Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity

Pilipow, Karolina; Scamardella, Eloise; Puccio, Simone; Gautam, Sanjivan; Paoli, Fédérica De; Mazza, Emilia Maria Cristina; Simone, Gabriele De; Polletti, Sara; Buccilli, Marta; Zanon, Veronica; Lucia, Pietro Di; Iannacone, Matteo; Gattinoni, Luca; Lugli, Enrico

doi:10.1172/jci.insight.122299

Cited by 97 publications

(90 citation statements)

References 60 publications

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“…An alternative strategy can be to deeper investigate and overcome initial T cell defects in the autologous setting. For example, it is possible to further optimize the manufacturing procedure by supplementing compounds known to expand T SCM , e.g., N-acetylcysteine (NAC), a reagent able to inhibit the metabolism of reactive oxygen species (24) or to pre-select definite T cell subsets as source material to get rid of more differentiated T cells. Directly inhibiting T cell exhaustion is another valuable option that can be achieved by combining CAR T cell therapy with checkpoint inhibitors (50,51) or by additional genetic engineering of CAR T cell products (8).…”

Section: Discussionmentioning

confidence: 99%

“…This goal has been accomplished by providing both signal one and signal two in the proper steric conformation, e.g., through cell-sized beads (20) or polymeric nanomatrices (21), and in the presence of homeostatic cytokines, such as IL-7 and IL-15. More recently, it has been described that the activation of pre-selected T N cells in the presence of specific cytokines (22,23), Wnt agonists (13) or antioxidant molecules (24) could further improve the quality of the final T cell product (10).…”

Section: Introductionmentioning

confidence: 99%

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Next-Generation Manufacturing Protocols Enriching TSCM CAR T Cells Can Overcome Disease-Specific T Cell Defects in Cancer Patients

et al. 2020

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Chimeric antigen receptor (CAR) T cell expansion and persistence emerged as key efficacy determinants in cancer patients. These features are typical of early-memory T cells, which can be enriched with specific manufacturing procedures, providing signal one and signal two in the proper steric conformation and in the presence of homeostatic cytokines. In this project, we exploited our expertise with paramagnetic beads and IL-7/IL-15 to develop an optimized protocol for CAR T cell production based on reagents, including a polymeric nanomatrix, which are compatible with automated manufacturing via the CliniMACS Prodigy. We found that both procedures generate similar CAR T cell products, highly enriched of stem cell memory T cells (T SCM) and equally effective in counteracting tumor growth in xenograft mouse models. Most importantly, the optimized protocol was able to expand CAR T SCM from B-cell acute lymphoblastic leukemia (B-ALL) patients, which in origin were highly enriched of late-memory and exhausted T cells. Notably, CAR T cells derived from BALL patients proved to be as efficient as healthy donor-derived CAR T cells in mediating profound and prolonged anti-tumor responses in xenograft mouse models. On the contrary, the protocol failed to expand fully functional CAR T SCM from patients with pancreatic ductal adenocarcinoma, suggesting that patient-specific factors may profoundly affect intrinsic T cell quality. Finally, by retrospective analysis of in vivo data, we observed that the proportion of T SCM in the final CAR T cell product positively correlated with in vivo expansion, which in turn proved to be crucial for achieving long-term remissions. Collectively, our data indicate that next-generation manufacturing protocols can overcome initial T cell defects, resulting in T SCM-enriched CAR T cell products qualitatively equivalent to the ones generated from healthy donors. However, this positive effect may be decreased in specific conditions, for which the development of further improved protocols and novel strategies might be highly beneficial.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Next-Generation Manufacturing Protocols Enriching TSCM CAR T Cells Can Overcome Disease-Specific T Cell Defects in Cancer Patients

et al. 2020

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“…Overall, PGC‐1α activation results in an increased number of tumor‐reactive T lymphocytes infiltrating the TME thereby boosting PD‐1 blockade therapy . By contrast to the effects of Luperox in vivo, Pilipow and colleagues demonstrated that ROS limitation, using the antioxidant N‐acetylcysteine (NAC), favors the generation of long‐lived stem cell memory T (Tscm) cells . ACT using NAC‐generated Tscm CD19 CAR‐T lymphocytes demonstrated enhanced clearance of lymphoblastic leukemia cells in immunodeficient mice .…”

Section: Approaches To Manipulate T Cell and Tumor Mitochondrial Metamentioning

confidence: 99%

“…By contrast to the effects of Luperox in vivo, Pilipow and colleagues demonstrated that ROS limitation, using the antioxidant N‐acetylcysteine (NAC), favors the generation of long‐lived stem cell memory T (Tscm) cells . ACT using NAC‐generated Tscm CD19 CAR‐T lymphocytes demonstrated enhanced clearance of lymphoblastic leukemia cells in immunodeficient mice . These studies demonstrate that targeting ROS in antitumor therapy has complex context‐dependent effects.…”

Section: Approaches To Manipulate T Cell and Tumor Mitochondrial Metamentioning

confidence: 99%

Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy

Hope

Salmond

2019

Eur J Immunol

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The successful implementation of immunotherapies has provided new impetus in the fight against cancer. Antibody‐mediated blockade of immune checkpoint molecules PD‐1/PD‐L1 and CTLA‐4 has had a dramatic impact upon the treatment of previously intractable cancers such as malignant melanoma, while adoptive cell therapies using chimeric antigen receptor‐bearing T cells have proven highly efficacious in B cell leukemia. Furthermore, significant progress has been made in understanding the mechanisms by which tumors evade or become resistant to these immunotherapies. In this regard, approaches to broaden the applicability and enhance the efficacy of immunotherapies increasingly include modulation of tumor and immune cell metabolism. In this mini‐review, we highlight the most recent studies describing novel approaches and targets for the manipulation of the tumor microenvironment and T cell metabolism and describe how these approaches are being combined with current immunotherapies in preclinical studies.

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“…Fraietta et al reported that early memory-related genes with reduced glycolysis signatures were enriched in CAR-T cells from complete-responding patients against chronic lymphocytic leukemia (CLL) [17]. Less-differentiated CAR-T induction was obtained by inhibiting the Akt-mTOR pathway, enhancing FOXO1 activity, and potentiating mitochondrial function [68,[71][72][73][74][75]. Additionally, IL-21 in combination with rapamycin has been reported to enhance generation of tumor antigen-specific T SCM -like cells [64], and IL-21 enhances T CM cell formation in a FAO-dependent manner [76].…”

Section: Application Of T Scm For Cancer Immunotherapymentioning

confidence: 99%

Memory T cell, exhaustion, and tumor immunity

Ando

Ito

Srirat

et al. 2019

Immunological Medicine

149

107

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CD8 þ T cells are important in protective immunity against intracellular pathogens and tumors. In chronic infections or cancer, CD8 þ T cells are constantly exposed to antigens and inflammatory signals. Such excessive and constitutive signals lead to the deterioration of T cell function, called 'exhaustion'. Exhausted T cells are characterized by low proliferation in response to antigen stimulation, progressive loss of effector function (cytokine production and killing function), expression of multiple inhibitory receptors such as PD-1, Tim3, and LAG3, and metabolic alterations from oxidative phosphorylation to glycolysis. These dysfunctions are associated with altered transcriptional programs and epigenetic regulations and recent studies suggested that NR4a and TOX transcription factors are deeply involved in exhaustion phenotypes. However, an increase the early memory T cells including stem cell memory T (T SCM) cells is critical for T cell persistence and efficient tumor killing especially for adoptive cancer immunotherapy such as CART cell therapy. An increasing amount of evidence supports the therapeutic potential of targeting exhausted T cells and T SCM cells. We have begun to understand the molecular mechanisms of T cell exhaustion and early memory formation, and the clinical application of converting exhausted T cells to rejuvenated early memory T cells is the goal of our study.

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Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity

Cited by 97 publications

References 60 publications

Next-Generation Manufacturing Protocols Enriching TSCM CAR T Cells Can Overcome Disease-Specific T Cell Defects in Cancer Patients

Next-Generation Manufacturing Protocols Enriching TSCM CAR T Cells Can Overcome Disease-Specific T Cell Defects in Cancer Patients

Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy

Memory T cell, exhaustion, and tumor immunity

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