Page 71 - 2021_04-Haematologica-web

Cell Therapy & Immunotherapy
CD28.OX40 co-stimulatory combination is associated with long in vivo persistence and high activity of CAR.CD30 T cells
Ferrata Storti Foundation
Haematologica 2021 Volume 106(4):987-999
Marika Guercio,1 Domenico Orlando,1 Stefano Di Cecca,1 Matilde Sinibaldi,1 Iolanda Boffa,1 Simona Caruso,1 Zeinab Abbaszadeh,1 Antonio Camera,1 Biancamaria Cembrola,1 Katia Bovetti,1 Simona Manni,1 Ignazio Caruana,1 Roselia Ciccone,1 Francesca Del Bufalo,1 Pietro Merli,1 Luciana Vinti,1 Katia Girardi,1 Annalisa Ruggeri,1 Cristiano De Stefanis,1 Marco Pezzullo,1 Ezio Giorda,1 Marco Scarsella,1 Rita De Vito,2 Sabina Barresi,3 Andrea Ciolfi,3 Marco Tartaglia,3 Lorenzo Moretta,4 Franco Locatelli,1,5# Concetta Quintarelli1,6# and Biagio De Angelis1#
1Department of Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome; 2Department of Laboratories, Pathology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome; 3Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCSS, Rome; 4Department of Immunology, Bambino Gesù Children’s Hospital, IRCCS, Rome; 5Department of Pediatrics, Sapienza, University of Rome, Rome and 6Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
#FL, CQ and BDA contributed equally as co-senior authors.
ABSTRACT
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 sin- gle-chain variable-fragment cassette, linked to CD3ζ by the signaling domains of two co-stimulatory molecules, namely CD28.4-1BB or CD28.OX40. We found that CAR.CD30 T cells exhibit remarkable cytolytic activity in vitro against both HL and NHL cell lines, with sus- tained 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 co-stimulatory domains and manufactured in the presence of interleukin 7 and interleukin 15, were associated with the best overall survival in the treated mice, along with establishment of a long-term immunological memory able to protect mice from further tumor re-chal- lenge. Our data indicate that, in the context of in vivo systemic metastatic xenograft mouse models, the co-stimulatory machinery of CD28.OX40 is crucial for improving persistence, in vivo expansion and proliferation of CAR.CD30 T cells upon tumor encounter. The CD28.OX40 co-stimula- tory combination is ultimately responsible for the anti-tumor efficacy of the approach, paving the way to translate this therapeutic strategy into clinical use for patients with CD30+ HL and NHL.
Introduction
Use of chimeric antigen receptor (CAR) T cells is a new promising approach of adoptive cancer cell immunotherapy, combining antigen recognition by a mono- clonal antibody with the effector function of T cells.1 CAR T cells directed against CD19 have been shown to induce sustained complete responses in patients with relapsed/refractory B-cell non-Hodgkin (NHL) lymphomas, particularly diffuse
Correspondence:
BIAGIO DE ANGELIS
biagio.deangelis@opbg.net
FRANCO LOCATELLI
franco.locatelli@opbg.net
Received: July 8, 2019. Accepted: March 24, 2020. Pre-published: May 7, 2020.
https://doi.org/10.3324/haematol.2019.231183
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2021; 106(4)
987
ARTICLE