@article{Marika Guercio_Domenico Orlando_Stefano Di Cecca_Matilde Sinibaldi_Iolanda Boffa_Simona Caruso_Zeinab Abbaszadeh_Antonio Camera_Biancamaria Cembrola_Katia Bovetti_Simona Manni_Ignazio Caruana_Roselia Ciccone_Francesca Del Bufalo_Pietro Merli_Luciana Vinti_Katia Girardi_Annalisa Ruggeri_Cristiano De Stefanis_Marco Pezzullo_Ezio Giorda_Marco Scarsella_Rita De Vito_Sabina Barresi_Andrea Ciolfi_Marco Tartaglia_Lorenzo Moretta_Franco Locatelli_Concetta Quintarelli_Biagio De Angelis_2021, place={Pavia, Italy}, title={CD28.OX40 co-stimulatory combination is associated with long in vivo persistence and high activity of CAR.CD30 T-cells}, volume={106}, url={https://haematologica.org/article/view/9747}, DOI={10.3324/haematol.2019.231183}, abstractNote={<p>The prognosis of many patients with chemotherapy-refractory or multiply relapsed CD30+ non-Hodgkin Lymphoma (NHL) or Hodgkin lymphoma (HL) still remains poor, and novel therapeutic approaches are warranted to address this unmet clinical need. In light of this consideration, we designed and pre-clinically validated a Chimeric Antigen Receptor (CAR) construct characterized by a novel anti-CD30 single-chain variable-fragment cassette, linked to CD3ΞΆ by the signaling domains of two costimulatory molecules, namely either CD28.4-1BB or CD28.OX40. We found that CAR.CD30 T-cells exhibit remarkable cytolytic activity in vitro against HL and NHL cell lines, with sustained proliferation and pro-inflammatory cytokine production, even after multiple and sequential lymphoma cell challenges. CAR.CD30 T-cells also demonstrated anti-lymphoma activity in two in vivo xenograft immune-deficient mouse models of metastatic HL and NHL. We observed that administration of CAR.CD30 T-cells, incorporating the CD28.OX40 costimulatory domains and manufactured in the presence of IL7 and IL15, were associated with the best overall survival in the treated mice, along with the establishment of a long-term immunological memory, able to protect mice from further tumor re-challenge. Our data indicate that, in the context of in vivo systemic metastatic xenograft mouse models, the costimulatory machinery of CD28.OX40 is crucial for improving persistence, in vivo expansion and proliferation of CAR.CD30 T-cells upon tumor encounter. CD28.OX40 costimulatory combination is ultimately responsible for the antitumor efficacy of the approach, paving the way to translate this therapeutic strategy in patients with CD30+ HL and NHL.</p&gt;}, number={4}, journal={Haematologica}, author={Marika Guercio and Domenico Orlando and Stefano Di Cecca and Matilde Sinibaldi and Iolanda Boffa and Simona Caruso and Zeinab Abbaszadeh and Antonio Camera and Biancamaria Cembrola and Katia Bovetti and Simona Manni and Ignazio Caruana and Roselia Ciccone and Francesca Del Bufalo and Pietro Merli and Luciana Vinti and Katia Girardi and Annalisa Ruggeri and Cristiano De Stefanis and Marco Pezzullo and Ezio Giorda and Marco Scarsella and Rita De Vito and Sabina Barresi and Andrea Ciolfi and Marco Tartaglia and Lorenzo Moretta and Franco Locatelli and Concetta Quintarelli and Biagio De Angelis}, year={2021}, month={Apr.}, pages={987-999} }