The efficacy of anti-CD19 chimeric antigen receptor T cells for B-cell malignancies

Cao, Jinglin; Gao, Weijia; You, Jia; Wu, Lihua; Liu, Jinlong; Wang, Zheng-Xu

doi:10.1016/j.jcyt.2019.04.005

Cited by 19 publications

(15 citation statements)

References 57 publications

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“…A broad range of defects of the innate and adaptive immune response is found in CLL patients since early disease stage. Over the years, several approaches aimed at evoking the immune response against leukemia have been developed, although none of them so far appeared to be as revolutionary and successful in CLL as some of them are in other tumor models, including lymphomas [135,136]. This is the case, for example, of the PD-1 blocking antibodies that did not show any evidence of clinical response or benefit in CLL trials, neither as single agents nor in combination with ibrutinib, unless patients underwent Richter's transformation [137,138].…”

Section: Discussionmentioning

confidence: 99%

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Arruga

Gyau

Iannello

et al. 2020

IJMS

103

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Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease. Effectors of the innate and the adaptive immune response show marked dysfunction and skewing towards the generation of a tolerant environment that favors disease expansion. Major deregulations are found in the T lymphocyte compartment, with inhibition of CD8+ cytotoxic and CD4+ activated effector T cells, replaced by exhausted and more tolerogenic subsets. Likewise, differentiation of monocytes towards a suppressive M2-like phenotype is induced at the expense of pro-inflammatory sub-populations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell–cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis. Specifically, molecular pathways modulating T-cell activity in CLL, spanning from the best known cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) to the emerging T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)/CD155 axes, are attracting increasing research interest and therapeutic relevance also in the CLL field. On the other hand, in the microenvironment, the B cell receptor (BCR), which is undoubtedly the master regulator of leukemic cell behavior, plays an important role in orchestrating immune responses, as well. Lastly, local conditions of hypoxia, typical of the lymphoid niche, have major effects both on CLL cells and on non-leukemic immune cells, partly mediated through adenosine signaling, for which novel specific inhibitors are currently under development. In summary, this review will provide an overview of the molecular and microenvironmental mechanisms that modify innate and adaptive immune responses of CLL patients, focusing attention on those that may have therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Arruga

Gyau

Iannello

et al. 2020

IJMS

103

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“…Porter reported a durable remission in a third of R/R CLL patients with second-generation anti-CD19 CAR-T cells [65]. Several clinical trials assessed the efficacy of CAR-T cells in CLL, showing a lower overall response rate (ORR) in R/R CLL (ORR 70%) than in R/R acute lymphocytic leukemia (ALL) patients (ORR 81%) [66].…”

Section: Of 14mentioning

confidence: 99%

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Mhibik¹,

Wiestner²,

Sun³

2019

IJMS

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B-cell receptor (BCR) signaling and tumor–microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2–inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy.

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“…Most trials studying CAR T-cell therapy in CLL used constructs recognizing CD19 on CLL tumor cells, while containing either a CD28 or 4-1BB co-stimulatory domain [75,76,77,78,79]. Despite a high response rate of similar constructs in ALL, the results of CAR T-cell therapy in CLL were relatively disappointing [14,80]. Although approximately 70% of CLL patients showed a response to therapy, the rate of complete remissions (CR) was much lower in CLL than in ALL (30% in CLL versus 70% in ALL) [78].…”

Section: Responses To Immunotherapy In Cllmentioning

confidence: 99%

“…The immunomodulatory environment of CLL is assumed to have an important role in determining the response to CAR T-cell therapy. This is demonstrated by the fact that reducing the tumor load before transfusion of CAR T cells with lymphodepleting agents was shown to improve responses to CAR T-cell therapy [14,81]. Since CLL cells are able to modulate T-cell functionality, it was also recognized that intrinsic T-cell qualities may play a role.…”

Section: Responses To Immunotherapy In Cllmentioning

confidence: 99%

“…Bi- and tri-specific antibody constructs, which recruit immune effector cells toward tumor cells by binding to both cell types simultaneously, target tumor cells for immune recognition, and showed activity in several non-Hodgkin lymphomas (NHL), like diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) [10,11,12]. Finally, introducing chimeric antigen receptors (CAR) on the surface of cytotoxic cells redirects them toward tumor cells while simultaneously inducing immune activation, which was remarkably effective as a treatment in acute lymphoblastic leukemia (ALL) and, to a lesser extent, in NHL [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Engaging Cytotoxic T and NK Cells for Immunotherapy in Chronic Lymphocytic Leukemia

Hofland

Eldering

Kater

et al. 2019

IJMS

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Chronic lymphocytic leukemia (CLL) is characterized by an acquired immune dysfunction. CLL cells affect the phenotype and function of the entire spectrum of innate and adaptive immune cells, including monocytes, T cells, and natural killer (NK) cells, leading to a tumor-supportive environment and reduced immunosurveillance. Novel immunotherapies like immune checkpoint blockade, bi- and tri-specific antibodies, and chimeric antigen receptor (CAR) T cells use the patients’ immune system to induce therapeutic responses. Although these novel immunotherapies showed impressive results in several B cell lymphomas, responses in CLL were often disappointing. The strong immunomodulatory effect of CLL is believed to play a pivotal role in the low response rates to these immunotherapeutic strategies. In this review, we summarize how CLL influences the function of non-malignant lymphocytes, with a special focus on T and NK cells, two important cellular mediators for immunotherapy. Secondly, we provide a short overview of the activity of several immunotherapeutics in CLL, and discuss how novel strategies may overcome the disappointing response rates in CLL.

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The efficacy of anti-CD19 chimeric antigen receptor T cells for B-cell malignancies

Cited by 19 publications

References 57 publications

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Engaging Cytotoxic T and NK Cells for Immunotherapy in Chronic Lymphocytic Leukemia

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