Adenosine Deaminase 1 Overexpression Enhances the Antitumor Efficacy of Chimeric Antigen Receptor-Engineered T Cells

Qu, Yun; Dunn, Zachary Spencer; Chen, Xianhui; MacMullan, Melanie A.; Cinay, Gunce E.; Wang, Hsuan-Yao; Liu, Jiangyue; Hu, Fangheng; Wang, Pin

doi:10.1089/hum.2021.050

Cited by 25 publications

(23 citation statements)

References 71 publications

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“…Our labs specialize in developing cell therapies, particularly CAR-T and hematopoietic stem cell-engineered invariant natural killer T (CAR-HSC-iNKT) cell therapies, for cancer treatment [ 58 , 59 ]. While we validated IVIPL for application in i.p.…”

Section: Discussionmentioning

confidence: 99%

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

Dunn

et al. 2022

Cancers

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Intraperitoneal (i.p.) experimental models in mice can recapitulate the process of i.p. dissemination in abdominal cancers and may help uncover critical information about future successful clinical treatments. i.p. cellular composition is studied in preclinical models addressing a wide spectrum of other pathophysiological states such as liver cirrhosis, infectious disease, autoimmunity, and aging. The peritoneal cavity is a multifaceted microenvironment that contains various immune cell populations, including T, B, NK, and various myeloid cells, such as macrophages. Analysis of the peritoneal cavity is often obtained by euthanizing mice and performing terminal peritoneal lavage. This procedure inhibits continuous monitoring of the peritoneal cavity in a single mouse and necessitates the usage of more mice to assess the cavity at multiple timepoints, increasing the cost, time, and variability of i.p. studies. Here, we present a simple, novel method termed in vivo intraperitoneal lavage (IVIPL) for the minimally invasive monitoring of cells in the peritoneal cavity of mice. In this proof-of-concept, IVIPL provided real-time insights into the i.p. tumor microenvironment for the development and study of ovarian cancer therapies. Specifically, we studied CAR-T cell therapy in a human high-grade serous ovarian cancer (HGSOC) xenograft mouse model, and we studied the immune composition of the i.p. tumor microenvironment (TME) in a mouse HGSOC syngeneic model.

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Section: Discussionmentioning

confidence: 99%

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

Dunn

et al. 2022

Cancers

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“…Although further clinical evaluation is needed, the potential of the seven tumor antigens to become successful targets for anti-PRAD mRNA vaccines has been consolidated in previous reports. For example, Yun Qu et al have reported that the overexpression of ADA could enhance the antitumor efﬁcacy of CART cells which has been proved as an effective immunotherapy for several tumors ( Qu et al, 2021 ). Also, Daniela Zanini et al demonstrated that ADA activity had poor prognostic significance in lung adenocarcinoma ( Zanini et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Neoantigens and Construction of Immune Subtypes in Prostate Adenocarcinoma

et al. 2022

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Background: Messenger ribonucleic acid (mRNA) vaccine has been considered as a potential therapeutic strategy and the next research hotspot, but their efficacy against prostate adenocarcinoma (PRAD) remains undefined. This study aimed to find potential antigens of PRAD for mRNA vaccine development and identify suitable patients for vaccination through immunophenotyping.Methods: Gene expression profiles and clinical information were obtained from TCGA and ICGC. GEPIA2 was used to calculate the prognostic index of the selected antigens. The genetic alterations were compared on cBioPortal and the correlation between potential antigen and immune infiltrating cells was explored by TIMER. ConsensusClusterPlus was used to construct a consistency matrix, and identify the immune subtypes. Graph learning-based dimensional reduction was performed to depict immune landscape. Boruta algorithm and LASSO logistic analysis were used to screen PRAD patients who may benefit from mRNA vaccine.Results: Seven potential tumor antigens selected were signiﬁcantly positively associated with poor prognosis and the antigen-presenting immune cells (APCs) in PRAD, including ADA, FYN, HDC, NFKBIZ, RASSF4, SLC6A3, and UPP1. Five immune subtypes of PRAD were identified by differential molecular, cellular, and clinical characteristics in both cohorts. C3 and C5 had immune “hot” and immunosuppressive phenotype, On the contrary, C1&C2 had immune “cold” phenotype. Finally, the immune landscape characterization showed the immune heterogeneity among patients with PRAD.Conclusions: ADA, FYN, HDC, NFKBIZ, RASSF4, SLC6A3, and UPP1 are potential antigens for mRNA vaccine development against PRAD, and patients in type C1 and C2 are suitable for vaccination.

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“…Finally, it has been recently demonstrated that T cells can utilize inosine as an alternative source of carbon to glucose to sustain their functions and that inosine supplementation enhances the anti-tumor effect of ICIs [81]. Based on this evidence, we hypothesized that encoding ADA into OVs could exert pleiotropic antitumor benefits by: (i) depriving cancer cells of adenosinergic survival signaling; (ii) restoring antitumor functions of immune cell populations (T, NK, DC, APC); (iii) suppressing tolerogenic immune cells (Treg, MDSC, M2 macrophages) through eADO clearance; (iv) improving antigen presentation and Tfh cells by Tcell-to-DC crosslinking by CD26 and A2Ar [75][76][77][78][79][80]; (v) supplying intratumor inosine to reinforce antitumor T cell metabolism [81][82][83].…”

Section: Discussionmentioning

confidence: 99%

Generation of a Retargeted Oncolytic Herpes Virus Encoding Adenosine Deaminase for Tumor Adenosine Clearance

Gentile

Finizio

Froechlich

et al. 2021

IJMS

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Background: Oncolytic viruses are immunotherapeutic agents that can be engineered to encode payloads of interest within the tumor microenvironment to enhance therapeutic efficacy. Their therapeutic potential could be limited by many avenues for immune evasion exerted by the tumor. One such is mediated by adenosine, which induces pleiotropic immunosuppression by inhibiting antitumor immune populations as well as activating tolerogenic stimuli. Adenosine is produced starting from the highly immunostimulatory ATP, which is progressively hydrolyzed to ADP and adenosine by CD39 and CD73. Cancer cells express high levels of CD39 and CD73 ectoenzymes, thus converting immunostimulatory purinergic signal of ATP into an immunosuppressive signal. For this reason, CD39, CD73 and adenosine receptors are currently investigated in clinical trials as targets for metabolic cancer immunotherapy. This is of particular relevance in the context of oncovirotherapy, as immunogenic cell death induced by oncolytic viruses causes the secretion of a high amount of ATP which is available to be quickly converted into adenosine. Methods: Here, we took advantage of adenosine deaminase enzyme that naturally converts adenosine into the corresponding inosine derivative, devoid of immunoregulatory function. We encoded ADA into an oncolytic targeted herpes virus redirected to human HER2. An engineered ADA with an ectopic signal peptide was also generated to improve enzyme secretion (ADA-SP). Results: Insertion of the expression cassette was not detrimental for viral yield and cancer cell cytotoxicity. The THV_ADA and THV_ADA-SP successfully mediated the secretion of functional ADA enzyme. In in vitro model of human monocytes THP1, this ability of THV_ADA and THV_ADA-SP resulted in the retrieval of eADO-exposed monocytes replication rate, suggesting the proficiency of the viruses in rescuing the immune function. Conclusions: Encoding ADA into oncolytic viruses revealed promising properties for preclinical exploitation.

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Adenosine Deaminase 1 Overexpression Enhances the Antitumor Efficacy of Chimeric Antigen Receptor-Engineered T Cells

Cited by 25 publications

References 71 publications

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

Identification of Neoantigens and Construction of Immune Subtypes in Prostate Adenocarcinoma

Generation of a Retargeted Oncolytic Herpes Virus Encoding Adenosine Deaminase for Tumor Adenosine Clearance

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