Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

Klebanoff, Christopher A.; Scott, Christopher D.; Leonardi, Anthony; Yamamoto, Tori N.; Cruz, Anthony; Ouyang, Claudia; Ramaswamy, Madhu; Roychoudhuri, Rahul; Ji, Yun; Eil, Robert L.; Sukumar, Madhusudhanan; Crompton, Joseph G.; Palmer, Douglas C.; Borman, Zachary A.; Clever, David; Thomas, Sarah M.; Patel, Shashankkumar Jitendra; Yu, Zhiya; Muranski, Pawel; Liu, Hui; Wang, Ena; Marincola, Francesco M.; Gros, Alena; Gattinoni, Luca; Rosenberg, Steven A.; Siegel, Richard M.; Restifo, Nicholas P.

doi:10.1172/jci81217

Cited by 208 publications

(231 citation statements)

References 78 publications

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“…In this way, late memory and effector T cells can no longer stimulate the differentiation of antigen-specific T cells. 28 Starting with CD8 + T N cells resulted in an elevated CD62L expression in all cultures, though variation remained high. This variation between cultures might be explained by basal donor variation in AKT expression and phosphorylation, 48 showing that optimal dosing is important.…”

Section: Discussionmentioning

confidence: 93%

“…Since effector T (T EFF ) cells can accelerate the differentiation of naïve T cells 28 and the frequency of T EFF differs per donor, we aimed to increase the robustness of our culture protocol by starting the culture with CD8 + T N cells instead of total CD8 + T cells. Here, we selected the most effective AKT-inhibitors of the allosteric and ATP-competitive group: AktiVIII and GDC, respectively.…”

Section: Resultsmentioning

confidence: 99%

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Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Mousset

Hobo

et al. 2018

OncoImmunology

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Adoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivo inhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8+ T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action. We analyzed phenotype, functionality, metabolism and transcriptome of AKT-inhibited CD8+ T cells using different T cell activation models. Most inhibitors facilitated T cell expansion while preserving an early memory phenotype, reflected by maintenance of CD62L, CCR7 and CXCR4 expression. Moreover, transcriptome profiling revealed that AKT-inhibited CD8+ T cells clustered closely to naturally occurring stem cell-memory CD8+ T cells, while control T cells resembled effector-memory T cells. Interestingly, AKT-inhibited CD8+ T cells showed enrichment of hypoxia-associated genes, which was consistent with enhanced glycolytic function. Notably, AKT-inhibition during MiHA-specific CD8+ T cell priming uncoupled preservation of early memory differentiation from ex vivo expansion. Furthermore, AKT-inhibited MiHA-specific CD8+ T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall. Together, these data demonstrate that AKT-inhibitors with different modality of action promote the ex vivo generation of stem cell memory-like CD8+ T cells with a unique metabolic profile and retained polyfunctionality. Akt-inhibitor VIII and GDC-0068 outperformed other inhibitors, and are therefore promising candidates for ex vivo generation of superior tumor-reactive T cells for adoptive immunotherapy in cancer patients.

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Mousset

Hobo

et al. 2018

OncoImmunology

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“…These results are consistent with the fratricide of naive T cells by T effector memory cells that has been recently described. 5 …”

Section: Depletion Of Cd27mentioning

confidence: 99%

“…3 Importantly, one of the major off-target effects of these therapies is damage to healthy T cells 4 and loss of the naive and central memory T-cell subsets that have the most potent expansion potential and anticancer activity in vivo. 5 Loss of naive and central memory T cells in previously treated cancer patients is particularly pronounced in adult patients with DLBCL and has been shown to a result of FasL-mediated fratricide from terminally differentiated effector cells. 5 The end result of cellintrinsic deficits in T-cell function in heavily pretreated patients can lead to inadequate ex vivo T-cell expansion, leading to CAR T-cell manufacturing failures and lack of adequate in vivo expansion of reinfused CAR T cells.…”

Section: Introductionmentioning

confidence: 99%

“…5 Loss of naive and central memory T cells in previously treated cancer patients is particularly pronounced in adult patients with DLBCL and has been shown to a result of FasL-mediated fratricide from terminally differentiated effector cells. 5 The end result of cellintrinsic deficits in T-cell function in heavily pretreated patients can lead to inadequate ex vivo T-cell expansion, leading to CAR T-cell manufacturing failures and lack of adequate in vivo expansion of reinfused CAR T cells. 6 Durable response rates of 30% to 40% have been reported for lymphoma patients treated with CAR T cells, 3,7 with manufacturing failure rates of up to 6%.…”

Section: Introductionmentioning

confidence: 99%

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Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists

et al. 2018

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Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment

Moraly,

Kondo,

Benzaoui

et al. 2024

Molecular Oncology

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Tumor‐infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as “living drugs,” their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post‐translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic‐based strategies to enhance T cell immunotherapy.

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Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

Cited by 208 publications

References 78 publications

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists

Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment

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Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

Cited by 208 publications

References 78 publications

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists

Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment

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Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy