Development of CAR-T Cell Persistence in Adoptive Immunotherapy of Solid Tumors

Fan, Jiaqiao; Das, Jugal Kishore; Xiong, Xiaofang; Chen, Hailong; Song, Jianxun

doi:10.3389/fonc.2020.574860

Cited by 15 publications

(15 citation statements)

References 51 publications

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“…The MSGV1 γ retroviral vector backbone was modified to express CEA specific scFv, as described in our previous study. 14 Briefly, CD8 + T cells isolated from B6 Thy 1.2 mice were transduced with the viral supernatants containing CEA in the presence of 5 µg/mL Polybrene (Sigma Aldrich, USA), following a protocol as described previously. 15 The transduced cells were positively identified by expression of c-Myc.…”

Section: Methodsmentioning

confidence: 99%

Live attenuated bacterium limits cancer resistance to CAR-T therapy by remodeling the tumor microenvironment

Guo

Das

Kobayashi

et al. 2022

J Immunother Cancer

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The tumor microenvironment (TME) is characterized by the activation of immune checkpoints, which limit the ability of immune cells to attack the growing cancer. To overcome immune suppression in the clinic, antigen-expressing viruses and bacteria have been developed to induce antitumor immunity. However, the safety and targeting specificity are the main concerns of using bacteria in clinical practice as antitumor agents. In our previous studies, we have developed an attenuated bacterial strain (Brucella melitensis 16M ∆vjbR, henceforth Bm∆vjbR) for clinical use, which is safe in all tested animal models and has been removed from the select agent list by the Centers for Disease Control and Prevention. In this study, we demonstrated that Bm∆vjbR homed to tumor tissue and improved the TME in a murine model of solid cancer. In addition, live Bm∆vjbR promoted proinflammatory M1 polarization of tumor macrophages and increased the number and activity of CD8+ T cells in the tumor. In a murine colon adenocarcinoma model, when combined with adoptive transfer of tumor-specific carcinoembryonic antigen chimeric antigen receptor CD8+ T cells, tumor cell growth and proliferation was almost completely abrogated, and host survival was 100%. Taken together, these findings demonstrate that the live attenuated bacterial treatment can defeat cancer resistance to chimeric antigen receptor T-cell therapy by remodeling the TME to promote macrophage and T cell-mediated antitumor immunity.

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Section: Methodsmentioning

confidence: 99%

Live attenuated bacterium limits cancer resistance to CAR-T therapy by remodeling the tumor microenvironment

Guo

Das

Kobayashi

et al. 2022

J Immunother Cancer

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“…Moreover, immunological clearance due to CAR rejection by the host immune system has been reported in several clinical trials. Therefore, the molecular design of the CAR construct and the ex vivo culturing procedures play important roles in shaping the response to CAR T-cell therapy, in terms of both potency and duration [ 38 , 39 , 40 , 41 ]. In this section, we will discuss the determinants of CAR T-cell therapy efficacy and highlight that peak expansion and persistence should be considered when choosing a CAR T-cell product.…”

Section: Factors Influencing T-cell Persistence In Clinical Settingsmentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

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Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.

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“…Mounting evidence suggests that successful outcomes in patients treated with CAR-T cells depend on the cells’ ability to expand and persist after infusion. One of the major issues of using CAR-T cells for the treatment of solid tumors is the low persistence of the cells infused within the tumor mass ( 12 ). Long-term persistence and robust in vivo expansion of CAR-T cells infused during ACT are associated with sustained clinical remission and survival of recipient patients ( 11 , 13 – 15 ).…”

Section: Introductionmentioning

confidence: 99%

CAR-T Cell Performance: How to Improve Their Persistence?

López-Cantillo¹,

Urueña

Camacho³

et al. 2022

Front. Immunol.

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Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs.

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Development of CAR-T Cell Persistence in Adoptive Immunotherapy of Solid Tumors

Cited by 15 publications

References 51 publications

Live attenuated bacterium limits cancer resistance to CAR-T therapy by remodeling the tumor microenvironment

Live attenuated bacterium limits cancer resistance to CAR-T therapy by remodeling the tumor microenvironment

Improving CAR T-Cell Persistence

CAR-T Cell Performance: How to Improve Their Persistence?

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