Harnessing the chemokine system to home CAR-T cells into solid tumors

Foeng, Jade; Comerford, Iain; McColl, Shaun R.

doi:10.1016/j.xcrm.2022.100543

Cited by 43 publications

(36 citation statements)

References 148 publications

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“…Indeed, co-expression of IL-7 with anti-CD19 CAR T cells has been shown to prolong the persistence of infused T-cells and enhanced anti-tumor response via metabolic reprogramming of CAR-T cells, thus provided clinical rationale to IL-7 signaling for modulation of T-cell function to enhance CAR-T cell persistence and induce durable remission upon CAR-T cell therapy 36 . Furthermore, coexpression CAR T cells with chemokines or chemokine receptors has been shown to target CAR T cells and endogenous immune cells into solid tumors 37 . Consistently, our preclinical study of 7 × 19 CAR T cells as well as previously reported anti-CD20 CAR T cells constitutively co-expressing IL-7 and CCL19 15 demonstrated increased proliferation, survival and central and stem memory T cell differentiation upon tumor antigen stimulation in vitro and enhanced CAR T cell expansion, persistence, tumor-targeting and complete elimination of pre-established lymphoma in xenograft tumor models compared to parental CAR T cells.…”

Section: Discussionmentioning

confidence: 99%

Safety and Feasibility of Anti-CD19 CAR T Cells Expressing Inducible IL-7 and CCL19 in Patients with Relapsed or Refractory Large B-cell Lymphoma

Han

Gao

Zhang

et al. 2022

Preprint

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Chimeric antigen receptor (CAR) T cell therapy provides a potentially curative option for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL). However, there are major limitations of this therapy which result in treatment resistance in B-cell malignancies, including the inadequate CAR T cell trafficking and tumor infiltration, frequent tumor antigen escape and poor CAR T cell persistence. Here we report the development of the CD19-specific CAR T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR T cells), the preclinical study and multicenter phase 1b clinical trial of 7 × 19 CAR T cell therapy in patients with R/R LBCL (NCT03258047). The clinical trial of 7 × 19 CAR T cells showed a favorable safety profile in a cohort of R/R LBCL patients (n = 39), with grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and grade 3 or higher neurotoxicity in 4 (10.3%) patients. The overall response rate at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression-free survival was 13 months, and the median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3–72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.

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Section: Discussionmentioning

confidence: 99%

Safety and Feasibility of Anti-CD19 CAR T Cells Expressing Inducible IL-7 and CCL19 in Patients with Relapsed or Refractory Large B-cell Lymphoma

Han

Gao

Zhang

et al. 2022

Preprint

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“…One strategy to improve CAR T-cell trafficking into solid tumors involves the expression of chemokine receptors that correspond to chemokines found in the tumor microenvironment 70 . For example, mesothelin-directed CAR T cells, designed to also express chemokine receptors CCR2b and CCR4, were better able to infiltrate into MCP-1–producing tumors in a non–small cell lung carcinoma model 71 .…”

Section: Car T-cell Advancesmentioning

confidence: 99%

Chimeric Antigen Receptor T-Cell Therapy

Brookens

Posey

2023

Cancer J

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Genetically engineered chimeric antigen receptor (CAR) T-cell therapy leverages the ability of the immune system to eliminate tumors and redirects cytotoxic functions toward cells expressing specified tumor-restricted antigens. Although 6 CAR T-cell therapies have received Food and Drug Administration (FDA) approval for the treatment of many hematological malignancies, limitations involving T cell-intrinsic, T cell-extrinsic, and therapeutic factors remain in the treatment of both liquid and solid tumors. Chimeric antigen receptor design, signals from the tumor microenvironment, tumor antigen escape mechanisms, and systemic inflammatory consequences of CAR T-cell infusion all influence the efficacy and feasibility of CAR T-cell therapy in different malignancies. Here, we review the core structure of the CAR, the evolution of different CAR generations, CAR T-cell therapy limitations, and current strategies being investigated to overcome the T cell-intrinsic, T cell-independent, and therapeutic barriers to successful CAR T-cell therapy.

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“…Further studies have revealed a significant correlation between chemokine genes and T cell migration. Hence, some studies have focused on rescuing the chemokine and CCR axes to improve the activity of CAR-T cells [ 166 ]. Linchun Jin et al demonstrated that the coexpression of CXCR1 or CXCR2 , the CXCL8 receptor, increased the migration and persistence of CAR-T cells in the TME.…”

Section: Strategies For Enhancing Car-t Cell Function By Genetic Mani...mentioning

confidence: 99%

“…Moreover, expression levels of proinflammatory cytokines, including IL-2, IFN-γ, and TNF-α, were increased by CCR2 in the treatment of non-small cell lung carcinoma [ 169 ]. Another study showed that adoptive T cell intratumoral trafficking is improved by CXCL16-CXCR6 (significantly higher IFN-γ production compared to conventional CAR-T) [ 170 ], CXCL12-CXCR4 (enhanced CAR-T cells recruitment into CXCL12-rich bone marrow in an acute myeloid leukemia mouse model) [ 171 ], and CCL22-CCR4 (enhanced antitumor efficacy against a subcutaneous xenograft model of human Hodgkin’s lymphoma) [ 166 , 172 ]. Taken together, the results from abundant studies have highlighted the potential of combining the chemokine and receptor systems with CAR-T cells to markedly enhance immunotherapy, especially against solid tumors.…”

Section: Strategies For Enhancing Car-t Cell Function By Genetic Mani...mentioning

confidence: 99%

Strategies to enhance CAR-T persistence

Liu

Huang

et al. 2022

Biomark Res

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Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved the life expectancy for patients with refractory or relapse B cell lymphoma. As for B cell acute lymphoblastic leukemia (B-ALL), although the primary response rate is promising, the high incidence of early relapse has caused modest long-term survival with CAR-T cell alone. One of the main challenges is the limited persistence of CAR-T cells. To further optimize the clinical effects of CAR-T cells, many studies have focused on modifying the CAR structure and regulating CAR-T cell differentiation. In this review, we focus on CAR-T cell persistence and summarize the latest progress and strategies adopted during the in vitro culture stage to optimize CAR-T immunotherapy by improving long-term persistence. Such strategies include choosing a suitable cell source, improving culture conditions, combining CAR-T cells with conventional drugs, and applying genetic manipulations, all of which may improve the survival of patients with hematologic malignancies by reducing the probability of recurrence after CAR-T cell infusion and provide clues for solid tumor CAR-T cell therapy development.

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Harnessing the chemokine system to home CAR-T cells into solid tumors

Cited by 43 publications

References 148 publications

Safety and Feasibility of Anti-CD19 CAR T Cells Expressing Inducible IL-7 and CCL19 in Patients with Relapsed or Refractory Large B-cell Lymphoma

Safety and Feasibility of Anti-CD19 CAR T Cells Expressing Inducible IL-7 and CCL19 in Patients with Relapsed or Refractory Large B-cell Lymphoma

Chimeric Antigen Receptor T-Cell Therapy

Strategies to enhance CAR-T persistence

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