Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma

Bruggen, Jaco A. C. van; Martens, Anne W. J.; Tonino, Sanne H.; Kater, Arnon P.

doi:10.3390/cancers12123837

Cited by 10 publications

(8 citation statements)

References 223 publications

(338 reference statements)

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“…Third, the expanded effector cell populations must persist-both in sufficient quantity and activity-until the entirety of the malignant cell cohort is eliminated. T-cell persistence is multifactorial and heavily influenced by the balance of receptor signaling, cytokine stimulation, and memory T-cell differentiation [97,98]. Finally, an ideal immune response is one that generates immunologic memory so that future encounters with the TAA can be recognized and eliminated swiftly before creating complications for the patient.…”

Section: Activation Persistence Memorymentioning

confidence: 99%

“…Vaccines to promote tumor antigen presentation on dendritic cells continue to be studied as well [160]. Finally, adoptive cell therapies have ushered in a new era of cellular immunotherapy, with chimeric antigen receptor (CAR) Tcells approved for several B-cell neoplasms and numerous additional CAR-T and CAR-NK cell products under clinical investigation [97,98,161].…”

Section: Engaging the Antitumor Immune Responsementioning

confidence: 99%

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Engaging the Innate and Adaptive Antitumor Immune Response in Lymphoma

Csizmar

Ansell

2021

IJMS

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Immunotherapy has emerged as a powerful therapeutic strategy for many malignancies, including lymphoma. As in solid tumors, early clinical trials have revealed that immunotherapy is not equally efficacious across all lymphoma subtypes. For example, immune checkpoint inhibition has a higher overall response rate and leads to more durable outcomes in Hodgkin lymphomas compared to non-Hodgkin lymphomas. These observations, combined with a growing understanding of tumor biology, have implicated the tumor microenvironment as a major determinant of treatment response and prognosis. Interactions between lymphoma cells and their microenvironment facilitate several mechanisms that impair the antitumor immune response, including loss of major histocompatibility complexes, expression of immunosuppressive ligands, secretion of immunosuppressive cytokines, and the recruitment, expansion, and skewing of suppressive cell populations. Accordingly, treatments to overcome these barriers are being rapidly developed and translated into clinical trials. This review will discuss the mechanisms of immune evasion, current avenues for optimizing the antitumor immune response, clinical successes and failures of lymphoma immunotherapy, and outstanding hurdles that remain to be addressed.

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Section: Activation Persistence Memorymentioning

confidence: 99%

Section: Engaging the Antitumor Immune Responsementioning

confidence: 99%

Engaging the Innate and Adaptive Antitumor Immune Response in Lymphoma

Csizmar

Ansell

2021

IJMS

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“… 9,10 We have shown that CD8 T cells in CLL have impaired glucose metabolism upon activation and decreased mitochondrial fitness in the resting state, 7,11 both of which could contribute to the low efficacy of T cell–based therapies in CLL. 12 Although a clear relation between metabolism and function was recently described in CD8 T cells of patients with CLL, 7 CD4 T-cell metabolism remains an unexplored but important issue to address, because these cell types can play distinct roles in CLL.…”

Section: Introductionmentioning

confidence: 99%

Depletion of CLL cells by venetoclax treatment reverses oxidative stress and impaired glycolysis in CD4 T cells

et al. 2022

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Acquired T-cell dysfunction is characteristic of CLL and is associated with reduced efficacy of T-cell based therapies. A recently described feature of dysfunctional CLL-derived CD8 T cells is reduced metabolic plasticity. To what extend CD4 T cells are affected, and if CD4 T-cell metabolism and function can be restored upon clinical depletion of CLL cells is currently unknown. Here we address these unresolved issues by a comprehensive phenotypic, metabolic, transcriptomic and functional analysis of CD4 T cells of untreated CLL patients, and by analyzing the effects of venetoclax + obinutuzumab on the CD4 population. Resting CD4 T cells derived from CLL patients expressed lower levels of GLUT-1, displayed deteriorated oxidative phosphorylation (OXPHOS) and overall reduced mitochondrial fitness. Upon T-cell stimulation, CLL T cells were unable to initiate glycolysis. Transcriptome analysis revealed that depletion of CLL cells in vitro resulted in upregulation of OXPHOS and glycolysis pathways and restored T-cell function in vitro. Analysis of CD4 T cells from CLL patients prior and after venetoclax + obinutuzumab treatment, which led to effective clearance of CLL in blood and bone marrow, revealed recovery of T-cell activation and restoration of the switch to glycolysis, as well as improved T-cell proliferation. Collectively these data demonstrate that CLL cells impose metabolic restrictions on CD4 T cells which lead to reduced CD4 T-cell functionality. This trial is registered in the Netherlands Trial Registry ID: NTR6043.

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“…The authors integrate clinical data from trials using ICIs, bispecific antibodies, and CAR-T cells with T-cell alterations observed in B-NHL patients. The authors list possible solutions to overcome T-cell dysfunction (such as exhaustion and skewing or the expansion of regulatory T cells), including combination therapies with immunomodulatory drugs (IMIDs) or improvement of CAR-T-cell manufacturing to maximize their persistence [ 2 ]. Alternatively, strategies engaging innate immune cells to fight B-cell malignancies represent an attractive and rapidly evolving field.…”

mentioning

confidence: 99%