TGF-β1 Induces Preferential Rapid Expansion and Persistence of Tumor Antigen-specific CD8+ T Cells for Adoptive Immunotherapy

Liu, Shujuan; Etto, Tamara Louise; Rodriguez-Cruz, Tanya; Li, Yufeng; Wu, Cheng-Han; Fulbright, Orenthial J.; Hwu, Patrick; Radvanyi, Laszlo G.; Lizee, Gregory

doi:10.1097/cji.0b013e3181cd1180

Cited by 12 publications

(9 citation statements)

References 30 publications

(36 reference statements)

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“…Alternatively, small molecules targeting the CD28 signaling pathway as, for example, Akt kinase inhibitors may allow separation of aGvHD suppression and GvT effect preservation in recipients of allogeneic BM transplantations. Also, blocking the actions of TGF‐β in vitro beneficially influenced the GvT effect in our experiments and, indeed, also in other experimental systems . CD28‐SA stimulation in the presence of TGF‐β blockade could, thus, follow up on the results obtained in a first phase I clinical trial using in vitro costimulated human T cells to perform activated donor lymphocyte infusions .…”

Section: Discussionsupporting

confidence: 67%

In vitro polyclonal activation of conventional T cells with a CD28 superagonist protects mice from acute graft versus host disease

et al. 2015

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Upon transplantation of T cells from a CD28 superagonist (CD28-SAKeywords: aGvHD r Conventional T cells r CD28 superagonist r GvT effect Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAcute graft versus host disease (aGvHD) still constitutes a major obstacle to successful treatment of hematological malignancies by the transplantation of allogeneic T cells [1]. It is the allogeneic T cells themselves that mediate the beneficial graft versus tumor (GvT) effect and induce the potentially life-threatening aGvHD [2]. Therefore, it has been a long-standing aim to establish protocols that prevent aGvHD while not abrogating the GvT effect [1][2][3]. In this respect, the use of CD4 + CD25 + Foxp3 + regulatory T cells (T reg cells) has proven very promising in that they have, indeed, been shown to suppress aGvHD [4][5][6][7][8][9], but not the GvT effect in experimental animal models [4][5][6][7][8][9][10]. In the human system, T reg cell numbers are very low in the peripheral blood to Correspondence: Dr. Niklas Beyersdorf e-mail: niklas.beyersdorf@vim.uni-wuerzburg.de begin with and it may, thus, well be that demanding protocols for large-scale amplification of still functional T reg cells in vitro prior to transplantation in vivo might have to be implicated to robustly achieve prevention of aGvHD in humans [11][12][13]. An alternative to the transplantation of T reg cells for aGvHD prevention is to manipulate, also in the human system amply available, conventional CD4 + T cells (CD4 + T conv cells). Published work indicates that effector memory-phenotype T cells [14][15][16][17][18] and in vitro preactivated CD4 + T cells induce less aGvHD in allogeneic recipients than resting CD4 + T cells [8,[19][20][21][22]. However, at least for some of these settings, including the stimulation of total CD4 + T cells with a superagonistic anti-CD28 monoclonal antibody (CD28-SA) in vitro, it has been shown that it is the preferential expansion of T reg cells over CD4 + T conv cells, which underlies the reduced induction of aGvHD [8,23]. Therefore, we determined whether polyclonal stimulation of T conv cells would be sufficient for protection from aGvHD while, ideally, maintaining the GvT effect. To this end we compared two protocols: one Eur. J. Immunol. 2015. 45: 1997 employing CD28-SA-coated beads and the other anti-CD3/anti-CD28 mAb-coated beads. One reason for immobilizing the CD28-SA on beads was to be able to separate the CD28-SA from the T cells so that only T cells, but not the CD28-SA is infused into the allogeneic host. This appeared to be an essential component of our protocol at the time we designed these experiments as a CD28-SA had elicited a cytokine storm during phase I clinical testing in healthy volunteers in vivo [24]. Very recent data from another phase I study, however, clearly show that low dosages of CD28-SA do not induce a cytokine storm in humans but lead to an IL-10-dominated immunoregulatory response [25]. This means that rigorou...

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Section: Discussionsupporting

confidence: 67%

In vitro polyclonal activation of conventional T cells with a CD28 superagonist protects mice from acute graft versus host disease

et al. 2015

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“…There is currently no consensus on how to culture NK cells for adoptive cell therapy, in contrast to the extensive experimentation performed to determine optimal culture conditions for the expansion of T cells and development of the rapid expansion protocol. [33][34][35][36][37] These T cells studies have been made possible by a comprehensive understanding of B and T cell expansion mechanisms and kinetics, provided in part by our group. [38][39][40][41][42][43] Here, we apply our methods for quantifying lymphocyte kinetics to NK cells and document the dynamic range of NK cell responses over a broad range of IL-15 concentrations in vitro.…”

Section: Deletion Ofmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantifying NK cell growth and survival changes in response to cytokines and regulatory checkpoint blockade helps identify optimal culture and expansion conditions

Hennessy

Pham

Delconte

et al. 2019

Journal of Leukocyte Biology

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NK cells are innate lymphocytes critical for immune surveillance, particularly in eradication of metastatic cancer cells and acute antiviral responses. In contrast to T cells, NK cell‐mediated immunity is rapid, with spontaneous cytotoxicity and cytokine/chemokine production upon pathogen detection. The renaissance in cancer immunology has cast NK cell biology back into the spotlight with an urgent need for deeper understanding of the regulatory networks that govern NK cell antitumor activity. To this end, we have adapted and refined a series of quantitative cellular calculus methods, previously applied to T and B lymphocytes, to dissect the biologic outcomes of NK cells following stimulation with cytokines (IL‐15, IL‐12, IL‐18) or deletion of genes that regulate NK cell proliferation (Cish), survival (Bcl2l11), and activation‐induced‐cell‐death (AICD; Fas). Our methodology is well suited to delineate effects on division rate, intrinsic apoptosis, and AICD, permitting variables such as population half‐life, rate of cell division, and their combined influence on population numbers in response to stimuli to be accurately measured and modelled. Changes in these variables that result from gene deletion, concentration of stimuli, time, and cell density give insight into the dynamics of NK cell responses and serve as a platform to dissect the mechanism of action of putative checkpoints in NK cell activation and novel NK cell immunotherapy agents.

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“…Other approaches suggested by others include using TGF-β which has been shown to augment the expansion of CD8 + T cells during the REP and may preserve memory functioning (119) or activators of Wnt/β-catenin signaling pathway (e.g, Wnt-3A, or pharmacologic inhibitor of glycogen synthase kinase-3β (GSK-3β), such as lithium chloride) to arrest CD8 + differentiation during the REP (120, 121). IL-21 was also reported to have Wnt-like effect in maintaining memory features of CD8 + T cells (116, 122).…”

Section: Consequences Of Til Expansion Needed For Therapy: Loss Of Crmentioning

confidence: 99%

Adoptive T-Cell Therapy Using Autologous Tumor-Infiltrating Lymphocytes for Metastatic Melanoma

et al. 2012

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Immunotherapy using autologous T-cells has emerged to be a powerful treatment option for patients with metastatic melanoma. These include the adoptive transfer of autologous tumor-infiltrating lymphocytes (TIL), T-cells transduced with high-affinity T-cell receptors (TCR) against major melanosomal tumor antigens, and T cells transduced with chimeric antigen receptors (CAR) composed of hybrid immunoglobulin light chains with endo-domains of T-cell signaling molecules. Among these and other options for T-cell therapy, TIL together with high-dose IL-2 has had the longest clinical history with multiple clinical trials in centers across the world consistently demonstrating durable clinical response rates near 50% or more. A distinct advantage of TIL therapy making it still the T-cell therapy of choice is the broad nature of the T-cell recognition against both defined as well as un-defined tumors antigens against all possible MHC, rather than the single specificity and limited MHC coverage of the newer TCR and CAR transduction technologies. In the past decade, significant inroads have been made in defining the phenotypes of T cells in TIL mediating tumor regression. CD8+ T cells are emerging to be critical, although the exact subset of CD8+ T cells exhibiting the highest clinical activity in terms of memory and effector markers is still controversial. We present a model in which both effector-memory and more differentiated effector T cells ultimately may need to cooperate to mediate long-term tumor control in responding patients. Although TIL therapy has shown great potential to treat metastatic melanoma, a number of issues have emerged that need to be addressed to bring it more into the mainstream of melanoma care. First, we have a reached the point where a pivotal phase II or phase III trials are needed in an attempt to gain regulatory approval of TIL as standard-of-care. Second, improvements in how we expand TIL for therapy are needed, that minimize the time the T-cells are in culture and improve the memory and effector characteristics of the T cells for longer persistence and enhanced anti-tumor activity in vivo. Third, there is a critical need to identify surrogate and predictive biomarkers in order to better select suitable patients for TIL therapy in order to improve response rate and duration. Overall, the outlook for TIL therapy for melanoma is very bright. We predict that TIL will indeed emerge to become an approved treatment in the upcoming years through pivotal clinical trials. Moreover, new approaches combining TIL with targeted signaling pathway drugs, such as mutant B-RAF inhibitors, and synergistic immunomodulatory interventions enhancing T-cell costimulation and preventing negative regulation, should further increase therapeutic efficacy and durable complete response rates.

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TGF-β1 Induces Preferential Rapid Expansion and Persistence of Tumor Antigen-specific CD8+ T Cells for Adoptive Immunotherapy

Cited by 12 publications

References 30 publications

In vitro polyclonal activation of conventional T cells with a CD28 superagonist protects mice from acute graft versus host disease

In vitro polyclonal activation of conventional T cells with a CD28 superagonist protects mice from acute graft versus host disease

Quantifying NK cell growth and survival changes in response to cytokines and regulatory checkpoint blockade helps identify optimal culture and expansion conditions

Adoptive T-Cell Therapy Using Autologous Tumor-Infiltrating Lymphocytes for Metastatic Melanoma

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