CAR-T cell therapy: current limitations and potential strategies

Sterner, Robert C.; Sterner, Rosalie M.

doi:10.1038/s41408-021-00459-7

Cited by 1,012 publications

(593 citation statements)

References 105 publications

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“…Chimeric antigen receptor-modified T cells targeting CD19 (CAR-19) are among new immunotherapy options for patients with diffuse large B-cell lymphoma (DLBCL) [1][2][3] . Unfortunately, treatment failures and relapses are common [4][5][6][7][8][9] , and underlying mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

Jain

Ziccheddu

Coughlin

et al. 2021

Preprint

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Chimeric antigen receptor-reprogrammed autologous T cells directed to CD19 are breakthrough immunotherapies for heavily pretreated patients with aggressive B-cell lymphomas but still fail to cure most patients. Host inflammatory and tumor microenvironmental factors associate with CAR-19 resistance, but the tumor-intrinsic factors underlying these phenomena remain undefined. To characterize genomic drivers of resistance, we interrogated whole genome sequencing of 30 tumor samples from 28 uniformly CAR-19-treated large-cell lymphoma patients. We reveal that patterns of genomic complexity (i.e., chromothripsis and APOBEC mutational activity), and distinct genomic alterations (deletions of RB1 or RHOA) associate with more exhausted immune microenvironments and poor outcome after CAR-19 therapy. Strikingly, pretreatment reduced expression or sub-clonal mutation of CD19 did not affect responses, suggesting CAR-19 therapy successes are due not only to direct antigen-dependent cytotoxicity but require surmounting immune exhaustion in tumor microenvironments to permit broader host responses that eliminate tumors

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Section: Introductionmentioning

confidence: 99%

Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

Jain

Ziccheddu

Coughlin

et al. 2021

Preprint

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“…However, the tumor microenvironment usually favors immune escape by downregulation of the costimulatory signals that prompt an insufficient activation of effector cells [20,23]. Similarly, the short half-life of the adoptive T cells in vivo is one of the primary obstacles of T cell-based cancer immunotherapy due to the lack of costimulatory signals in the tumor microenvironment [24,25]. Therefore, immunotherapy utilizing the costimulatory molecules may circumvent these problems.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activities of Immune Costimulatory Molecules of TNF Superfamily in Colorectal and Lung Cancers

Gui¹,

Wang²,

Pan³

et al. 2021

austinjcancerclinres

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Cancer immunotherapy has emerged as a promising treatment that utilizes the innate or adaptive immunity to generate a robust killing of malignant cells. However, only a limited number of cancer patients showed responsiveness to immunotherapies such as checkpoint inhibitors, suggesting the need for potent alternative strategies. In the present study, we explored the therapeutic potentials of costimulatory molecules including TNF superfamily member 4 (TNFSF4), member 9 (TNFSF9), and member 18 (TNFSF18). In tumor samples from human colorectal and lung cancer patients, expression of these factors positively correlated with lymphocyte infiltration and expression of several immune effector genes. In syngeneic mouse tumor models, overexpression of the TNF superfamily costimulatory factors in murine colorectal or lung cancer cells significantly suppressed tumor progression. Especially, TNFSF9 and 18 showed stronger antitumor effects than TNFSF4. Together, our study demonstrated the great potential of cancer immunotherapy targeting these immune costimulatory molecules.

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“…The immunosuppressive tumor microenvironment suppresses NK cell function (16), and although many drugs and radiation can sensitize tumors for recognition by NK cells, chemotherapy, anesthesia, and radiation therapies can also adversely affect NK cell numbers and function (17)(18)(19)(20)(21). While much effort has gone into T-cell based approaches for immunotherapy, including chimeric antigen receptor (CAR) Tcells and immune checkpoint inhibition, these approaches can have significant problems that may impede their application such as graft-vs. host disease (GVHD), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or severe on-target off-tissue toxicities (22,23). Adoptive NK cell therapy is not associated with GVHD (24), thus making it potentially safer than T-cell based therapies and because allogeneic transfer is tolerated, NK cell products can be manufactured and stored for later use in patients as needed, rather than manufacturing "on-demand" for patient-specific use.…”

Section: Rationale For Adoptive Nk Cell Immunotherapymentioning

confidence: 99%

Adoptive Natural Killer Cell Immunotherapy for Canine Osteosarcoma

Kisseberth

Lee

2021

Front. Vet. Sci.

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Osteosarcoma is the most common primary bone tumor in both humans and dogs. It is a highly metastatic cancer and therapy has not improved significantly since the inclusion of adjuvant chemotherapy into disease treatment strategies. Osteosarcoma is an immunogenic tumor, and thus development of immunotherapies for its treatment, especially treatment of microscopic pulmonary metastases might improve outcomes. NK cells are lymphocytes of the innate immune system and can recognize a variety of stressed cells, including cancer cells, in the absence of major histocompatibility complex (MHC)-restricted receptor ligand interactions. NK cells have a role in controlling tumor progression and metastasis and are important mediators of different therapeutic interventions. The core hypothesis of adoptive natural killer (NK) cell therapy is there exists a natural defect in innate immunity (a combination of cancer-induced reduction in NK cell numbers and immunosuppressive mechanisms resulting in suppressed function) that can be restored by adoptive transfer of NK cells. Here, we review the rationale for adoptive NK cell immunotherapy, NK cell biology, TGFβ and the immunosuppressive microenvironment in osteosarcoma, manufacturing of ex vivo expanded NK cells for the dog and provide perspective on the present and future clinical applications of adoptive NK cell immunotherapy in spontaneous osteosarcoma and other cancers in the dog.

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CAR-T cell therapy: current limitations and potential strategies

Cited by 1,012 publications

References 105 publications

Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

Antitumor Activities of Immune Costimulatory Molecules of TNF Superfamily in Colorectal and Lung Cancers

Adoptive Natural Killer Cell Immunotherapy for Canine Osteosarcoma

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