Chimeric Antigen Receptor T Cell Therapy for Solid Tumors: Current Status, Obstacles and Future Strategies

Heyman, Benjamin; Yang, Yiping

doi:10.3390/cancers11020191

Cited by 36 publications

(29 citation statements)

References 132 publications

(160 reference statements)

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“…Some approaches for generating tumorand patient-specific CAR-Ts were proposed using lymphoma as a model; however, manufacturing of the cell product requires several weeks and is not fully applicable for solid tumors [46]. The variety of antigens amenable for CAR-T immunotherapy is limited due to the overall tumor heterogeneity and nonuniformity of antigen expression [55]. The suitable antigens are often shared between the tumor and healthy tissues differing only in antigen density that makes potential toxicity a major issue.…”

Section: Is Selection Of An Optimal Target a Cornerstone Of Car T-celmentioning

confidence: 99%

Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

Titov

Valiullina

Zmievskaya

et al. 2020

Cancers

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Chimeric antigen receptor (CAR) immunotherapy is one of the most promising modern approaches for the treatment of cancer. To date only two CAR T-cell products, Kymriah® and Yescarta®, have been approved by the Food and Drug Administration (FDA) for the treatment of lymphoblastic leukemia and B-cell lymphoma. Administration of CAR T-cells to control solid tumors has long been envisaged as one of the most difficult therapeutic tasks. The first two clinical trials conducted in sarcoma and neuroblastoma patients showed clinical benefits of CAR T-cells, yet multiple obstacles still hold us back from having accessible and efficient therapy. Why did such an effective treatment for relapsed and refractory hematological malignancies demonstrate only relatively modest efficiency in the context of solid tumors? Is it due to the lucky selection of the “magic” CD19 antigen, which might be one of a kind? Or do lymphomas lack the immunosuppressive features of solid tumors? Here we review the existing knowledge in the field of CAR T-cell therapy and address the heterogeneity of solid tumors and their diverse strategies of immunoevasion. We also provide an insight into prospective developments of CAR T-cell technologies against solid tumors.

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Section: Is Selection Of An Optimal Target a Cornerstone Of Car T-celmentioning

confidence: 99%

Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

Titov

Valiullina

Zmievskaya

et al. 2020

Cancers

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“…Targeting TAAs, on the other hand can potentially lead to "on-target, off-tumor" effects [52]. Regardless, many TAAs are currently under investigation for the treatment of solid tumors, including CEA, GD2, mesothelin, HER2, MUC1, FAP, LICAM, and IL13Rα [53]. More recently, researchers have increasingly focused on tumor neoantigens that are produced in tumor cells as a result of somatic mutation.…”

Section: Tumor Heterogeneitymentioning

confidence: 99%

“…Currently, several strategies to augment antigen expression targeted by CAR-T cells have achieved success in preclinical settings. Inhibition of gamma-secretase which increased the expression of BCMA or adding all-trans retinoic acid which upregulated CD38 both have found to be beneficial in augmenting CAR-T cell functions in multiple myeloma [24,53]. Additionally, several groups developed "Tandem CARs", which are bispecific CAR-T cells that have two scFvs against two different antigens linked by a single molecule in the same CAR-T construct or bicistronic CARs in which two monospecific CARs are expressed from the same vector ( Figure 1B).…”

Section: Strategies To Improve Carsmentioning

confidence: 99%

Chimeric Antigen Receptor Cell Therapy: Overcoming Obstacles to Battle Cancer

Petty

Heyman

Yang

2020

Cancers

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Chimeric antigen receptors (CAR) are fusion proteins engineered from antigen recognition, signaling, and costimulatory domains that can be used to reprogram T cells to specifically target tumor cells expressing specific antigens. Current CAR-T cell technology utilizes the patient’s own T cells to stably express CARs and has achieved exciting clinical success in the past few years. However, current CAR-T cell therapy still faces several challenges, including suboptimal persistence and potency, impaired trafficking to solid tumors, local immunosuppression within the tumor microenvironment and intrinsic toxicity associated with CAR-T cells. This review focuses on recent strategies to improve the clinical efficacy of CAR-T cell therapy and other exciting CAR approaches currently under investigation, including CAR natural killer (NK) and NKT cell therapies.

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“…Releasing the brakes of the immune inhibitory system is also an important strategy to boost the immune response against tumors. Checkpoint and immunosuppressive cytokines are the main actors that block the immune system from acting on tumors [115].…”

Section: Overcoming Immune Inhibition To Boost Immune Responses In Camentioning

confidence: 99%

“…T cells express co-inhibitory receptors, such as PD-1 [115], that decrease T cell-mediated tumor immunity and enhance tumor escape. Blocking antibodies against PD-1/PD-L1 have achieved beneficial activity in clinical practice [116][117][118][119].…”

Section: Targeting Immune Checkpointsmentioning

confidence: 99%

Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system

Wang

Qiu

et al. 2020

Front. Med.

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Chimeric antigen receptor (CAR) T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies. However, CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence, in addition to antigen-negative relapse and an immunosuppressive microenvironment. Various preclinical studies are exploring strategies to overcome the above challenges. Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors. In this review, we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies, especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response. We also explored the sensitizing effects of conventional treatment approaches, such as chemotherapy and radiotherapy, on CAR T cell therapy. Finally, we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.

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Chimeric Antigen Receptor T Cell Therapy for Solid Tumors: Current Status, Obstacles and Future Strategies

Cited by 36 publications

References 132 publications

Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

Chimeric Antigen Receptor Cell Therapy: Overcoming Obstacles to Battle Cancer

Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system

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