Abstract 54P
Background
Disialoganglioside (GD2) is a glycolipid antigen highly expressed in several solid tumors. A chimeric antigen receptor (CAR)-T cell targeting GD2 has been developed and recently showed promising results in clinical trials for neuroblastoma. Previous generations of aGD2-CAR-T cells belong to second—and third-generation CARs, which harbor one and two costimulatory domains within their CAR structures. Incorporation of co-stimulatory domains may help improve CAR T-cell functions. We aim to validate whether incorporating three costimulatory domains within fourth-generation CAR (CAR4) can improve antitumor efficiency against GD2-positive tumors in vitro.
Methods
A fourth-generation CAR containing humanized scFv-GD2, hu3F8, and three costimulatory domains composed of CD28, 4-1BB, and CD27 linked to a CD3 zeta was produced in primary human T cells by using a lentiviral vector system. Two versions of third-generation CAR were also maced (CAR3.1 and CAR3.2 containing co-stimulatory parts of CD28/BB or CD28/CD27, respectively), linked to a CD3z signaling domain. Antitumor activity, CAR-T cell proliferation, and cytokine production were compared between CAR3 and CAR4-T cells against human neuroblastoma and retinoblastoma cell lines.
Results
In vitro, co-culture assays showed that aGD2-CAR4-T exerted superior anti-tumor efficiency than aGD2-CAR3-T cells for killing neuroblastoma. In contrast, these aGD2-CAR-T did not destroy a normal retinal epithelial cell that lacks GD2 expression. However, upon long-term co-culture for 72 h, anti-GD2-CAR4-T showed more excellent cytolytic activities than CAR3-T cells. Interestingly, cytokine production levels, IFN-γ and TNF-α, secreted from anti-GD2-CAR4-T cells were slightly lower than those from CAR3-T cells. We observed that CAR3.2 containing CD27 (CD28/CD27z) had the highest proliferative capacity upon antigen engagement.
Conclusions
Our fourth-generation CAR T-cells targeting GD2 showed superior cytolytic activities than third-generation CAR T-cells against GD2-positive tumor cells in vitro. Anti-GD2-CAR4-T cells will be a promising therapeutic strategy for GD2-positive cancers.
Legal entity responsible for the study
The authors.
Funding
The Office of National Higher Education Science Research and Innovation Policy Council (NXPO) by Program Management Unit-Competitiveness (PMU-C) (grant no. C10F630063).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
89P - Safety and efficacy of rechallenge with immune checkpoint inhibitors in advanced solid tumor: A systematic review and meta-analysis
Presenter: Huijun Xu
Session: Poster Display session
Resources:
Abstract
90P - Meta-analysis of hypophysitis incidence in melanoma patients treated with immune checkpoint inhibitors
Presenter: Vincas Urbonas
Session: Poster Display session
Resources:
Abstract
91P - Territorial disparities in the use of hospitalization at home for immune checkpoint inhibitors infusion in France between 2021 and 2022
Presenter: Anne Claire Toffart
Session: Poster Display session
Resources:
Abstract
92P - An investigation on the differences between the pre-treatment nutritional and immunological status of nasopharyngeal carcinoma patients and the healthy population
Presenter: Qiao He
Session: Poster Display session
Resources:
Abstract
93P - Pseudoprogression in immunotherapy: Illusion or reality? P-PIT study
Presenter: Amelie Toulet
Session: Poster Display session
Resources:
Abstract
94P - Real-world characteristics, treatments and healthcare recourse utilization (HCRU) of patients (pts) with advanced/metastatic non-small cell lung cancer (mNSCLC) managed with first line (1L) immuno-oncology (IO) strategies in Greece: The IO-HORIZON study
Presenter: Dimitrios Ziogas
Session: Poster Display session
Resources:
Abstract
95P - Quality of life (QoL) and care pathway in patients with durable response to immune checkpoint inhibitors (ICI-DR) for advanced or metastatic non-small cell lung cancer (NSCLC) or melanoma: QUALICI study
Presenter: Nicolas Girard
Session: Poster Display session
Resources:
Abstract
96P - Comparative cardiovascular risks of PD-1 vs. PD-L1 inhibitors: A meta-analysis of incidence and severity of cardiotoxicity
Presenter: Mohammedbaqer Al-Ghuraibawi
Session: Poster Display session
Resources:
Abstract
97P - Cardiac risk stratification and serial monitoring during immune checkpoint inhibitor therapy: Prospective real-world experience
Presenter: James Knott
Session: Poster Display session
Resources:
Abstract
98P - Immuno-related cardiac toxicity: a prospective study applying multiparametric cardiac MRI
Presenter: Agnese Losurdo
Session: Poster Display session
Resources:
Abstract