Author: Dengel, Karen ; Shah, Payal D ; Brennan, Andrea ; Xu, Xiaowei ; Gilmore, Joan ; Schuchter, Lynn M ; Lacey, Simon F ; Huang, Alexander C ; Shea, Joanne ; Zhang, Paul ; Kulikovskaya, Irina ; Cervini, Amanda ; Amaravadi, Ravi K ; Wherry, E John ; June, Carl H ; Gonzalez, Vanessa ; Marshall, Amy ; Tchou, Julia ; Linette, Gerald P ; Orlowski, Robert ; Lledo, Lester ; Mitchell, Tara C ; Matlawski, Tina ; Plesa, Gabriela ; Vonderheide, Robert H

PurposeTreatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET.Experimental DesignMetastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated.ResultsMean age was 50 years (35-64); median Eastern Cooperative Oncology Group 0 (0-1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients' blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67.ConclusionsIntravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible.SignificanceData evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.

Nature CommunicationsQ1 · CROSS-FIELD

Remodelling of tumour microenvironment by microwave ablation potentiates immunotherapy of AXL-specific CAR T cells against non-small cell lung cancer

Q1 · CROSS-FIELD

ArticleOA

Author: Zhi, Cheng ; Xu, Linfeng ; Lian, Hui ; Yang, Lili ; Yang, Shuo ; Zhao, Qi ; Cai, Mingyue ; Wu, Qingde ; Fu, Shengyu ; Ye, Xiaodie ; Chen, Xiaopei ; Zhu, Kangshun ; Yang, Xin ; Zhang, Zhenfeng ; Liu, Manting ; Feng, Yunfei ; Cao, Bihui ; Zhao, Ming ; Zhang, Jian ; Wang, Lu ; Zhang, Zhiru

AbstractThe complex immunosuppressive tumour microenvironment (TME) and lack of tumour-specific targets hinder the application of chimeric antigen receptor (CAR) T cells in the treatment of solid tumours. Combining local treatment with CAR T cell immunotherapy may regulate the TME and enhance the killing potency of CAR T cells in solid tumours. Here, we show that AXL, which is highly expressed in non-small cell lung cancer (NSCLC) but not in normal tissues, might be a target for CAR T cell therapy. AXL-CAR T cells alone cause moderate tumour regression in subcutaneous and pulmonary metastatic lung cancer cell-derived xenograft models. Combination of microwave ablation (MWA) and AXL-CAR T cells have superior antitumour efficacy. MWA enhances the activation, infiltration, persistence and tumour suppressive properties of AXL-CAR T cells in AXL-positive NSCLC patient-derived xenograft tumours via TME remodelling. The combination therapy increases the mitochondrial oxidative metabolism of tumour-infiltrating CAR T cells. Combination treatment induces significant tumour suppression without observed toxicities in humanized immunocompetent mice. The synergistic therapeutic effect of MWA and AXL-CAR T cells may be valuable for NSCLC treatment.

Adapting Nanopore Sequencing Basecalling Models for Modification Detection via Incremental Learning and Anomaly Detection

Author: Ding, Hongxu ; Liu, Ziyang ; Hao, Ning ; Zhang, Hao Helen ; Wang, Ziyuan ; Que, Jianwen ; Sun, Xiaoxiao ; Fang, Yinshan

ABSTRACTWe leverage machine learning approaches to adapt nanopore sequencing basecallers for nucleotide modification detection. We first apply the incremental learning technique to improve the basecalling of modification-rich sequences, which are usually of high biological interests. With sequence backbones resolved, we further run anomaly detection on individual nucleotides to determine their modification status. By this means, our pipeline promises the single-molecule, single-nucleotide and sequence context-free detection of modifications. We benchmark the pipeline using control oligos, further apply it in the basecalling of densely-modified yeast tRNAs andE.coligenomic DNAs, the cross-species detection of N6-methyladenosine (m6A) in mammalian mRNAs, and the simultaneous detection of N1-methyladenosine (m1A) and m6A in human mRNAs. Our IL-AD workflow is available at:https://github.com/wangziyuan66/IL-AD.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma	Phase 1	AU	Chimeric Therapeutics Ltd.	10 Sep 2021

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