Facts and Challenges in Immunotherapy for T-Cell Acute Lymphoblastic Leukemia

Bayón-Calderón, Fátima; Toribio, Marı́a L.; González-García, Sara

doi:10.3390/ijms21207685

Cited by 40 publications

(41 citation statements)

References 313 publications

(323 reference statements)

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“…Two main mechanisms that attenuate the T cell-mediated antitumor immune response are well recognized: the expression of inhibitory checkpoint receptors on conventional T cells, and the accumulation and augmented suppressive function of Tregs. Moreover, in the case of T-ALL, a T cell-derived malignancy, even more challenges for potent T cell-mediated immune responses/immunotherapies are met [ 138 ]. This is partially due to the target antigens overlapping between leukemic and normal T cells, which can lead to various off-target effects.…”

Section: T Cellsmentioning

confidence: 99%

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Pastorczak

Domka

Fidyt

et al. 2021

Cancers

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Acute lymphoblastic leukemia (ALL) results from a clonal expansion of abnormal lymphoid progenitors of B cell (BCP-ALL) or T cell (T-ALL) origin that invade bone marrow, peripheral blood, and extramedullary sites. Leukemic cells, apart from their oncogene-driven ability to proliferate and avoid differentiation, also change the phenotype and function of innate and adaptive immune cells, leading to escape from the immune surveillance. In this review, we provide an overview of the genetic heterogeneity and treatment of BCP- and T-ALL. We outline the interactions of leukemic cells in the bone marrow microenvironment, mainly with mesenchymal stem cells and immune cells. We describe the mechanisms by which ALL cells escape from immune recognition and elimination by the immune system. We focus on the alterations in ALL cells, such as overexpression of ligands for various inhibitory receptors, including anti-phagocytic receptors on macrophages, NK cell inhibitory receptors, as well as T cell immune checkpoints. In addition, we describe how developing leukemia shapes the bone marrow microenvironment and alters the function of immune cells. Finally, we emphasize that an immunosuppressive microenvironment can reduce the efficacy of chemo- and immunotherapy and provide examples of preclinical studies showing strategies for improving ALL treatment by targeting these immunosuppressive interactions.

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Section: T Cellsmentioning

confidence: 99%

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Pastorczak

Domka

Fidyt

et al. 2021

Cancers

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“…with T cell depletion. CAR T cells are currently under development targeting several T cell antigens including CD5, CD7, CD3, and CD4, but ADCs have lagged behind [39]. CD30 expression is noted in 38% of T-ALL cases, with increased expression observed during courses of chemotherapy [40].…”

Section: Development Of Successful Immunotherapy For T-all Is Challenging Due To the Shared Expression Of Target Antigens Between Normal mentioning

confidence: 99%

Antibody–Drug Conjugates for the Treatment of Acute Pediatric Leukemia

Stokke

Bhojwani

2021

JCM

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The clinical development of antibody–drug conjugates (ADCs) has gained momentum in recent years and these agents are gradually moving into frontline regimens for pediatric acute leukemias. ADCs consist of a monoclonal antibody attached to a cytotoxic payload by a cleavable linker. This structure allows for highly cytotoxic agents to be directly delivered to leukemia cells leading to cell death and avoids excessive off-tumor toxicity. Near universal expression on B-cell acute lymphoblastic leukemia (ALL) blasts and the ability of rapid internalization has rendered CD22 an ideal target for ADC in B-ALL. Inotuzumab ozogamicin, the anti-CD22 antibody linked to calicheamicin led to complete remission rates of 60–80% in patients with relapsed/refractory B-ALL. In acute myeloid leukemia (AML), the CD33 targeting gemtuzumab ozogamicin has demonstrated modest improvements in survival and is the only ADC currently licensed in the United States for pediatric patients with de novo AML. Several other ADCs have been developed and tested clinically for leukemia but have achieved limited success to date. The search for additional leukemia-specific targets and optimization of ADC structure and specificity are ongoing efforts to improve their therapeutic window. This review provides a comprehensive overview of ADCs in acute leukemias, with a focus on pediatric ALL and AML.

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“…Additionally, ICOS-L and ICOS expression was found to be a predictor of OS and disease-free survival in patients with AML ( 126 ). Although there is no information regarding ICOS or ICOS-L in ALL, the relevance of ICOS in ALL immune escape is supported by studies showing that ICOS is part of the intracellular region of the signaling domain complexes that activate and induce cytotoxicity against target cells during chimeric antigen receptor (CAR) T cell immunotherapy ( 127 ).…”

Section: Immune Evasion Mechanisms In Allmentioning

confidence: 99%

“…In ALL, CD-38 and CD-52 have been identified as target antigens of mAbs for the treatment of relapsed T cell ALL. Currently, there are ongoing clinical trials testing the efficacy of anti-CD38 mAbs (isatuximab and daratumumab) and anti-CD52 mAbs (alemtuzumab) with favorable results for better disease prognosis ( 127 ).…”

Section: Into the Frontline Of All Treatment: Targeting The Immune Cellsmentioning

confidence: 99%

“…Although CAR T cell implementation in B cell ALL has obtained favorable results, its implementation in T cell ALL presents limitations because CAR T cells and malignant T cells share similar expression profiles of target antigens, which gives rise to a non-specific cytotoxic activity incapable of discriminating CAR T cells from malignant T cells, leading to T cell aplasia and eventual immunodeficiency. Notwithstanding, the identification of antigens, such as CD4, CD5, and CD7, on T cell ALL shows promise for the use of CAR T cell technology, the clinical trials of which are ongoing ( 127 ).…”

Section: Into the Frontline Of All Treatment: Targeting The Immune Cellsmentioning

confidence: 99%

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Mechanisms of Immunosuppressive Tumor Evasion: Focus on Acute Lymphoblastic Leukemia

et al. 2021

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Acute lymphoblastic leukemia (ALL) is a malignancy with high heterogeneity in its biological features and treatments. Although the overall survival (OS) of patients with ALL has recently improved considerably, owing to the application of conventional chemo-therapeutic agents, approximately 20% of the pediatric cases and 40–50% of the adult patients relapse during and after the treatment period. The potential mechanisms that cause relapse involve clonal evolution, innate and acquired chemoresistance, and the ability of ALL cells to escape the immune-suppressive tumor response. Currently, immunotherapy in combination with conventional treatment is used to enhance the immune response against tumor cells, thereby significantly improving the OS in patients with ALL. Therefore, understanding the mechanisms of immune evasion by leukemia cells could be useful for developing novel therapeutic strategies.

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Facts and Challenges in Immunotherapy for T-Cell Acute Lymphoblastic Leukemia

Cited by 40 publications

References 313 publications

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Antibody–Drug Conjugates for the Treatment of Acute Pediatric Leukemia

Mechanisms of Immunosuppressive Tumor Evasion: Focus on Acute Lymphoblastic Leukemia

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