Significantly increased anti‐tumor activity of carcinoembryonic antigen‐specific chimeric antigen receptor T cells in combination with recombinant human IL‐12

Chi, Xiaowei; Yang, Peiwei; Zhang, Erhao; Gu, Jieyi; Xu, Hui; Li, Mengwei; Gao, Xinmei; Li, Xin; Zhang, Yinan; Xu, Hong‐Xi

doi:10.1002/cam4.2361

Cited by 50 publications

(40 citation statements)

References 38 publications

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“…Interestingly, there were no CAR-T related severe adverse events observed among all the 10 patients involved in this study (150). Furthermore, combination treatment between CEA-CAR-T cells in addition to recombinant human interleukin 12 (rh-IL12) in mouce models show effective and elevated anti-tumor activity of CAR-T cells among various types of solid tumors including CRC (151).…”

Section: Adoptive Cell Transfer (Act)mentioning

confidence: 82%

Colorectal Cancer Immunotherapy: Options and Strategies

2020

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Colorectal cancer is the third most common cancer in the world with increasing incidence and mortality rates globally. Standard treatments for colorectal cancer have always been surgery, chemotherapy and radiotherapy which may be used in combination to treat patients. However, these treatments have many side effects due to their non-specificity and cytotoxicity toward any cells including normal cells that are growing and dividing. Furthermore, many patients succumb to relapse even after a series of treatments. Thus, it is crucial to have more alternative and effective treatments to treat CRC patients. Immunotherapy is one of the new alternatives in cancer treatment. The strategy is to utilize patients' own immune systems in combating the cancer cells. Cancer immunotherapy overcomes the issue of specificity which is the major problem in chemotherapy and radiotherapy. The normal cells with no cancer antigens are not affected. The outcomes of some cancer immunotherapy have been astonishing in some cases, but some which rely on the status of patients' own immune systems are not. Those patients who responded well to cancer immunotherapy have a better prognostic and better quality of life.

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Section: Adoptive Cell Transfer (Act)mentioning

confidence: 82%

Colorectal Cancer Immunotherapy: Options and Strategies

2020

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“…the Tn and STn antigens on MUC1, has already been shown to inhibit the growth of PDAC cell lines [ 169 ] and control PDAC xenograft growth in murine models [ 170 ]. The combination of CEA-CAR-T with rhIL-12 exerted significant antitumour effects in vitro and in vivo [ 171 ], and a phase II/III trial (NCT04037241) to evaluate the efficacy of CEA-CAR-T is recruiting patients. CD133 is a marker of cancer stem cells and is related to tumour metastasis and recurrence; a phase I trial (NCT02541370) confirmed the safety of CAR-T-133 in patients with advanced metastatic malignancies [ 172 ].…”

Section: The Immunosuppressive Microenvironment and Immunotherapy Inmentioning

confidence: 99%

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.

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“…Optimal T cell activation, amplification, and persistence require not only antigen engagement (signal 1) and costimulatory signals (signal 2), but also cytokine support (signal 3). However, signal 3 is deficient in the TME, which hampers the full activation of T cells [61]. Therefore, constructing CAR T cells that can provide signal 3 will help promote their activation and proliferation.…”

Section: Cytokine Strategymentioning

confidence: 99%

Gene modification strategies for next-generation CAR T cells against solid cancers

et al. 2020

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Immunotherapies have become the backbone of cancer treatment. Among them, chimeric antigen receptor (CAR) T cells have demonstrated great success in the treatment of hematological malignancies. However, CAR T therapy against solid tumors is less effective. Antigen targeting; an immunosuppressive tumor microenvironment (TME); and the infiltration, proliferation, and persistence of CAR T cells are the predominant barriers preventing the extension of CAR T therapy to solid tumors. To circumvent these obstacles, the next-generation CAR T cells will require more potent antitumor properties, which can be achieved by gene-editing technology. In this review, we summarize innovative strategies to enhance CAR T cell function by improving target identification, persistence, trafficking, and overcoming the suppressive TME. The construction of multi-target CAR T cells improves antigen recognition and reduces immune escape. Enhancing CAR T cell proliferation and persistence can be achieved by optimizing costimulatory signals and overexpressing cytokines. CAR T cells equipped with chemokines or chemokine receptors help overcome their poor homing to tumor sites. Strategies like knocking out immune checkpoint molecules, incorporating dominant negative receptors, and chimeric switch receptors can favor the depletion or reversal of negative T cell regulators in the TME.

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Significantly increased anti‐tumor activity of carcinoembryonic antigen‐specific chimeric antigen receptor T cells in combination with recombinant human IL‐12

Cited by 50 publications

References 38 publications

Colorectal Cancer Immunotherapy: Options and Strategies

Colorectal Cancer Immunotherapy: Options and Strategies

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

Gene modification strategies for next-generation CAR T cells against solid cancers

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