Coexpression of IL7 and CCL21 Increases Efficacy of CAR-T Cells in Solid Tumors without Requiring Preconditioned Lymphodepletion

Luo, Hong; Jingwen, Su; Sun, Ruixin; Sun, Yu; Wang, Yi; Dong, Yiwei; Shi, Bizhi; Jiang, Hua; Li, Zonghai

doi:10.1158/1078-0432.ccr-20-0777

Cited by 106 publications

(74 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies demonstrated that it is possible to co-express multiple cytokines in the same CAR T-cell. For example, Luo et al (2020) engineered CAR T-cells to produce IL-7 and CCL21 and demonstrated that this combination improved survival and infiltration of CAR T-cells in solid tumors in vivo, without requiring preconditioned lymphodepletion [ 208 ]. NCT04833504 is a clinical trial recently completed in which CD19 + CAR T-cells expressing IL-7 and CCL19 were tested in patients with relapsed or refractory B-cell lymphoma, however the results have not yet been reported.…”

Section: Strategies To Improve Car T-cell Persistence and Potencymentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

View full text Add to dashboard Cite

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.

show abstract

Section: Strategies To Improve Car T-cell Persistence and Potencymentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…It was found that the secretion of cytokine IL-7 and chemokine CCL19 could promote the infiltration of T cells and dendritic cells (DC) in tumor tissue, reduce T cell depletion, and improve the anti-tumor activity of CAR-T. 69 In addition, IL-7 and CCL21 also significantly improve the proliferation and chemotaxis of CAR-T cells, enhancing the survival and infiltration of CAR-T and DC; besides, CCL21 could inhibit tumor angiogenesis. 70 The modification of IL-8 receptor CXCR1 or CXCR2 significantly enhanced the migration and persistence of CAR-T cells in tumors. 71 CAR-T cells expressing CXCR2 modified by integrin αvβ6-CAR migrated more effectively to tumor cells producing IL-8 receptors.…”

Section: Discussionmentioning

confidence: 99%

Construction of PD1/CD28 chimeric-switch receptor enhances anti-tumor ability of c-Met CAR-T in gastric cancer

Chen

Zhang

et al. 2021

OncoImmunology

View full text Add to dashboard Cite

Chimeric antigen receptor (CAR) T cell is a promising method in cancer immunotherapy but faces many challenges in solid tumors. One of the major problems was immunosuppression caused by PD-1. In our study, the expression of c-Met in GC was analyzed from TCGA datasets, GC tissues, and cell lines. The c-Met CAR was a second-generation CAR with 4-1BB, cMet-PD1/CD28 CAR was c-Met CAR adding PD1/CD28 chimeric-switch receptor (CSR). In vitro, we measured the changes of different subgroups, phenotypes and PD-1 expression in CAR-T cells. We detected the secretion levels of different cytokines and the killing ability of CAR-Ts. In vivo, we established a xenograft GC model and observed the anti-tumor effect and offtarget toxicity of different CAR-Ts. We find that the expression of c-Met was increased in GC. CD3 + CD8 + T cells and CD62L + CCR7 + central memory T cells (T CM ) were increased in two CAR-Ts. The stimulation of target cells could promote the expression of PD-1 in c-Met CAR-T. Compared with Mock T, the secretion of cytokines as IFN-γ, TNF-α, IL-6, IL-10 secreted by two CAR-Ts was increased, and the killing ability to c-Met positive GC cells was enhanced. The PD1/CD28 CSR could further enhance the killing ability, especially the long-term anti-tumor effect of c-Met CAR-T, and reduce the release level of IL-6. CAR-Ts target c-Met had no obvious off-target toxicity to normal organs. Thus, the PD1/CD28 CSR could further enhance the antitumor ability of c-Met CAR-T, and provides a promising design strategy to improve the efficacy of CAR-T in GC.

show abstract

“…Expression of both IL-7 and CCL19 increased intra-tumoral infiltration of CAR T cells, endogenous T cells, and DCs, which achieved complete regression of established solid tumors and led to the formation of a T cell memory response via epitope spreading. CAR T cells engineered to express IL-7 with CCL19 or CCL21 also had improved antitumor activity due to enhanced CAR T cell proliferation and chemotaxis (98). These studies have been translated into clinical trials to evaluate the safety and efficacy of IL-7 and CCL19 expressing CAR T cells against lymphoma, multiple myeloma, and solid tumors (Table 1).…”

Section: Interleukinmentioning

confidence: 99%

Engineered Cytokine Signaling to Improve CAR T Cell Effector Function

Bell

Gottschalk

2021

Front. Immunol.

View full text Add to dashboard Cite

Adoptive immunotherapy with T cells genetically modified to express chimeric antigen receptors (CARs) is a promising approach to improve outcomes for cancer patients. While CAR T cell therapy is effective for hematological malignancies, there is a need to improve the efficacy of this therapeutic approach for patients with solid tumors and brain tumors. At present, several approaches are being pursued to improve the antitumor activity of CAR T cells including i) targeting multiple antigens, ii) improving T cell expansion/persistence, iii) enhancing homing to tumor sites, and iv) rendering CAR T cells resistant to the immunosuppressive tumor microenvironment (TME). Augmenting signal 3 of T cell activation by transgenic expression of cytokines or engineered cytokine receptors has emerged as a promising strategy since it not only improves CAR T cell expansion/persistence but also their ability to function in the immunosuppressive TME. In this review, we will provide an overview of cytokine biology and highlight genetic approaches that are actively being pursued to augment cytokine signaling in CAR T cells.

show abstract

Coexpression of IL7 and CCL21 Increases Efficacy of CAR-T Cells in Solid Tumors without Requiring Preconditioned Lymphodepletion

Cited by 106 publications

References 48 publications

Improving CAR T-Cell Persistence

Improving CAR T-Cell Persistence

Construction of PD1/CD28 chimeric-switch receptor enhances anti-tumor ability of c-Met CAR-T in gastric cancer

Engineered Cytokine Signaling to Improve CAR T Cell Effector Function

Contact Info

Product

Resources

About