Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion

Gumber, Diana; Wang, Leo D.

doi:10.1016/j.ebiom.2022.103941

Cited by 194 publications

(110 citation statements)

References 149 publications

(195 reference statements)

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…CAR-T therapy could target T cells directly to tumor cells by genetically modifying T cells ( 210 ). Since the initial proposition of CAR-T in 1989, its antitumor efficacy and persistence have been improved due to altering the construction in the advanced generations of CAR-T. Based on these remarkable clinical responses, the FDA has approved four anti-CD19 CAR T-cell products and one anti-BCMA CAR T-cell therapy in different hematological cancers ( 211 ). However, the clinical efficacy of CAR T cells in the solid tumor has shown much less satisfactory results.…”

Section: Strategies In Overcoming Resistance To Immune Checkpoint Blo...mentioning

confidence: 99%

Mechanisms of tumor resistance to immune checkpoint blockade and combination strategies to overcome resistance

Zhou

Liang

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Immune checkpoint blockade (ICB) has rapidly transformed the treatment paradigm for various cancer types. Multiple single or combinations of ICB treatments have been approved by the US Food and Drug Administration, providing more options for patients with advanced cancer. However, most patients could not benefit from these immunotherapies due to primary and acquired drug resistance. Thus, a better understanding of the mechanisms of ICB resistance is urgently needed to improve clinical outcomes. Here, we focused on the changes in the biological functions of CD8+ T cells to elucidate the underlying resistance mechanisms of ICB therapies and summarized the advanced coping strategies to increase ICB efficacy. Combinational ICB approaches and individualized immunotherapies require further in-depth investigation to facilitate longer-lasting efficacy and a more excellent safety of ICB in a broader range of patients.

show abstract

Section: Strategies In Overcoming Resistance To Immune Checkpoint Blo...mentioning

confidence: 99%

Mechanisms of tumor resistance to immune checkpoint blockade and combination strategies to overcome resistance

Zhou

Liang

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Chimeric antigen receptor (CAR) T cell therapy has emerged as an effective cancer treatment [100]. IL-18-secreting CAR T cells presented expansion and persistence and significantly increased long-term survival in mouse models for hematological and solid malignancies.…”

Section: Il-18mentioning

confidence: 99%

The role of pyroptosis in modulating the tumor immune microenvironment

Wang

2022

Biomark Res

View full text Add to dashboard Cite

The tumor immune microenvironment (TIME) plays a key role in immunosuppression in cancer, which results in tumorigenesis and tumor progression, and contributes to insensitivity to chemotherapy and immunotherapy. Understanding the mechanism of TIME formation is critical for overcoming cancer. Pyroptosis exerts a dual role in modulating the TIME. In this review, we summarize the regulatory mechanisms of pyroptosis in modulating the TIME and the potential application of targeted pyroptosis therapy in the clinic. Several treatments targeting pyroptosis have been developed; however, the majority of treatments are still in preclinical studies. Only a few agents have been used in clinic, but the outcomes are unsatisfactory. More studies are necessary to determine the role of pyroptosis in cancer, and more research is required to realize the application of treatments targeting pyroptosis in the clinic.

show abstract

“…In contrast, the production of cytokines and granzyme B release were lower under hypoxic conditions, even CAR T-cells generated under atmospheric conditions. Since hypoxia modulates tumor growth and immune editing, a dual oxygen-sensing switch was designed to provide stringent hypoxia-dependent regulation of a CAR ( 110 ). The microdevice platform mimics the 3-D tumor with an O 2 gradient that facilitates evaluation of CAR T-cell anti-tumor infiltration and efficacy.…”

Section: Design Strategies To Improve Car T-cell Efficacy In Cancer T...mentioning

confidence: 99%

Road testing new CAR design strategies in multiple myeloma

et al. 2022

View full text Add to dashboard Cite

A deeper understanding of basic immunology principles and advances in bioengineering have accelerated the mass production of genetically-reprogrammed T-cells as living drugs to treat human diseases. Autologous and allogeneic cytotoxic T-cells have been weaponized to brandish MHC-independent chimeric antigen receptors (CAR) that specifically engage antigenic regions on tumor cells. Two distinct CAR-based therapeutics designed to target BCMA are now FDA-approved based upon robust, sustained responses in heavily-pretreated multiple myeloma (MM) patients enrolled on the KarMMa and CARTITUDE-1 studies. While promising, CAR T-cells present unique challenges such as antigen escape and T-cell exhaustion. Here, we review novel strategies to design CARs that overcome current limitations. Co-stimulatory signaling regions were added to second-generation CARs to promote IL-2 synthesis, activate T-cells and preclude apoptosis. Third-generation CARs are composed of multiple co-stimulatory signaling units, e.g., CD28, OX40, 4-1BB, to reduce exhaustion. Typically, CAR T-cells incorporate a potent constitutive promoter that maximizes long-term CAR expression but extended CAR activation may also promote T-cell exhaustion. Hypoxia-inducible elements can be incorporated to conditionally drive CAR expression and selectively target MM cells within bone marrow. CAR T-cell survival and activity is further realized by blocking intrinsic regulators of T-cell inactivation. T-Cells Redirected for Universal Cytokine Killing (TRUCKs) bind a specific tumor antigen and produce cytokines to recruit endogenous immune cells. Suicide genes have been engineered into CAR T-cells given the potential for long-term on-target, off-tumor effects. Universal allo-CAR T-cells represent an off-the-shelf source, while logic-gated CAR T-cells are designed to recognize tumor-specific features coupled with Boolean-generated binary gates that then dictate cell-fate decisions. Future generations of CARs should further revitalize immune responses, enhance tumor specificity and reimagine strategies to treat myeloma and other cancers.

show abstract

Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion

Cited by 194 publications

References 149 publications

Mechanisms of tumor resistance to immune checkpoint blockade and combination strategies to overcome resistance

Mechanisms of tumor resistance to immune checkpoint blockade and combination strategies to overcome resistance

The role of pyroptosis in modulating the tumor immune microenvironment

Road testing new CAR design strategies in multiple myeloma

Contact Info

Product

Resources

About