PersonGen (China)

<div>AbstractPurpose:<p>Since CD7 may represent a potent target for T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) immunotherapy, this study aimed to investigate safety and efficacy of autologous CD7–chimeric antigen receptor (CAR) T cells in patients with relapsed and refractory (R/R) T-ALL/LBL, as well as its manufacturing feasibility.</p>Patients and Methods:<p>Preclinical phase was conducted in NPG mice injected with Luc+ GFP+CCRF-CEM cells. Open-label phase I clinical trial (NCT04004637) enrolled patients with R/R CD7-positive T-ALL/LBL who received autologous CD7-CAR T-cell infusion. Primary endpoint was safety; secondary endpoints included efficacy and pharmacokinetic and pharmacodynamic parameters.</p>Results:<p>CD7 blockade strategy was developed using tandem CD7 nanobody VHH6 coupled with an endoplasmic reticulum/Golgi-retention motif peptide to intracellularly fasten CD7 molecules. In preclinical phase CD7 blockade CAR T cells prevented fratricide and exerted potent cytolytic activity, significantly relieving leukemia progression and prolonged the median survival of mice. In clinical phase, the complete remission (CR) rate was 87.5% (7/8) 3 months after CAR T-cell infusion; 1 patient with leukemia achieved minimal residual disease–negative CR and 1 patient with lymphoma achieved CR for more than 12 months. Majority of patients (87.5%) only had grade 1 or 2 cytokine release syndrome with no T-cell hypoplasia or any neurologic toxicities observed. The median maximum concentration of CAR T cells was 857.2 cells/μL at approximately 12 days and remained detectable up to 270 days.</p>Conclusions:<p>Autologous nanobody-derived fratricide-resistant CD7-CAR T cells demonstrated a promising and durable antitumor response in R/R T-ALL/LBL with tolerable toxicity, warranting further studies in highly aggressive CD7-positive malignancies.</p></div>

Xu, Qian-Wen; Xu, Hui; Xue, Lei; Wang, Min; Pan, Gui-Wang; Zhang, Xu-Han; Song, Kai-Di; Yao, Wen; Wan, Xiang; Tong, Juan; Liu, Hui-Lan; Xu, Han-Ying; Liu, Xin; Zhu, Xiao-Yu; Sun, Zi-Min; Yang, Lin; Wang, Xing-BingEditor(s): Lyu, Peng Author Information

The great success of chimeric antigen receptor T (CAR-T)-cell therapy in B-cell malignancies has significantly promoted its rapid expansion to other targets and indications, including T-cell malignancies and acute myeloid leukemia. However, owing to the life-threatening T-cell hypoplasia caused by CD7-CAR-T cells specific cytotoxic against normal T cells, as well as CAR-T cell-fratricide caused by the shared CD7 antigen on the T-cell surface, the clinical application of CD7 as a potential target for CD7+ malignancies is lagging. Here, we generated CD7ΔT cells using an anti-CD7 nanobody fragment coupled with an endoplasmic reticulum/Golgi retention domain and demonstrated that these cells transduced with CD7-CAR could prevent fratricide and achieve expansion. Additionally, CD7ΔCD7-CAR-T cells exhibited robust antitumor potiential against CD7+ tumors in vitro as well as in cell-line and patient-derived xenograft models of CD7-positive malignancies. Furthermore, we confirmed that the antitumor activity of CD7-CAR-T cells was positively correlated with the antigen density of tumor cells. This strategy adapts well with current clinical-grade CAR-T-cell manufacturing processes and can be rapidly applied for the therapy of patients with CD7+ malignancies.

Multiple myeloma (MM) is a type of cancer characterized by abnormal proliferation of clonal cells; it is the very dangerous and highly prevalent disease. Although significant progress has been made in clinical research, especially with novel drugs such as bortezomib, lenalidomide, and carfilzomib, most of the patients with MM still suffer from often fetal relapses due to drug resistance. In this study, we aimed to develop immune cells that could specifically target and destroy MM cells. Chimeric antigen receptor–modified NK-92 (CAR-NK92) cells have been very effective against B-cell acute lymphoblastic leukemia (B-ALL); as MM shows high expression of CD138, we constructed CD138-directed CAR-NK-92MI cells (CAR-CD138). It 2is reported that there is a small subset of CD138–/CD19+ MM cells showing, to some extent, stem cell qualities. We therefore generated the CD19-directed CAR-NK-92MI cells (CAR-CD19) as well. These two CAR-NK cells showed strong in vitro biological activity in specifically killing target tumor cells. Thus, the concomitant use of these CAR-NK cells may achieve excellent results in vivo.

Este artigo analisa as interconexoes entre literatura e sociedade no poema “Becos de Goias”, de Cora Coralina (1889-1985). Nesse poema, observamos as relacoes sociais no interior brasileiro nos seculos XIX e XX, sob o olhar da periferia, dos que estavam a margem na considerada “boa sociedade”, percorrendo cenarios, personagens e destinos que divergem dos privilegiados tradicionalmente. Pretendemos, pela descricao dos becos, valvulas coronarias da velha cidade, analisar as estrategias utilizadas pela autora para retratar e criticar a realidade de seu tempo.

Resumo: Examinando particularmente a “síndrome de Diógenes” e a idéia de “gozo cínico” aplicado na tipificação do toxicômano das sociedades pós-modernas, este artigo retoma de maneira breve e sucinta o problema da leitura e das apropriações da antigüidade clássica na caracterização de fenômenos culturais contemporâneos (ou pelo menos descritos na contemporaneidade). Sem qualquer intenção crítica diante dos fenômenos descritos, já que a perspectiva adotada é a da história da filosofia e não a do domínio específico da psiquiatria e da psicanálise, busca-se apenas demonstrar, através de uma remissão sistemática ao texto das fontes antigas – neste caso, ao corpus cínico –, os limites metodológicos e os conseqüentes equívocos em que tal prática pode incorrer.Palavras-chave: cinismo; Diógenes de Sínope; “Síndrome de Diógenes”; “gozo cínico”; psiquiatria; psicanálise; história da filosofia; apropriação.Résumé: En examinant particulièrement la “syndrome de Diogène” ainsi que l’idée de “jouissance cynique”, utilisée pour définir le toxicomane des sociétés actuelles, cet article reprend brièvement le problème de la lecture et de l’appropriation de l’antiquité classique dans la caractérisation des phénomènes culturels contemporains (ou, du moins, ceux décrits dans la contemporanéité). Loin de toute intention critique face aux phénomènes décrits, car la perspective adoptée est celle de l’histoire de la philosophie et non pas celle du domaine spécifique de la psychiatrie et de la psychanalyse, on cherche à démontrer, par le renvoi systématique au texte des sources antiques – dans ce cas, au corpus cynique –, les limites méthodologiques et les équivoques qui découlent de cette pratique.Mots-clés: cynisme; Diogène de Sinope; “Syndrome de Diogène”; “Jouissance Cynique”; psychiatrie; psychanalyse; histoire de la philosophie; appropriation.