Cook, D.R.; et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 2016, 127, 1117–1127.
  71. Shanafelt, T.D.; Wang, X.V.; Kay, N.E.; Hanson, C.A.; O’Brien, S.; Barrientos, J.; Jelinek, D.F.; Braggio, E.; Leis, J.F.; Zhang, C.C.; et al. Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N. Engl. J. Med. 2019, 381, 432–443.
  72. Turtle, C.J.; Hay, K.; Hanafi, L.-A.; Li, D.; Cherian, S.; Chen, X.; Wood, B.; Lozanski, A.; Byrd, J.C.; Heimfeld, S.; et al. Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated with CD19-Specific Chimeric Antigen Receptor–Modified T Cells After Failure of Ibrutinib. J. Clin. Oncol. 2017, 35, 3010–3020.
  73. Ruella, M.; Kenderian, S.S.; Shestova, O.; Fraietta, J.A.; Qayyum, S.; Zhang, Q.; Maus, M.V.; Liu, X.; Nunez-Cruz, S.; Klichinsky, M.; et al. The Addition of the BTK Inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responses against Mantle Cell Lymphoma. Clin. Cancer Res. 2016, 22, 2684–2696.
  74. Gauthier, J.; Hirayama, A.V.; Purushe, J.; Hay, K.A.; Lymp, J.; Li, D.H.; Yeung, C.C.S.; Sheih, A.; Pender, B.S.; Hawkins, R.M.; et al. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure. Blood 2020, 135, 1650–1660.
  75. Gulati, P.; Rühl, J.; Kannan, A.; Pircher, M.; Schuberth, P.; Nytko, K.J.; Pruschy, M.N.; Sulser, S.; Haefner, M.D.; Jensen, S.M.; et al. Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice. Clin. Cancer Res. 2018, 24, 3981–3993.
  76. Gargett, T.; Yu, W.; Dotti, G.; Yvon, E.S.; Christo, S.N.; Hayball, J.D.; Lewis, I.D.; Brenner, M.K.; Brown, M.P. GD2-specific CAR T Cells Undergo Potent Activation and Deletion Following Antigen Encounter but can be Protected from Activation-induced Cell Death by PD-1 Blockade. Mol. Ther. 2016, 24, 1135–1149.
  77. Bansal, R.; Reshef, R. Revving the CAR—Combination strategies to enhance CAR T cell effectiveness. Blood Rev. 2021, 45, 100695.
  78. Chou, C.K.; Turtle, C.J. Insight into mechanisms associated with cytokine release syndrome and neurotoxicity after CD19 CAR-T cell immunotherapy. Bone Marrow Transplant. 2019, 54, 780–784.
  79. Sesques, P.; Ferrant, E.; Safar, V.; Wallet, F.; Tordo, J.; Dhomps, A.; Karlin, L.; Brisou, G.; Vercasson, M.; Msc, C.H.; et al. Commercial anti-CD19 CAR T cell therapy for patients with relapsed/refractory aggressive B cell lymphoma in a European center. Am. J. Hematol. 2020, 95, 1324–1333.
  80. Goto, H.; Makita, S.; Kato, K.; Tokushige, K.; Fujita, T.; Akashi, K.; Izutsu, K.; Teshima, T. Efficacy and safety of tisagenlecleucel in Japanese adult patients with relapsed/refractory diffuse large B-cell lymphoma. Int. J. Clin. Oncol. 2020, 25, 1736–1743.
  81. Lee, D.W.; Santomasso, B.D.; Locke, F.L.; Ghobadi, A.; Turtle, C.J.; Brudno, J.N.; Maus, M.V.; Park, J.H.; Mead, E.; Pavletic, S.; et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol. Blood Marrow Transplant. 2019, 25, 625–638.
  82. Jiang, H.; Liu, L.; Guo, T.; Wu, Y.; Ai, L.; Deng, J.; Dong, J.; Mei, H.; Hu, Y. Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy. Ann. Hematol. 2019, 98, 1721–1732.
  83. Hu, Y.; Wu, Z.; Luo, Y.; Shi, J.; Yu, J.; Pu, C.; Liang, Z.; Wei, G.; Cui, Q.; Sun, J.; et al. Potent Anti-leukemia Activities of Chimeric Antigen Receptor–Modified T Cells against CD19 in Chinese Patients with Relapsed/Refractory Acute Lymphocytic Leukemia. Clin. Cancer Res. 2017, 23, 3297–3306.
  84. Ma, F.; Ho, J.; Du, H.; Xuan, F.; Wu, X.; Wang, Q.; Wang, L.; Liu, Y.; Ba, M.; Wang, Y.; et al. Evidence of long-lasting anti-CD19 activity of engrafted CD19 chimeric antigen receptor–modified T cells in a phase I study targeting pediatrics with acute lymphoblastic leukemia. Hematol. Oncol. 2019, 37, 601–608.
  85. Park, J.H.; Romero, F.A.; Taur, Y.; Sadelain, M.; Brentjens, R.J.; Hohl, T.M.; Seo, S.K. Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated with Chimeric Antigen Receptor T Cells. Clin. Infect. Dis. 2018, 67, 533–540.
  86. Magnani, C.F.; Gaipa, G.; Lussana, F.; Belotti, D.; Gritti, G.; Napolitano, S.; Matera, G.; Cabiati, B.; Buracchi, C.; Borleri, G.; et al. Sleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities. J. Clin. Investig. 2020, 130, 6021–6033.
  87. Hu, Y.; Sun, J.; Wu, Z.; Yu, J.; Cui, Q.; Pu, C.; Liang, B.; Luo, Y.; Shi, J.; Jin, A.; et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J. Hematol. Oncol. 2016, 9, 70.
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Subjects: Immunology
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Qianzhen Liu
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Zengping Liu
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Rongxue Wan
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Wenhua Huang
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