Tuning the performance of CAR T cell immunotherapies

Richardson, Noah; Luttrell, Jordan; Bryant, Jonathan S.; Chamberlain, Damian; Khawaja, Saleem; Neeli, Indira; Radic, Marko

doi:10.1186/s12896-019-0576-9

Cited by 10 publications

(9 citation statements)

References 52 publications

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“…Current immunotherapeutic approaches are attempting to enhance the performance of antigen-expanded T cells [ 56 , 57 ]. There are a variety of immunomodulatory approaches that can be applied, including genetic modifications [ 58 , 59 ] or pharmacological interventions in signaling pathways, namely, interventions in the GSK3β-mTORC signaling axis whose modulation was reported to impact the differentiation and effector responses of CD8 + T cells [ 37 , 46 , 60 , 61 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

Acute Conditioning of Antigen-Expanded CD8+ T Cells via the GSK3β-mTORC Axis Differentially Dictates Their Immediate and Distal Responses after Antigen Rechallenge

Taborska

Stakheev

Svobodová

et al. 2020

Cancers

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CD8+ T cells protect against tumors and intracellular pathogens. The inflammatory cytokines IL-2, IL-15, and IL-7 are necessary for their expansion. However, elevated serum levels of these cytokines are often associated with cancer, poorer prognosis of cancer patients, and exhaustion of antigen-expanded CD8+ T cells. The impact of acute conditioning of antigen-expanded CD8+ T cells with these cytokines is unknown. Here, we generated antigen-expanded CD8+ T cells using dendritic cells and PC-3 cells. The cells were acutely (18–24 h) conditioned with IL-2 and either the GSK3β inhibitor TWS119, the mTORC1 inhibitor rapamycin, or the mTORC1/2 inhibitor Torin1, then their immediate and post-re-expansion (distal) cytokine responses after antigen rechallenge were evaluated. We found that acute IL-2 conditioning upregulated the immediate antigen-induced cytokine response of the tested cells. Following their re-expansion, however, the cells showed a decreased cytokine response. These IL-2 conditioning-mediated impacts were counteracted with TWS119 or rapamycin but not with Torin1. Our data revealed that the acute conditioning of antigen-expanded CD8+ T cells with IL-2 modulates the GSK3β-mTORC signaling axis. This modulation differentially affected the immediate and distal cytokine responses of the cells. The acute targeting of this signaling axis could, therefore, represent a novel strategy for the modulation of antigen-expanded CD8+ T cells.

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Section: Discussionmentioning

confidence: 99%

Acute Conditioning of Antigen-Expanded CD8+ T Cells via the GSK3β-mTORC Axis Differentially Dictates Their Immediate and Distal Responses after Antigen Rechallenge

Taborska

Stakheev

Svobodová

et al. 2020

Cancers

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“…As members of a technological field, we often harness the power of data to advance human health and approach challenging diseases with optimism that multidisciplinary effort can produce cure. [15][16][17] The systemic disease of racism is a glaring exception. Systemic racism continues to have devastating effects on the health and well-being of Black people across the socioeconomic spectrum.…”

Section: Practical Steps Forward For Radiation Oncologistsmentioning

confidence: 99%

Why Racial Justice Matters in Radiation Oncology

Chapman

Gabeau

Pinnix

et al. 2020

Advances in Radiation Oncology

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Recent events have reaffirmed that racism is a pervasive disease plaguing the United States and infiltrating the fabric of this nation. As health care professionals dedicated to understanding and alleviating disease, many radiation oncologists have failed to acknowledge how structural racism affects the health and well-being of the patients we aim to serve. The literature is full of descriptive statistics showing the higher incidence and mortality experienced by the Black population for health conditions ranging from infant mortality to infectious disease, including coronavirus disease 2019 . Acknowledgment that the root of health disparities experienced by Black people in this country are based in racism is essential to moving the nation and the field of radiation oncology forward. With this lens, a brief overview of structural and institutional racism shapes a discussion of what radiation oncologists and the organizations that represent them can do to address this scourge. As members of a technological field, we often harness the power of data to advance human health and approach challenging diseases with optimism that multidisciplinary effort can produce cure. A few principles to mitigate the longstanding issues of Black marginalization within the field have been recommended via the ATIP (Acknowledgment, Transparency, Intentionality, and rePresentation) and LEADS (Learn, Engage, Advocate, Defend, Support) approaches. However, additional introspection is encouraged. Just as individuals, practices, and organizations rallied to determine how best to address the issues related to the COVID-19 pandemic, the same investigational fervor must be applied to the issue of racism to combat this sinister and often deadly disease.

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“…Not only are “simple” molecules designed to interfere with therapeutic targets, but complex structures such as nanoparticles, viruses, bacteria, and even cells are engineered as therapeutic tools or delivery systems of (small) molecules to engage and interfere with target molecules or cells. In addition to these therapies directly influencing their targets, innovative vaccines or CAR-T cells aimed at enhancing or silencing specific immune responses against a molecular or cellular target are increasingly used in the treatment against various diseases such as cancer, auto-immune diseases, infections, or neurodegenerative diseases (including dementia) [ 11 , 12 ]. The scientific methodology and philosophy that clinical pharmacologists have developed for the evaluation of efficacy and safety of traditional drugs can (and should!)…”

Section: Step 3: What Are the Therapeutic Options?mentioning

confidence: 99%

The scientific basis of rational prescribing. A guide to precision clinical pharmacology based on the WHO 6-step method

Rongen

Marquet

Gerven³

2020

Eur J Clin Pharmacol

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Background and methods This opinion paper expanded on the WHO “six-step approach to optimal pharmacotherapy,” by detailed exploration of the underlying pharmacological and pathophysiological principles. This exercise led to the identification of a large number of domains of research that should be addressed to make clinical pharmacology progress toward “precision clinical pharmacology,” as a prerequisite for precision medicine. Result In order to improve clinical efficacy and safety in patient groups (to guide drug development) as well as in individuals (to guide therapeutic options and optimize clinical outcome), developments in clinical pharmacology should at least tackle the following: (1) molecular diagnostic assays to guide drug design and development and allow physicians to identify the optimal targets for therapy in the individual patient in a quick and precise manner (to guide selection of the right drug for the right patient); (2) the setting up and validation of biomarkers of target engagement and modification as predictors of clinical efficacy and safety; (3) integration of physiological PK/PD models and intermediate markers of pharmacological effects with the natural evolution of the disease to predict the drug dose that most effectively improves clinical outcome in patient groups and individuals, making use of advanced modeling technologies (building on deterministic models, machine-learning, and deep learning algorithms); (4) methodology to validate human or humanized in vitro, ex vivo, and in vivo models for their ability to predict clinical outcome with investigational therapies, including nucleic acids or recombinant genes together with vectors (including viruses or nanoparticles), cell therapy, or therapeutic vaccines; (5) methodological complements to the gold-standard, large Phase 3 randomized clinical trial to provide clinically relevant and reliable data on the efficacy and safety of all treatment options at the population level (pragmatic clinical trials), as well as in small groups of patients (as low as n = 1); (6) regulatory science, so as to optimize the ethical review process, documentation, and monitoring of clinical trials, improve efficiency, and reduce costs of clinical drug development; (7) interventions to effectively improve patient compliance and to rationalize polypharmacy for the reduction of adverse effects and the enhancement of therapeutic interactions; and (8) appraisal of the ecological and societal impact of drug use to safeguard against environmental hazards (following the “One Health” concept) and to reduce drug resistance. Discussion and conclusion As can be seen, precision clinical pharmacology aims at being highly translational, which will require very large panels of complementary skills. Interdisciplinary collaborations, including non-clinical pharmacologists, will be key to achieve such an ambitious program.

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Tuning the performance of CAR T cell immunotherapies

Cited by 10 publications

References 52 publications

Acute Conditioning of Antigen-Expanded CD8+ T Cells via the GSK3β-mTORC Axis Differentially Dictates Their Immediate and Distal Responses after Antigen Rechallenge

Acute Conditioning of Antigen-Expanded CD8+ T Cells via the GSK3β-mTORC Axis Differentially Dictates Their Immediate and Distal Responses after Antigen Rechallenge

Why Racial Justice Matters in Radiation Oncology

The scientific basis of rational prescribing. A guide to precision clinical pharmacology based on the WHO 6-step method

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