Abstract:In this systematic review, we foresee what could be the approved scenario in the next few years for CAR-T cell therapies directed against hematological and solid tumor malignancies. China and the USA are the leading regions in numbers of clinical studies involving CAR-T. Hematological antigens CD19 and BCMA are the most targeted, followed by mesothelin, GPC3, CEA, MUC1, HER2, and EGFR for solid tumors. Most CAR constructs are second-generation, although third and fourth generations are being largely explored. … Show more
“…Based on the latest counting, there are 292 solid tumor CART trials in the world ( 48 , 49 ), most of them are Phase I studies and have not completed. We were able to find 38 published solid tumor CART trials (total 453 patients).…”
Section: Correlation Of Abd Affinity and Clinical Efficacy Of Carts: ...mentioning
The overall efficacy of chimeric antigen receptor modified T cells (CARTs) remain limited in solid tumors despite intensive studies that aim at targeting multiple antigens, enhancing migration, reducing tonic signaling, and improving tumor microenvironment. On the other hand, how the affinity and engaging kinetics of antigen-binding domain (ABD) affects the CART’s efficacy has not been carefully investigated. In this article, we first analyzed 38 published solid tumor CART trials and correlated the response rate to their ABD affinity. Not surprisingly, majority (25 trials) of the CARTs utilized high-affinity ABDs, but generated merely 5.7% response rate. In contrast, 35% of the patients treated with the CARTs built from moderate-affinity ABDs had clinical responses. Thus, CARTs with moderate-affinity ABDs not only have less off-target toxicity, but also are more effective. We then reviewed the effects of ABD affinity on the biology and function of CARTs, providing further evidence that moderate-affinity ABDs may be better in CART development. In the end, we propose that a fast-on/fast-off (high Kon and Koff) kinetics of CART-target engagement in solid tumor allow CARTs to generate sufficient signaling to kill tumor cells without being driven to exhaustion. We believe that studying the ABD affinity and the kinetics of CART-tumor interaction may hold a key to designing effective CARTs for solid tumors.
“…Based on the latest counting, there are 292 solid tumor CART trials in the world ( 48 , 49 ), most of them are Phase I studies and have not completed. We were able to find 38 published solid tumor CART trials (total 453 patients).…”
Section: Correlation Of Abd Affinity and Clinical Efficacy Of Carts: ...mentioning
The overall efficacy of chimeric antigen receptor modified T cells (CARTs) remain limited in solid tumors despite intensive studies that aim at targeting multiple antigens, enhancing migration, reducing tonic signaling, and improving tumor microenvironment. On the other hand, how the affinity and engaging kinetics of antigen-binding domain (ABD) affects the CART’s efficacy has not been carefully investigated. In this article, we first analyzed 38 published solid tumor CART trials and correlated the response rate to their ABD affinity. Not surprisingly, majority (25 trials) of the CARTs utilized high-affinity ABDs, but generated merely 5.7% response rate. In contrast, 35% of the patients treated with the CARTs built from moderate-affinity ABDs had clinical responses. Thus, CARTs with moderate-affinity ABDs not only have less off-target toxicity, but also are more effective. We then reviewed the effects of ABD affinity on the biology and function of CARTs, providing further evidence that moderate-affinity ABDs may be better in CART development. In the end, we propose that a fast-on/fast-off (high Kon and Koff) kinetics of CART-target engagement in solid tumor allow CARTs to generate sufficient signaling to kill tumor cells without being driven to exhaustion. We believe that studying the ABD affinity and the kinetics of CART-tumor interaction may hold a key to designing effective CARTs for solid tumors.
“…So, they can enhance an immunostimulatory response in one immune subset and/or enhance an inhibitory response in another immune subset depending on the receptors’ type and involved signaling targets. Furthermore, the outcome of initiated immune response may differ according to concentration of neurotransmitters in circulation or in TME [ 53 , 54 ]. Fig.…”
Cancer is a major health problem as it is the first or second leading cause of death worldwide. The global cancer burden is expected to rise 47% relative to 2020 cancer incidence. Recently, the fields of neuroscience, neuroimmunology and oncology have elaborated the neuroimmune crosstalk role in tumor initiation, invasion, progression, and metastases. The nervous system exerts a broad impact on the tumor microenvironment by interacting with a complex network of cells such as stromal, endothelial, malignant cells and immune cells. This communication modulates cancer proliferation, invasion, metastasis, induce resistance to apoptosis and promote immune evasion. This paper has two aims, the first aim is to explain neuroimmune crosstalk in cancer, tumor innervation origin and peripheral nervous system, exosomes, and miRNA roles. The second aim is to elaborate neuroimmune crosstalk impact on cancer therapy and research highlighting various potential novel strategies such as use of immune checkpoint inhibitors and anti-neurogenic drugs as single agents, drug repurposing, miRNA-based and si-RNA-based therapies, tumor denervation, cellular therapies, and oncolytic virus therapy.
“…T cells modified with these CAR constructs were able to show antigen-specific cellular cytotoxicity, cytokine production, and favor T cell proliferation both in vitro and in animal models. However, the results collected in these clinical trials were largely disappointing [ 24 ], mostly due to limited proliferation and persistence of engineered cells.…”
Section: The Experience With Car-based Therapies In Solid Tumorsmentioning
confidence: 99%
“…In nature, immune cell activation is usually the result of several signals that cooperate to trigger finely-tuned downstream signaling cascades, ultimately leading to the induction of cytotoxicity against the target cells, metabolic rewiring, and the induction of differentiation/proliferation processes [ 118 , 119 , 120 ]. Therefore, it is not surprising that an ongoing debate on which the signal is sufficient for optimized anti-tumor activity of engineered cells has continued since the first studies of second-generation CAR [ 24 , 121 , 122 , 123 , 124 ]. Due to historical reasons, the vast majority of preclinical and clinical evidences have been collected on costimulation signals for CAR T cells and, in particular, on CD28 and 4-1BB- derived costimulatory domains.…”
Section: Designing the Best Car Construct Against Solid Tumorsmentioning
Chimeric antigen receptor T cell therapies are revolutionizing the clinical practice of hematological tumors, whereas minimal progresses have been achieved in the solid tumor arena. Multiple reasons have been ascribed to this slower pace: The higher heterogeneity, the hurdles of defining reliable tumor antigens to target, and the broad repertoire of immune escape strategies developed by solid tumors are considered among the major ones. Currently, several CAR therapies are being investigated in preclinical and early clinical trials against solid tumors differing in the type of construct, the cells that are engineered, and the additional signals included with the CAR constructs to overcome solid tumor barriers. Additionally, novel approaches in development aim at overcoming some of the limitations that emerged with the approved therapies, such as large-scale manufacturing, duration of manufacturing, and logistical issues. In this review, we analyze the advantages and challenges of the different approaches under development, balancing the scientific evidences supporting specific choices with the manufacturing and regulatory issues that are essential for their further clinical development.
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