Characterization of the Therapeutic Effects of Novel Chimeric Antigen Receptor T Cells Targeting CD38 on Multiple Myeloma

Li, Xiaorui; Feng, Yaru; Shang, Fengqin; Yu, Zhuoying; Wang, Tieshan; Zhang, Jing; Song, Zhiru; Wang, Ping; Shi, Bingjie; Wang, Jianxun

doi:10.3389/fonc.2021.703087

Cited by 4 publications

(3 citation statements)

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“…CD38 is expressed at high levels on PCs and preclinical results supports the anti-myeloma effect of CAR T-cells that target CD38 ( 63 ). CD38 is similarly detected on healthy erythrocytes, NK cells, and other cell types, increasing the likelihood of “on-target, off-tumor” effects ( 64 ).…”

Section: Alternative Antigenic Proteins For Car T-cells To Target In ...mentioning

confidence: 99%

Road testing new CAR design strategies in multiple myeloma

et al. 2022

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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.

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Section: Alternative Antigenic Proteins For Car T-cells To Target In ...mentioning

confidence: 99%

Road testing new CAR design strategies in multiple myeloma

et al. 2022

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“…("Created with BioRender.com.") CAR-T (chimeric antigen receptor T cell) therapy is a type of immunotherapy that manipulates T cells to better recognize and attack tumor cells [11][12][13]. A monoclonal antibody derivative forms the extracellular antigen-binding domain of CAR-T cells, allowing them to recognize specifics antigen and bind to them [14][15][16].…”

Section: Fig 1 a Schematic Representation Of In Vivo Versus Ex Vivo G...mentioning

confidence: 99%

Gene Therapy: Recent Advancement and Challenges

Aggarwal

Mittal

2022

AJBGMB

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Background: Gene therapy involves delivering therapeutic genomic material to a target tissue to modify expression of a protein or induce other characteristic changes. Recent advancements in the field, including FDA-approval of numerous gene therapies, are paving the way for future technological progress. While gene therapy can be either somatic or germline, most research and drug development has focused on somatic cells. In this article, we discuss the recent advancements and challenges associated with gene therapy. Main Text: There are multiple types of gene therapies, including hematopoietic stem cell therapy, CAR-T cell therapy, and Crispr/Cas9 gene therapy. Rare diseases and cancers are being researched to determine methods of treatment using gene therapy, and several clinical trials have been performed within the last decade to test the efficacy of new therapeutic drugs, many of them at least somewhat successful. However, gene therapy does pose some challenges, including large-scale manufacturing of vectors, precision of gene delivery to target tissue, and, most importantly, the immune responses of patients. Conclusions: The near future is an exciting time for new gene therapy technologies and strategies. Researchers and patients can look forward to new advancements in base editing, prime editing, and RNA-targeted editing technologies. Furthermore, future research can focus on new genetic targets, such as genes whose functions may still be unknown and epigenomic elements.

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“…31,32 In NK cells, ADO suppresses their cytotoxic activity toward tumor cells and their production of IFN-g, tumor necrosis factor (TNF-a) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are critical cytokines for effective ADCC. 29,30,33,34 In tumor cells that highly express CD38, such as MM, [35][36][37] NB [38][39][40] and acute lymphocytic leukemia (ALL), 41,42 both reduction in NAD + levels and overproduction of ADO lead to immunosuppression. Recent evidence suggests that CD38 up regulation is one of the most important factors in mediating resistance to checkpoint blockade in MM and other cancers.…”

Section: Introductionmentioning

confidence: 99%