Despite many clinical trials, CAR-T cells are not yet approved for human solid tumor therapy. One popular target is mesothelin (MSLN) which is highly expressed on the surface of about 30% of cancers including mesothelioma and cancers of the ovary, pancreas, and lung. MSLN is shed by proteases that cleave near the C terminus, leaving a short peptide attached to the cell. Most anti-MSLN antibodies bind to shed MSLN, which can prevent their binding to target cells. To overcome this limitation, we developed an antibody (15B6) that binds next to the membrane at the protease-sensitive region, does not bind to shed MSLN, and makes CAR-T cells that have much higher anti-tumor activity than a CAR-T that binds to shed MSLN. We have now humanized the Fv (h15B6), so the CAR-T can be used to treat patients and show that h15B6 CAR-T produces complete regressions in a hard-to-treat pancreatic cancer patient derived xenograft model, whereas CAR-T targeting a shed epitope (SS1) have no anti-tumor activity. In these pancreatic cancers, the h15B6 CAR-T replicates and replaces the cancer cells, whereas there are no CAR-T cells in the tumors receiving SS1 CAR-T. To determine the mechanism accounting for high activity, we used an OVCAR-8 intraperitoneal model to show that poorly active SS1-CAR-T cells are bound to shed MSLN, whereas highly active h15B6 CAR-T do not contain bound MSLN enabling them to bind to and kill cancer cells.

2023-05-01·British Journal of Haematology

Outcome of early treatment of SARS‐CoV‐2 infection in patients with haematological disorders

Article

作者: Miselli, Filippo ; Bartoletti, Michele ; Raiola, Anna Maria ; Lemoli, Roberto ; Testi, Diletta ; Aquino, Sara ; Giacobbe, Daniele Roberto ; Cilli, Alessandro ; Zinzani, Pierluigi ; Vena, Antonio ; Viale, Pierluigi ; Di Grazia, Carmen ; Giannella, Maddalena ; Bussini, Linda ; Ghiggi, Chiara ; Campoli, Caterina ; Cavo, Michele ; Magne, Federica ; Mikulska, Malgorzata ; Dentone, Chiara ; Balletto, Elisa ; Bonifazi, Francesca ; Russo, Chiara ; Angelucci, Emanuele ; Sepulcri, Chiara ; Policarpo, Sílvia ; Bassetti, Matteo

SummaryOutcome of early treatment of COVID‐19 with antivirals or anti‐spike monoclonal antibodies (MABs) in patients with haematological malignancies (HM) is unknown. A retrospective study of HM patients treated for mild/moderate COVID‐19 between March 2021 and July 2022 was performed. The main composite end‐point was treatment failure (severe COVID‐19 or COVID‐19‐related death). We included 328 consecutive patients who received MABs (n = 120, 37%; sotrovimab, n = 73) or antivirals (n = 208, 63%; nirmatrelvir/ritonavir, n = 116) over a median of two days after symptoms started; 111 (33.8%) had non‐Hodgkin lymphoma (NHL); 89 (27%) were transplant/CAR‐T (chimaeric antigen receptor T‐cell therapy) recipients. Most infections (n = 309, 94%) occurred during the Omicron period. Failure developed in 31 patients (9.5%). Its independent predictors were older age, fewer vaccine doses, and treatment with MABs. Rate of failure was lower in the Omicron versus the pre‐Omicron period (7.8% versus 36.8%, p < 0.001). During the Omicron period, predictors of failure were age, fewer vaccine doses and diagnosis of acute myeloid leukaemia/myelodysplastic syndrome (AML/MDS). Independent predictors of longer viral shedding were age, comorbidities, hospital admission at diagnosis, NHL/CLL, treatment with MABs. COVID‐19‐associated mortality was 3.4% (n = 11). The mortality in those who developed severe COVID‐19 after early treatment was 26% in the Omicron period. Patients with HM had a significant risk of failure of early treatment, even during the Omicron period, with high mortality rate.

2022-09-01·Nature Medicine1区 · 医学

Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma

1区 · 医学

Article

作者: Slowik, Kara ; Ferry, Judith ; Danysh, Brian P ; Rhrissorrakrai, Kahn ; Livak, Kenneth J ; Larson, Rebecca C ; Silva, Harrison ; Wu, Catherine J ; Parida, Laxmi ; Getz, Gad ; Maus, Marcela V ; Jacobs, Raquel A ; Frigault, Matthew J ; Leick, Mark B ; Gohil, Satyen H ; Utro, Filippo ; Haradhvala, Nicholas J ; Yao, Ning ; Katsis, Katelin ; Southard, Jackson ; Jan, Max ; Levovitz, Chaya ; Maurer, Katie ; Gallagher, Kathleen M E ; Kann, Michael C ; Li, Shuqiang ; Jacobson, Caron

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain new insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pretreatment and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with large B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells among nonresponders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-T regulatory cells to drive relapse.

100 项与 CAR-511 相关的药物交易

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