PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells

Lee, Young-Ho; Lee, Hyeong Ji; Kim, Hyung Cheol; Lee, Yujean; Nam, Su Kyung; Hupperetz, Cedric; S.Y., Jennifer; Wang, Xinxin; Singer, Oded; Kim, Won Seog; Kim, Seok Jin; Koh, Youngil; Jung, Inkyung; Kim, Chan Hyuk

doi:10.1016/j.ymthe.2021.10.004

Cited by 43 publications

(24 citation statements)

References 75 publications

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“…Therefore, we considered that the re-expansion of CAR-T cells and the curative effect were associated with the expression of PD-1 or PD-L1. In addition to the use of PD-1 inhibitors, some researchers have used other methods to inhibit the expression of PD-1 or other checkpoint receptors on CAR-T cells, such as adenine base editors or short hairpin RNAs, and these new CAR-T cells have shown better anticancer effects in vitro ( 18 , 19 ). Nevertheless, further clinical trials should be conducted to determine the effect of such CAR-T cells in patients.…”

Section: Discussionmentioning

confidence: 99%

Strategies to overcome CAR-T cell resistance in clinical work: A single-institute experience

Nan

Chen

et al. 2022

Front. Immunol.

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The emergence of chimeric antigen receptor (CAR) T cell therapy has shifted the paradigm of malignant tumor treatment, especially the advent of CD19-directed CAR-T cell therapy for the treatment of relapsed/refractory (R/R) B-cell malignancies. Although CAR-T cell therapy has promising effects, some patients are resistant to this treatment, leaving them with limited options. Therefore, strategies to overcome resistance to CAR-T cell therapy are needed. We retrospectively studied three R/R diffuse large B-cell lymphoma patients who were resistant to CAR-T cell therapy and whose disease was controlled after receiving pembrolizumab, 21D4 CAR-T cells, or ibrutinib and venetoclax. Some promising prevention and treatment strategies to overcome treatment resistance are also discussed.

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Section: Discussionmentioning

confidence: 99%

Strategies to overcome CAR-T cell resistance in clinical work: A single-institute experience

Nan

Chen

et al. 2022

Front. Immunol.

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“…Additionally, it was recently demonstrated that PD-1 and TIGIT simultaneous downregulation in CAR-T cells using shRNA promoted a robust antitumor response and improved in vivo CAR-T-cell persistence [ 72 ]. Currently, there is a clinical trial underway to evaluate the use of PD-1/TIGIT-downregulated anti-CD19 CAR-T cells in patients with relapsed or refractory DLBCL (NCT04836507).…”

Section: Combining Adoptive T-cell Transfer With Immunological Checkp...mentioning

confidence: 99%

Combination of genetically engineered T cells and immune checkpoint blockade for the treatment of cancer

Rossetti

Brand

Lima

et al. 2022

Immunotherapy Advances

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Immune checkpoint (IC) blockade using monoclonal antibodies is currently one of the most successful immunotherapeutic interventions to treat cancer. By reinvigorating antitumor exhausted T cells, this approach can lead to durable clinical responses. However, the majority of patients either does not respond or present a short-lived response to IC blockade, in part due to a scarcity of tumor-specific T cells within the tumor microenvironment. Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) provide the necessary tumor-specific immune cell population to target cancer cells. However, this therapy has been considerably ineffective against solid tumors in part due to IC-mediated immunosuppressive effects within tumor microenvironment. These limitations could be overcome by associating adoptive cell transfer of genetically engineered T cells and IC blockade. In this comprehensive review, we highlight the strategies and outcomes of preclinical and clinical attempts to disrupt IC signaling in adoptive T cell transfer against cancer. These strategies include combined administration of genetically engineered T cells and IC inhibitors, engineered T cells with intrinsic modifications to disrupt IC signaling and the design of CARs against IC molecules. The current landscape indicates that the synergy of the fast-paced refinements of gene-editing technologies and synthetic biology and the increased comprehension of IC signaling will certainly translate into novel and more effective immunotherapeutic approaches to treat patients with cancer.

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“…This feature targets CD155/TIGIT combined with PD-1 blocking therapy to improve the immune response. A chimeric antigen receptor (CAR) T cell targeting CD19 that integrates PD-1 and TIGIT has shown effective anti-tumor activity in relapsed or refractory large B-cell lymphoma, and significantly enhanced CAR-T persistence cells in vivo ( 57 ).…”

Section: Regulation Of Cd155/tigit In Immune Cellsmentioning

confidence: 99%

Role of CD155/TIGIT in Digestive Cancers: Promising Cancer Target for Immunotherapy

et al. 2022

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The tumor microenvironment restricts the function and survival of various immune cells by up-regulating inhibitory immune checkpoints, and participates in the immune escape of tumors. The development of immunotherapies targeting immune checkpoints, such as programmed cell death receptor 1 antibody and anti-cytotoxic T lymphocyte-associated antigen 4 antibody, has provided many options for cancer treatment. The efficacy of other immune checkpoint inhibitors is also under development and research. Among them, T cell immunoreceptor with Ig and ITIM domains (TIGIT) has shown excellent clinical application prospects. Correspondingly, poliovirus receptor (PVR, CD155), one of the main ligands of TIGIT, is mainly expressed in various human malignant tumors and myeloid cells. CD155 interacts with TIGIT on natural killer cells and T cells, mediating inhibitory immunomodulatory regulation. This study summarized the mechanism of CD155/TIGIT in regulating immune cells and its role in the occurrence and development of digestive system tumors, aiming to provide a new perspective for immunotherapy of digestive cancers.

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PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells

Cited by 43 publications

References 75 publications

Strategies to overcome CAR-T cell resistance in clinical work: A single-institute experience

Strategies to overcome CAR-T cell resistance in clinical work: A single-institute experience

Combination of genetically engineered T cells and immune checkpoint blockade for the treatment of cancer

Role of CD155/TIGIT in Digestive Cancers: Promising Cancer Target for Immunotherapy

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