Next Article in Journal
Mutation Profiles of Ovarian Seromucinous Borderline Tumors in Japanese Patients
Next Article in Special Issue
Effect of Lenalidomide Maintenance in Chronic Lymphocytic Leukemia: A Meta-Analysis and Trial-Sequential Analysis
Previous Article in Journal
Treatment Outcomes for Primary Hepatic Angiosarcoma: National Cancer Database Analysis 2004–2014
Previous Article in Special Issue
Invasive Fungal Disease in Patients with Chronic Lymphocytic Leukemia in Japan: A Retrospective Database Study
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Current Oncology
Volume 29
Issue 5
10.3390/curroncol29050293
curroncol-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings

by
Zeljko Todorovic
1,
Dusan Todorovic
2,
Vladimir Markovic
3,
Nevena Ladjevac
3,
Natasa Zdravkovic
1,
Predrag Djurdjevic
1,
Nebojsa Arsenijevic
3,
Marija Milovanovic
3,
Aleksandar Arsenijevic
3,* and
Jelena Milovanovic
3,4,*
1
Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
2
Department of Ophthalmology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
3
Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
4
Department of Histology and Embryology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
*
Authors to whom correspondence should be addressed.
Curr. Oncol. 2022, 29(5), 3647-3657; https://0-doi-org.brum.beds.ac.uk/10.3390/curroncol29050293
Submission received: 31 March 2022 / Revised: 6 May 2022 / Accepted: 10 May 2022 / Published: 18 May 2022
(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: Therapy and Outcome)
Browse Figures
Review Reports Versions Notes

Abstract

:
Chimeric antigen receptor T (CAR T) cell therapy achieved remarkable success in B-cell leukemia and lymphoma which led to its incorporation in treatment protocols for these diseases. CAR T cell therapy for chronic lymphocytic leukemia (CLL) patients showed less success compared to other malignant tumors. In this review, we discuss the published results regarding CAR T cell therapy of CLL, possible mechanisms of failures and expected developments.

1. Introduction

Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disease characterized by malignant transformation of mature antigen-experienced B lymphocyte and accumulation of monoclonal malignant B cells in peripheral blood, bone marrow, lymph nodes, spleen [1]. CLL is the most common leukemia in Western countries. The incidence of CLL in North America and Eastern Europe is 4.7 per 100,000 people per year, while the CLL incidence is higher than 35 in the population over 85 years of age [2]. Clinical management of CLL is challenging and depends on patients ages, comorbidities and biological features of CLL cells such as immunoglobulin heavy chain gene mutation, 17p deletion, TP53 mutation and, as recent research showed, number and type of CLL tumor clones in patient [3,4]. Treatment option varies from watch and wait approach in the asymptomatic early-stage CLL to chemo-immunotherapy and novel targeted therapies, such as Bruton’s tyrosine kinase inhibitors and inhibitors of Bcl-2 family proteins, for symptomatic and advanced disease [3]. However, despite the expansion of novel therapeutic approaches, CLL is still mostly an incurable disease.
In the last decades, cell-based immunotherapy has emerged as a novel treatment for malignant diseases. Cell based immunotherapy relies on using immune cells obtained from patients, raised in vitro, and genetically modified to increase their ability to find and kill tumor cells (Figure 1). Various T cell based treatments of malignant disorders have been developed, including tumor-infiltrating lymphocytes, T cell receptor (TCR)-modified T cells and chimeric antigen receptor T (CAR T) cells [5]. Therapy of malignancies with CAR T cells is accompanied with better and durable clinical responses compared to the treatment with tumor-infiltrating lymphocytes and TCR modified T cells [6,7]. CAR T cells are T lymphocytes with engineered synthetic receptors made to recognize and destroy the cells expressing the target antigen. CARs are artificially made proteins consisting of the single-chain variable fragment of an antibody (ScFv) that recognizes tumor antigen and the T-cell activation domain [8].
According to the T-cell activation domain, which is part of the hybrid receptor, CAR T cells are classified into four generations. The first generation of CAR T cells contains only CD3 zeta domain in fusion with receptors specific for a specified tumor antigen. These first generation CAR T cells showed limited clinical effects. Hybrid receptors of the second generation of CAR T cells in addition to CD3 contain one of the additional costimulatory molecules such as CD28, ICOS, CD-137/4-1BB or OX40, while coupling two or more costimulatory molecules into the receptor sequence led to the creation of the third generation CAR T cells [8]. The fourth CAR T cells’ generation is engineered with the inducible expression of cytokines that potentiate antitumor immunity and a self-withdrawal mechanism, with a suicide gene that can be activated after the achievement of the anti-tumor effect whose product rapidly withdraws CAR T cells [9]. The good clinical responses to CAR T cell therapy in some malignancies are frequently accompanied by several obstacles (Figure 2). Since most of the patients are highly medicated resulting in a low number and quality of T cells, manufacturing and expanding autologous CAR T cells from such patients can be difficult [10]. The manufacture of allogenic CAR T cells from healthy donors is promising but allogenic CAR T cells can cause a serious graft-versus-host disease (GvHD) [11]. However, the fact that allogenic NK cells have reduced the risk for induction of GvDH led to the construction of CAR Natural Killer (NK) cells. CAR constructs in CAR NK cells play the role in the NK cell activation and also improve the efficiency of innate ability of NK cells to kill malignant cells [12].
Although the use of cellular immunotherapy in many hematologic malignancies is already approved outside clinical trials [13,14,15,16], the benefit of CAR T and CAR NK cells in CLL treatment is still not clear. In this review, we summarize existing data regarding results of CAR T and CAR NK therapy of CLL, associated difficulties, and potential strategies to overcome them.

2. CAR-T as Promising CLL Therapy

In the early stage of development of CAR-T cells for B cell leukemia, CD19 has become attractive target antigen because it is expressed on the most B-cell malignancies [17]. Results of preclinical studies indicate better in vivo expansion and far greater effectiveness of the second generation of CAR-T cells, with CARs constructed to target CD19 coupled with CD137 signaling or CD28 costimulatory domain, in comparison to the first generation of CAR T cells [18,19]. The first use of CAR T cells in the therapy of CLL was reported in 2011 [20]. Porter et al. reported the treatment of two patients with refractory/relapsed CLL with reinfusion of approximately 1.5 × 105 autologous CAR T cells per kilogram of body weight that expanded to a level that was more than 1000 times higher than the initial engraftment level in vivo [20]. After treatment, patients achieved complete remission (CR) [20]. Further, it has been recently reported that both patients sustained remission for more than ten years after the therapy and that CAR T cells are still detectable in their blood [21]. These long-persisting CAR T cells are CD4+ cells with cytotoxic capabilities, but also an expanded population of gamma delta CAR T cells has been found in one patient concomitant with CD8+ CAR T cells during the initial response phase [21].
So far, over 100 CLL patients have been treated with anti-CD19 CAR-T cells (Table 1). The majority of studies included relapsed patients or patients refractory to conventional therapy regimens, except for one which enrolled patients with only a partial response (PR) to the first line therapy [22]. Overall response rate (ORR; sum of CR and PR) varies between studies. Brentjens et al. suggested that chemotherapy that induced the depletion of lymphocytes prior to CAR T infusion enhanced the efficacy of CAR T cells [23]. In line with this are the results of the studies reporting the lowest ORR in patients without lymphodepletion therapy prior to CAR T infusion [23,24,25,26]. It is considered that lymphodepletion chemotherapy reduced tumor mass but also the number of regulatory cells, which may attenuate the antitumor activity of the infused CAR T cells.
Another factor that could influence response to therapy is a number of CLL T applied to patients. One recent study has shown that a higher dose of anti-CD19 CAR T cells (5.0 × 108 vs. 5.0 × 107) produces higher rates of ORR (55% vs. 31%) and CR (36% vs. 8%) [31].

3. Resistance to CAR-T Therapy in CLL and Attempts to Overcome It

The average CR in the studies listed in Table 1 is around 30%, ranging from 0% to 67%. Nevertheless, CAR T efficiency in CLL is low compared to other B cell malignancies such as acute B-lymphoblastic leukemia [13] and B-cell lymphoma [14,15,16]. Considering that only every third CLL patient achieves CR, it is crucial to find reasons for low efficiency of CAR T cell therapy in CLL. One explanation lies in T cell dysfunction in CLL patients. Defective immunological synapse formation of both CD4+ and CD8+ T cells with antigen presenting cells, including CLL cells, has been reported in CLL. Incomplete immune synapse formation has been linked to altered gene expression in T cells including the genes coding the molecules involved in actin polymerization, cytoskeletal organization and vesicle trafficking [36]. However, the same effect has been observed on allogenic T cells derived from healthy donors after contact with CLL cells [37]. It has been shown that circulating extracellular vesicles originating from CLL cells, which are abundant in CLL patients, induce exhaustion and attenuate CAR T cell function [38]. Defective immune synapse formation of CLL and both autologous and allogeneic T cells could be the consequence of the higher expression of B7- and TNF- receptor families of inhibitory transmembrane molecules [39]. Treatment of autologous T cells with the immunomodulating drug lenalidomide resulted in improved synapse formation [13,40], suggesting the therapeutic potential of a CAR T and lenalidomide combination strategy in CLL. The functional condition of T lymphocytes in CLL is described as exhaustion, due to the persistent antigenic stimulation with tumor antigens and consequent loss of their effector functions [41]. The tumor microenvironment in CLL is composed of tumor associated macrophages, myeloid derived suppressor cells, cancer associated fibroblasts, and nurse like cells (M2 macrophages) which create immunosuppressive environment and support maintenance of CLL cells [42]. However, nurse like cells and cancer associated fibroblasts probably contribute to CAR T cell failure in CLL [43,44]. These exhausted T lymphocytes in CLL patients highly express several transmembrane inhibitory receptors, including CTLA-4, PD-1 and LAG-3 [45,46]. It has also been reported that CLL patients with progressive disease have higher numbers of PD-1 and CTLA-4 expressing CD4+ and CD8+ lymphocytes compared to healthy controls [47,48]. These findings suggested that immune checkpoint inhibitors could have an important role in CLL treatment. Interestingly, it has been found that treatment with Bruton tyrosine kinase inhibitor (BTK), ibrutinib, decreases expression of the PD-1 on T cells and significantly increases expansion of CAR T cells in vivo [49]. In correlation with these results Gill et al. showed ORR in 71% and CR in 43% of patients who had not achieved CR despite 6 months of prior ibrutinib therapy and received anti-CD19 CAR T cells following standard lymphodepletion [32]. Gauthier et al. reported similar results in 19 CLL patients treated with anti-CD19 CAR T cells after ibrutinib failure [50]. In this study, patients had been treated with ibrutinib at least two weeks prior to leukapheresis and continued with ibrutinib for three and even more months after CAR T cell infusion. Overall response rate was 83% in CLL patients who received ibrutinib prior to CAR T cells therapy compared to 56% in patients who received CAR T cells without ibrutinib. Eighty-five percent of patients in the ibrutinib group achieved CR in bone marrow, compared to 50% in the group without ibrutinib [50].
Although CD19 is a promising CAR T cells target, one likely mechanism of resistance to CAR T cells therapy is the loss of the target antigen [51]. Mutations of the CD19 coding gene and alternative splicing of CD19 mRNA [52,53] are some of the known mechanisms that contribute to antigen escape and relapse in acute lymphoblast leukemia, and possibly can contribute to a poor response to CAR T therapy in CLL. Several potential target antigens, besides CD19, have been investigated. These include anti-CD20 CAR T cells, tested on non-Hodgkin lymphomas with promising results [54]. Three patients received the third generation anti-CD20 CAR T cells, two patients without evaluable disease remained progression-free for 12 and 24 months and the third patient had an objective partial remission and relapsed at 12 months after infusions [54]. One ongoing study using anti-CD20 CAR T cells on relapsed/refractory B-cell malignancy including CLL (NCT03277729) is still in progress. Due to long-term B cell aplasia and hypogammaglobulinemia following anti-CD19 CAR T therapy, some studies focused on antigens that are highly expressed on malignant B lymphocytes but with low or without expression on normal B cells. Considering that CLL cells are monoclonal, they express only one type of light chain, κ or λ [55]. Different clones of normal B lymphocytes express monoclonal immunoglobulins with either κ or λ light chains implicating that CAR T cells targeting one type of light chain could partially spare normal B cells [10]. Results of one study that monitored the use of anti-κ light chain CAR T cells were modest, probably due to the lack of lymphodepletion regimen before CAR T therapy [31]. One possible target antigen highly expressed on CLL cells but without expression in normal mature B cells is a receptor tyrosine kinase-like orphan receptor 1 (ROR1) [56]. There are promising in vitro data [10] and one ongoing trial for the evaluation of anti-ROR1 CAR T therapy in ROR1+ malignancy including CLL patients (NCT02706392). Another selective target antigen for malignant B cells which can be used in CAR T therapy is the Fc receptor for immunoglobulin M (FcμR). FcμR is highly expressed by CLL cells and only minor levels are detected in healthy B cells. Anti-FcμR CAR-T cells from CLL patients purged their autologous CLL cells in vitro without reducing the number of healthy B cells [57]. These novel approaches to improve CAR T cell therapy in CLL are summarized in Figure 3.

4. Allogenic CAR T or CAR NK Cells in CLL Therapy?

Autologous CAR T cells therapy for CLL is promising, but there are several difficulties. Major problems are inability to collect enough viable T cells from CLL patients due to chemotherapy pretreatment and T cell dysfunction seen in CLL patient [15,39]. Another problem is long manufacturing time and delayed therapy. Despite promising results, CAR T cells therapy is linked to serious side effects such as cytokine-release syndrome grade 3 or 4 as a consequence of massive T cells activation and secretion of pro-inflammatory cytokines in large amounts. Immune effector cell associated neurotoxicity syndrome (ICANS) is also a potentially serious side effect of CAR T cells therapy [58].
Allogenic CAR T cells as a premanufactured product could be solution for previously listed problems. These cells are derived from a healthy donor’s lymphocytes. Using healthy donors provides high numbers of cells and peripheral blood mononuclear cells are fit, as donors, in contrast to cancer patients, who do not receive chemo- or radiotherapy [59]. Other cell sources for allogeneic CAR T cell development are umbilical cord blood-derived T cells. GVHD frequency and intensity can be decreased when using T cells obtained from umbilical cord blood, as these have reduced reactivity due to lower activation of the NF-κB pathway, resulting in decreased production of several pro-inflammatory cytokines [60,61]. Major advantages of allogenic CAR T cells are high antitumor potency and the ability to apply them immediately, without long manufacturing time. So far, allogenic CAR T cells have been used only in patients with B-cell malignancy, including five patients with CLL, who relapsed after allogenic stem cell transplant. Only one of these CLL patients achieved CR [25]. There are some trials using allogenic CAR T cells in acute lymphoblastic leukemia. UCART19 is a universal anti-CD19 CAR T-cell product that has been generated by simultaneously knocking out TCR and CD52, with the introduction of a CD19 directed CAR. Deletion of TCR and CD52 was performed to reduce the risk of UCART19 rejection [62]. The ORR was 67% in a phase 1 clinical trial of UCART19 in 21 patients with relapsed/refractory B-cell acute lymphoblastic leukemia [63]. UCART19 showed great results in children with relapsed/refractory acute lymphoblastic leukemia; two infants achieved complete molecular remission after lymphodepleting chemotherapy followed by a single-dose infusion of UCART19 cells [64]. Similarly, genetically modified allogenic CAR T cell product, PBCAR0191, achieved a CR rate of 71% in patients with relapsed/refractory diffuse large B cell lymphoma who received enhanced lymphodepletion prior to CAR T therapy [65]. Hence, allogenic CAR T cells from healthy donors could be a promising therapeutic strategy, although there are some concerns. Allogenic T cells could be activated by a recipient’s human leukocyte antigens (HLA) and in the state of the recipient’s immunosuppression can cause serious GvHD [66].
Since Natural Killer (NK) cells do not participate in immune rejection reactions, a new kind of allogenic CAR cells has been constructed—CAR NK cells [12]. These cells have a natural ability to kill malignant and infected cells without prior activation by antigen presenting cells and HLA restriction [67]. Problems with NK cells lie in poor expansion, difficulties in viral transduction and a shorter lifespan than T lymphocytes [68], but some authors achieved impressive results by co-culturing NK cells with modified feeder cells or activation beads [69,70] (Table 2).
CAR used for engineering CAR NK cells consists of an antigen-recognition domain and activation domains, similar to CAR T cells. There are four CAR NK generations, depending on CAR construction. The first generation of CAR NK cells contains only one activation domain, CD3 zeta, DAP10, or DAP12. The second generation includes one co-stimulatory domain (CD28, 4-1BB or 2B4) in tandem with CD3 zeta, or DAP10, or DAP12, while the third generation of CAR NK contains two co-stimulatory domains in the same tandem. The fourth CAR NK cells generation has been engineered to produce cytokine, the same as the fourth CAR T cells generation [67].
NK cells can be obtained from different sources—adult blood, cord blood, human induced pluripotent stem cells (hiPSCs) or human embryonic stem cells (hESCs) [71,72]. Some studies demonstrated higher activity and better expansion in vivo of cord blood CAR NK cells in comparison to CAR NK derived from adult blood [71,73]. These cord blood CART NK cells are currently being used in several clinical trials for the treatment of relapse/refractory CLL patients among other hematology malignancies (NCT03056339, NCT04796675).
In the last few years, hiPSCs have become the most promising source of NK cells. HiPSC-NK cells can be manufactured from standardized cells resulting in a homogeneous NK cell population [67]. These cells are perfect candidates for CAR NK manufacturing. IPSC-derived CAR NK cells known as FT596 have been used in a phase I clinical trial (NCT04245722) along with anti-CD20 monoclonal antibodies for relapsed/refractory B cell lymphoma. In the second and third single-dose cohorts of the monotherapy and combination arms comprising of a total of 14 patients, 10 of 14 patients (71%) achieved an objective response, including seven patients (50%) that achieved a complete response.
Nowadays, indications for CAR NK cells therapy in CLL remain an open question. CAR NK cells will probably be a good choice for patients without enough viable T cells for CAR T therapy and patients with aggressive disease who need early treatment. Additionally, for those patients that have relapsed after CAR T therapy or patients who develop high toxicity after CAR T infusion CAR NK, therapy may be a wise choice.

5. Conclusions and Future Perspective

CAR T cell therapy is promising for relapse/refractory CLL patients. Complete and durable remission of CLL is possible in patients treated with CAR T cells but further investigations are necessary to understand and possibly predict how patient specific factors influence the outcome of this treatment. It is also crucial to find ways to modulate recipients’ intrinsic immune milieu and enhance the efficiency of CAR T therapy. Concurrent use of ibrutinib with CAR T cells is promising. Despite high efficiency of CAR T therapy, there are major concerns related to debatable viability of CAR T cells derived from CLL patient and prolonged manufacturing time. CAR NK cells or allogeneic CAR T-cells with knocked out key genes associated with GvDH and immune rejection are maybe the answer for these problems. CAR NK can be derived from healthy donors and used as off-the-shelf product without prolonged manufacturing time.

Author Contributions

Conceptualization, Z.T., M.M. and J.M.; methodology, D.T., V.M. and N.L.; writing-original draft preparation, Z.T., M.M. and J.M.; writing-review and editing, N.Z., P.D., V.M. and N.L.; visualization, D.T. and A.A.; supervision, N.A. and A.A. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by grants from the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant no. ON175069), the Serbian bilateral project with PR China (06/2018), and The Faculty of Medical Sciences, University of Kragujevac (JP 17/19).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Hodgson, K.; Ferrer, G.; Montserrat, E.; Moreno, C. Chronic lymphocytic leukemia and autoimmunity: A systematic review. Haematologica 2011, 96, 752–761. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Noone, A.M.; Howlader, N.; Krapcho, M.; Miller, D.; Brest, A.; Yu, M.; Ruhl, J.; Tatalovich, Z.; Mariotto, A.; Lewis, D.R.; et al. (Eds.) SEER Cancer Statistics Review, 1975–2015; Based on November 2017 SEER Data Submission, Posted to the SEERWeb Site; National Cancer Institute: Bethesda, MD, USA, 2018. [Google Scholar]
  3. Eichhorst, B.; Robak, T.; Montserrat, E.; Ghia, P.; Niemann, C.U.; Kater, A.P.; Gregor, M.; Cymbalista, F.; Buske, C.; Hillmen, P.; et al. ESMO Guidelines Committee. Electronic address: [email protected]. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2021, 32, 23–33. [Google Scholar] [CrossRef] [PubMed]
  4. Mimmi, S.; Maisano, D.; Nisticò, N.; Vecchio, E.; Chiurazzi, F.; Ferrara, K.; Iannalfo, M.; D’Ambrosio, A.; Fiume, G.; Iaccino, E.; et al. Detection of chronic lymphocytic leukemia subpopulations in peripheral blood by phage ligands of tumor immunoglobulin B cell receptors. Leukemia 2021, 35, 610–614. [Google Scholar] [CrossRef] [PubMed]
  5. Barrett, D.M.; Grupp, S.A.; June, C.H. Chimeric antigen receptor-and TCR-modified T cells enter main street and wall street. J. Immunol. 2015, 195, 755–761. [Google Scholar] [CrossRef]
  6. Fujiwara, H. Adoptive immunotherapy for hematological malignancies using T cells gene-modified to express tumor antigen-specific receptors. Pharmaceuticals 2014, 7, 1049–1068. [Google Scholar] [CrossRef]
  7. Chmielewski, M.; Hombach, A.A.; Abken, H. Antigen-specific T-cell activation independently of the MHC: Chimeric antigen receptor-redirected T cells. Front. Immunol. 2013, 4, 371. [Google Scholar] [CrossRef] [Green Version]
  8. Srivastava, S.; Riddell, S.R. Engineering CAR-T cells: Design concepts. Trends Immunol. 2015, 36, 494–502. [Google Scholar] [CrossRef] [Green Version]
  9. Chmielewski, M.; Abken, H. TRUCKs: The fourth generation of CARs. Expert Opin. Biol. Ther. 2015, 15, 1145–1154. [Google Scholar] [CrossRef]
  10. Mancikova, V.; Smida, M. Current State of CAR T-Cell Therapy in Chronic Lymphocytic Leukemia. Int. J. Mol. Sci. 2021, 22, 5536. [Google Scholar] [CrossRef]
  11. Frey, N.V.; Porter, D.L. Graft-versus-host disease after donor leukocyte infusions: Presentation and management. Best Pract. Res. Clin. Haematol. 2008, 21, 205–222. [Google Scholar] [CrossRef] [Green Version]
  12. Corral Sánchez, M.D.; Fernández Casanova, L.; Pérez-Martínez, A. Beyond CAR-T cells: Natural killer cells immunotherapy. Med. Clin. 2020, 154, 134–141. [Google Scholar] [CrossRef]
  13. Park, J.H.; Rivière, I.; Gonen, M.; Wang, X.; Sénéchal, B.; Curran, K.J.; Sauter, C.; Wang, Y.; Santomasso, B.; Mead, E.; et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 2018, 378, 449–459. [Google Scholar] [CrossRef]
  14. 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. [Google Scholar] [CrossRef]
  15. 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. [Google Scholar] [CrossRef]
  16. Wang, M.; Munoz, J.; Goy, A.; Locke, F.L.; Jacobson, C.A.; Hill, B.T.; Timmerman, J.M.; Holmes, H.; Jaglowski, S.; Flinn, I.W.; et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 2020, 382, 1331–1342. [Google Scholar] [CrossRef]
  17. Scheuermann, R.H.; Racila, E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk Lymphoma 1995, 18, 385–397. [Google Scholar] [CrossRef]
  18. Carpenito, C.; Milone, M.C.; Hassan, R.; Simonet, J.C.; Lakhal, M.; Suhoski, M.M.; Varela-Rohena, A.; Haines, K.M.; Heitjan, D.F.; Albelda, S.M.; et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc. Natl. Acad. Sci. USA 2009, 106, 3360–3365. [Google Scholar] [CrossRef] [Green Version]
  19. Milone, M.C.; Fish, J.D.; Carpenito, C.; Carroll, R.G.; Binder, G.K.; Teachey, D.; Samanta, M.; Lakhal, M.; Gloss, B.; Campana, D.; et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol. Ther. 2009, 17, 1453–1464. [Google Scholar] [CrossRef]
  20. Porter, D.L.; Levine, B.L.; Kalos, M.; Carroll, R.G.; Binder, G.K.; Teachey, D.; Samanta, M.; Lakhal, M.; Gloss, B. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 2011, 365, 725–733. [Google Scholar] [CrossRef] [Green Version]
  21. 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. [Google Scholar] [CrossRef]
  22. 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. [Google Scholar] [CrossRef] [Green Version]
  23. Brentjens, R.J.; Rivière, I.; Park, J.H.; Wang, X.; Wang, Y.; Purdon, T.J.; Hsu, M.; Devlin, S.M.; Halton, E.; Lamanna, N.; et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 2011, 118, 4817–4828. [Google Scholar] [CrossRef]
  24. Cruz, C.R.Y.; Micklethwaite, K.P.; Savoldo, B.; Ramos, C.A.; Lam, S.; Ku, S.; Diouf, O.; Liu, E.; Barrett, A.J.; Ito, S.; et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: A phase 1 study. Blood 2013, 122, 2965–2973. [Google Scholar] [CrossRef]
  25. Brudno, J.N.; Somerville, R.P.; Shi, V.; Rose, J.J.; Halverson, D.C.; Fowler, D.H.; Gea-Banacloche, J.C.; Pavletic, S.Z.; Hickstein, D.D.; Lu, T.; et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J. Clin. Oncol. 2016, 34, 1112–1121. [Google Scholar] [CrossRef] [Green Version]
  26. Ramos, C.A.; Savoldo, B.; Torrano, V.; Ballard, B.; Zhang, H.; Dakhova, O.; Liu, E.; Carrum, G.; Kamble, R.T.; Gee, A.P.; et al. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J. Clin. Investig. 2016, 126, 2588–2596. [Google Scholar] [CrossRef] [Green Version]
  27. Kalos, M.; Levine, B.L.; Porter, D.L.; Katz, S.; Grupp, S.A.; Bagg, A.; June, C.H. T Cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 2011, 3, 95ra73. [Google Scholar] [CrossRef] [Green Version]
  28. Kochenderfer, J.N.; Dudley, M.E.; Feldman, S.A.; Wilson, W.H.; Spaner, D.E.; Maric, I.; Stetler-Stevenson, M.; Phan, G.Q.; Hughes, M.S.; Sherry, R.M.; et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor–transduced T cells. Blood 2012, 119, 2709–2720. [Google Scholar] [CrossRef]
  29. Kochenderfer, J.N.; Dudley, M.E.; Kassim, S.H.; Somerville, R.P.; Carpenter, R.O.; Stetler-Stevenson, M.; Yang, J.C.; Phan, G.Q.; Hughes, M.S.; Sherry, R.M.; et al. Chemotherapy-refractory diffuse large B-Cell lymphoma and indolent b-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 2015, 33, 540–549. [Google Scholar] [CrossRef] [Green Version]
  30. Porter, D.L.; Hwang, W.T.; Frey, N.V.; Lacey, S.F.; Shaw, P.A.; Loren, A.W.; Bagg, A.; Marcucci, K.T.; Shen, A.; Gonzalez, V.; et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 2015, 7, 303ra139. [Google Scholar] [CrossRef] [Green Version]
  31. Frey, N.V.; Gill, S.; Hexner, E.O.; Schuster, S.; Nasta, S.; Loren, A.; Svoboda, J.; Stadtmauer, E.; Landsburg, D.J.; Mato, A.; et al. Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified T cells in relapsed chronic lymphocytic leukemia. J. Clin. Oncol. 2020, 38, 2862–2871. [Google Scholar] [CrossRef]
  32. Gill, M.S.I.; Vides, B.V.; Frey, N.V.; Metzger, S.; O’Brien, M.; Hexner, E.; Mato, A.R.; Lacey, S.F.; Melenhorst, J.; Pequignot, E.; et al. Prospective clinical trial of anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia shows a high response rate. Blood 2018, 132, 298. [Google Scholar] [CrossRef]
  33. Siddiqi, T.; Soumerai, J.D.; Wierda, W.G.; Dubovsky, J.A.; Gillenwater, H.H.; Gong, L.; Mitchell, A.; Thorpe, J.; Yang, L.; Dorritie, K.A. Rapid MRD-negative responses in patients with relapsed/refractory CLL Treated with Liso-Cel, a CD19-directed CAR T-cell product: Preliminary results from transcend CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib. Blood 2018, 132, 300. [Google Scholar]
  34. 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.; et al. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure. Blood 2020, 135, 1650–1660. [Google Scholar] [CrossRef] [PubMed]
  35. 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. [Google Scholar] [CrossRef]
  36. Riches, J.C.; Ramsay, A.G.; Gribben, J.G. Immune dysfunction in chronic lymphocytic leukemia: The role for immunotherapy. Curr. Pharm. Des. 2012, 18, 3389–3398. [Google Scholar] [CrossRef]
  37. Ramsay, A.G.; Johnson, A.J.; Lee, A.M.; Gorgün, G.; Le Dieu, R.; Blum, W.; Byrd, J.C.; Gribben, J.G. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J. Clin. Investig. 2008, 118, 427–2437. [Google Scholar] [CrossRef]
  38. Cox, M.J.; Lucien, F.; Sakemura, R.; Boysen, J.C.; Kim, Y.; Horvei, P.; Manriquez Roman, C.; Hansen, M.J.; Tapper, E.E.; Siegler, E.L.; et al. Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia. Mol. Ther. 2021, 29, 1529–1540. [Google Scholar] [CrossRef]
  39. Ramsay, A.G.; Clear, A.J.; Fatah, R.; Gribben, J.G. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: Establishing a reversible immune evasion mechanism in human cancer. Blood 2012, 120, 1412–1421. [Google Scholar] [CrossRef]
  40. Tettamanti, S.; Rotiroti, M.C.; Giordano Attianese, G.; Arcangeli, S.; Zhang, R.; Banerjee, P.; Galletti, G.; McManus, S.; Mazza, M.; Nicolini, F.; et al. Lenalidomide enhances CD23.CAR T cell therapy in chronic lymphocytic leukemia. Leuk Lymphoma 2022, 8, 1–14. [Google Scholar] [CrossRef]
  41. Zenz, T. Exhausting T cells in CLL. Blood 2013, 121, 1485–1486. [Google Scholar] [CrossRef]
  42. Can, I.; Cox, M.J.; Siegler, E.L.; Sakemura, R.; Kenderian, S.S. Challenges of chimeric antigen receptor T-cell therapy in chronic lymphocytic leukemia: Lessons learned. Exp. Hematol. 2022, 108, 1–7. [Google Scholar] [CrossRef]
  43. Sakemura, R.; Cox, M.J.; Hansen, M.J.; Cox, M.J.; Larson, D.P.; Hansen, M.J.; Manriquez Roman, C.; Schick, K.J.; Can, I. Targeting cancer associated fibroblasts in the bone marrow prevents resistance to chimeric antigen receptor T cell therapy in multiple myeloma. Blood 2019, 134 (Suppl. 1), 865. [Google Scholar] [CrossRef]
  44. Burger, J.A.; Tsukada, N.; Burger, M.; Zvaifler, N.J.; Dell’Aquila, M.; Kipps, T.J. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell−derived factor-1. Blood 2000, 96, 2655–2663. [Google Scholar] [CrossRef]
  45. Shapiro, M.; Herishanu, Y.; Katz, B.Z.; Dezorella, N.; Sun, C.; Kay, S.; Polliack, A.; Avivi, I.; Wiestner, A.; Perry, C. Lymphocyte activation gene 3: A novel therapeutic target in chronic lymphocytic leukemia. Haematologica 2017, 102, 874–882. [Google Scholar] [CrossRef] [Green Version]
  46. Vlachonikola, E.; Stamatopoulos, K.; Chatzidimitriou, A. T cells in chronic lymphocytic leukemia: A two-edged sword. Front. Immunol. 2021, 11, 612244. [Google Scholar] [CrossRef]
  47. Buchbinder, E.I.; Desai, A. CTLA-4 and PD-1 pathways: Similarities, differences, and implications of their inhibition. Am. J. Clin. Oncol. 2016, 39, 98–106. [Google Scholar] [CrossRef] [Green Version]
  48. Palma, M.; Gentilcore, G.; Heimersson, K.; Mozaffari, F.; Näsman-Glaser, B.; Young, E.; Rosenquist, R.; Hansson, L.; Österborg, A.; Mellstedt, H. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers. Haematologica 2017, 102, 562–572. [Google Scholar] [CrossRef] [Green Version]
  49. 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. [Google Scholar] [CrossRef] [Green Version]
  50. Gauthier, J. Comparison of efficacy and toxicity of CD19-specific chimeric antigen receptor T cells alone or in combination with ibrutinib for relapsed and/or refractory CLL. Blood 2018, 132, 299. [Google Scholar] [CrossRef]
  51. Shalabi, H.; Kraft, I.L.; Wang, H.W.; Yuan, C.M.; Yates, B.; Delbrook, C.; Zimbelman, J.D.; Giller, R.; Stetler-Stevenson, M.; Jaffe, E.S.; et al. Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma. Haematologica 2018, 103, e215–e218. [Google Scholar] [CrossRef]
  52. Sotillo, E.; Barrett, D.M.; Black, K.L.; Bagashev, A.; Oldridge, D.; Wu, G.; Sussman, R.; Lanauze, C.; Ruella, M.; Gazzara, M.R.; et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015, 5, 1282–1295. [Google Scholar] [CrossRef] [Green Version]
  53. Gardner, R.; Wu, D.; Cherian, S.; Fang, M.; Hanafi, L.A.; Finney, O.; Smithers, H.; Jensen, M.C.; Riddell, S.R.; Maloney, D.G.; et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 2016, 127, 2406–2410. [Google Scholar] [CrossRef] [Green Version]
  54. Till, B.G.; Jensen, M.C.; Wang, J.; Qian, X.; Gopal, A.K.; Maloney, D.G.; Lindgren, C.G.; Lin, Y.; Pagel, J.M.; Budde, L.E.; et al. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: Pilot clinical trial results. Blood 2012, 119, 3940–3950. [Google Scholar] [CrossRef] [Green Version]
  55. Fialkow, P.J.; Najfeld, V.; Reddy, A.L.; Singer, J.; Steinmann, L. Chronic lymphocytic leukæmia: Clonal origin in a committed b-lymphocyte progenitor. Lancet 1978, 312, 444–446. [Google Scholar] [CrossRef]
  56. Hudecek, M.; Schmitt, T.M.; Baskar, S.; Lupo-Stanghellini, M.T.; Nishida, T.; Yamamoto, T.N.; Bleakley, M.; Turtle, C.J.; Chang, W.C.; Greisman, H.A.; et al. The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood 2010, 116, 4532–4541. [Google Scholar] [CrossRef] [Green Version]
  57. Faitschuk, E.; Hombach, A.A.; Frenzel, L.P.; Wendtner, C.M.; Abken, H. Chimeric antigen receptor T cells targeting Fc μ receptor selectively eliminate CLL cells while sparing healthy B cells. Blood 2016, 128, 1711–1722. [Google Scholar]
  58. Gill, S.; Brudno, J.N. CAR T-cell therapy in hematologic malignancies: Clinical role, toxicity, and unanswered questions. Am. Soc. Clin. Oncol. Educ. Book 2021, 41, e246–e265. [Google Scholar] [CrossRef]
  59. Depil, S.; Duchateau, P.; Grupp, S.A.; Mufti, G.; Poirot, L. “Off-the-shelf” allogeneic CAR T cells: Development and challenges. Nat. Rev. Drug Discov. 2020, 19, 185–199. [Google Scholar] [CrossRef]
  60. Kaminski, B.A.; Kadereit, S.; Miller, R.E.; Leahy, P.; Stein, K.R.; Topa, D.A.; Radivoyevitch, T.; Veigl, M.L.; Laughlin, M.J. Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation. Blood 2003, 102, 4608–4617. [Google Scholar]
  61. Nitsche, A.; Zhang, M.; Clauss, T.; Siegert, W.; Brune, K.; Pahl, A. Cytokine profiles of cord and adult blood leukocytes: Differences in expression are due to differences in expression and activation of transcription factors. BMC Immunol. 2007, 8, 18. [Google Scholar] [CrossRef] [Green Version]
  62. Poirot, L.; Philip, B.; Schiffer-Mannioui, C.; le Clerre, D.; Chion-Sotinel, I.; Derniame, S.; Potrel, P.; Bas, C.; Lemaire, L.; Galetto, R.; et al. Multiplex genome-edited T-cell manufacturing platform for “Off-the-Shelf” adoptive T-cell immunotherapies. Cancer Res. 2015, 75, 3853–3864. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Benjamin, R.; Graham, C.; Yallop, D.; Jozwik, A.; Mirci-Danicar, O.C.; Lucchini, G.; Pinner, D.; Jain, N.; Kantarjian, H.; Boissel, N.; et al. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: Results of two phase 1 studies. Lancet 2020, 396, 1885–1894. [Google Scholar] [CrossRef]
  64. Qasim, W.; Zhan, H.; Samarasinghe, S.; Adams, S.; Amrolia, P.; Stafford, S.; Butler, K.; Rivat, C.; Wright, G.; Somana, K.; et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl. Med. 2017, 9, eaaj2013. [Google Scholar] [CrossRef] [PubMed]
  65. Shah, B.D.; Jacobson, C.A.; Solomon, S.; Jain, N.; Vainorius, M.; Heery, C.R.; He, F.C.; Reshef, R.; Herrera, A.F.; Akard, L.P.; et al. Preliminary safety and efficacy of PBCAR0191, an allogeneic, off-the-shelf CD19-targeting CAR-T product in relapsed/refractory CD19+ NHL. J. Clin. Oncol. 2021, 39, 7516. [Google Scholar] [CrossRef]
  66. Zeiser, R.; Blazar, B.R. Acute graft-versus-host disease—Biologic process, prevention, and therapy. N. Engl. J. Med. 2017, 377, 2167–2179. [Google Scholar] [CrossRef]
  67. Hermanson, D.L.; Kaufman, D.S. Utilizing chimeric antigen receptors to direct natural killer cell activity. Front. Immunol. 2015, 6, 195. [Google Scholar] [CrossRef] [Green Version]
  68. Herrera, L.; Santos, S.; Vesga, M.A.; Carrascosa, T.; Garcia-Ruiz, J.C.; Pérez-Martínez, A.; Juan, M.; Eguizabal, C. The race of CAR therapies: CAR-NK cells for fighting B-cell hematological cancers. Cancers 2021, 13, 5418. [Google Scholar] [CrossRef]
  69. Liu, E.; Tong, Y.; Dotti, G.; Shaim, H.; Savoldo, B.; Mukherjee, M.; Orange, J.; Wan, X.; Lu, X.; Reynolds, A.; et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 2018, 32, 520–531. [Google Scholar] [CrossRef]
  70. Quintarelli, C.; Sivori, S.; Caruso, S.; Carlomagno, S.; Falco, M.; Boffa, I.; Orlando, D.; Guercio, M.; Abbaszadeh, Z.; Sinibaldi, M.; et al. Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia. Leukemia 2020, 34, 1102–1115. [Google Scholar] [CrossRef]
  71. Herrera, L.; Santos, S.; Vesga, M.A.; Anguita, J.; Martin-Ruiz, I.; Carrascosa, T.; Juan, M.; Eguizabal, C. Adult peripheral blood and umbilical cord blood NK cells are good sources for effective CAR therapy against CD19 positive leukemic cells. Sci. Rep. 2019, 9, 18729. [Google Scholar] [CrossRef] [Green Version]
  72. Knorr, D.A.; Kaufman, D.S. Pluripotent stem cell-derived natural killer cells for cancer therapy. Transl. Res. 2010, 156, 147–154. [Google Scholar] [CrossRef] [Green Version]
  73. Herrera, L.; Juan, M.; Eguizabal, C. Purification, culture, and CD19-CAR lentiviral transduction of adult and umbilical cord blood NK cells. Curr. Protoc. Immunol. 2020, 131, e108. [Google Scholar] [CrossRef]
Curroncol 29 00293 g001 550
Figure 1. The process of autologous CAR T cell therapy. T cells are collected via apheresis, genetically reengineered in a laboratory by introducing DNA that encodes CAR, multiplied, and then infused into the patient. The CAR T cells may eliminate all of the cancer cells and may remain in the body months after the infusion.
Figure 1. The process of autologous CAR T cell therapy. T cells are collected via apheresis, genetically reengineered in a laboratory by introducing DNA that encodes CAR, multiplied, and then infused into the patient. The CAR T cells may eliminate all of the cancer cells and may remain in the body months after the infusion.
Curroncol 29 00293 g001
Curroncol 29 00293 g002 550
Figure 2. Challenges in CAR T-cell therapy. The first problem associated with CAR T cell therapy is access which can be limited by the cost of the manufacture of CAR T cells, time needed to manufacture and expand CAR T cells, failure to produce autologous CAR T cells, and eligibility for the clinical trial. The second problem associated with CAR T cell therapy are serious adverse event: cytokine-release storm (widespread pyroptosis of tumor cells is followed by the release of different factors that activate macrophages to produce inflammatory cytokines that induce systemic inflammatory response), and neurotoxicity syndrome (toxic encephalopathy caused by the disruption of the blood-brain-barrier). CAR T cell therapy may be accompanied by the primary resistance due to the impaired CAR T cell function and the inability to induce remission and limited CAR T cell expansion.
Figure 2. Challenges in CAR T-cell therapy. The first problem associated with CAR T cell therapy is access which can be limited by the cost of the manufacture of CAR T cells, time needed to manufacture and expand CAR T cells, failure to produce autologous CAR T cells, and eligibility for the clinical trial. The second problem associated with CAR T cell therapy are serious adverse event: cytokine-release storm (widespread pyroptosis of tumor cells is followed by the release of different factors that activate macrophages to produce inflammatory cytokines that induce systemic inflammatory response), and neurotoxicity syndrome (toxic encephalopathy caused by the disruption of the blood-brain-barrier). CAR T cell therapy may be accompanied by the primary resistance due to the impaired CAR T cell function and the inability to induce remission and limited CAR T cell expansion.
Curroncol 29 00293 g002
Curroncol 29 00293 g003 550
Figure 3. Novel attempts to improve CAR T cell therapy in CLL.
Figure 3. Novel attempts to improve CAR T cell therapy in CLL.
Curroncol 29 00293 g003
Table
Table 1. CAR T cells trials in CLL. Abbreviation: ORR—overall response rate, CR—complete response, CLL—chronic lymphocytic leukemia.
Table 1. CAR T cells trials in CLL. Abbreviation: ORR—overall response rate, CR—complete response, CLL—chronic lymphocytic leukemia.
Study (Reff. Number)Number of CLL PatientsTarget AntigenCostimulatory DomainORR (%)CR (%)
CAR-T
[23]8CD19CD2800
[27]3CD194–1BB10067
[28]4CD19CD287525
[24]4CD19CD28250
[29]5CD19CD2810060
[30]14CD194–1BB5729
[25]5CD19CD284020
[26]2IgKappaCD2800
[31]32CD194–1BB4428
[13]24CD194–1BB7117
[22]8CD19CD287525
[32]19CD194–1BB5353
[33]10CD194–1BB6040
[34]19CD194–1BB7921
[35]3CD194–1BB10067
Table
Table 2. Comparison of allogenic CAR T and CAR NK cellsn.
Table 2. Comparison of allogenic CAR T and CAR NK cellsn.
Allogenic CAR T CellsCAR NK Cells
short manufacturing timeXX
graft versus host reactionX
poor expansion in vitro X
difficult viral transduction X
long lifespan in vivoX
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Todorovic, Z.; Todorovic, D.; Markovic, V.; Ladjevac, N.; Zdravkovic, N.; Djurdjevic, P.; Arsenijevic, N.; Milovanovic, M.; Arsenijevic, A.; Milovanovic, J. CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings. Curr. Oncol. 2022, 29, 3647-3657. https://0-doi-org.brum.beds.ac.uk/10.3390/curroncol29050293

AMA Style

Todorovic Z, Todorovic D, Markovic V, Ladjevac N, Zdravkovic N, Djurdjevic P, Arsenijevic N, Milovanovic M, Arsenijevic A, Milovanovic J. CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings. Current Oncology. 2022; 29(5):3647-3657. https://0-doi-org.brum.beds.ac.uk/10.3390/curroncol29050293

Chicago/Turabian Style

Todorovic, Zeljko, Dusan Todorovic, Vladimir Markovic, Nevena Ladjevac, Natasa Zdravkovic, Predrag Djurdjevic, Nebojsa Arsenijevic, Marija Milovanovic, Aleksandar Arsenijevic, and Jelena Milovanovic. 2022. "CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings" Current Oncology 29, no. 5: 3647-3657. https://0-doi-org.brum.beds.ac.uk/10.3390/curroncol29050293

Article Metrics

Back to TopTop