Cytolytic Activity of CAR T Cells and Maintenance of Their CD4+ Subset Is Critical for Optimal Antitumor Activity in Preclinical Solid Tumor Models
1
Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
2
MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
3
Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
4
Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary
*
Authors to whom correspondence should be addressed.
†
Equally senior authors.
Academic Editors: Antonio Curti, Alessandro Isidori, Giuseppe Lo Russo and Marina Chiara Garassino
Cancers 2021, 13(17), 4301; https://doi.org/10.3390/cancers13174301
Received: 20 July 2021
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Revised: 23 August 2021
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Accepted: 24 August 2021
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Published: 26 August 2021
(This article belongs to the Collection Mechanism of Immunotherapy in Cancers)
Simple Summary
Adoptively transferred T cells expressing recombinant chimeric antigen receptors (CAR T cells) have been approved for the therapy of hematological malignancies of the B cell lineage. However, CAR T cell therapy for patients with solid tumors so far has shown limited benefits. Correlative clinical studies of patients with hematological malignancies have suggested that less differentiated CAR T cells have improved anti-leukemic activity. We have therefore investigated the role of differentiation on the anti-tumor activity of CAR T cells targeting the solid tumor antigen HER2 in preclinical models. We utilized different activation/expansion protocols, and explored whether different co-stimulatory domains in the CAR construct influence the short- and long-term efficacy of HER2-CAR T cells. We demonstrate that the CAR T cell product with the highest proportion of effector cells and maintaining a good balance of CD4+/CD8+ cells is the most effective against solid tumors both in vitro and in vivo.
Correlative studies of clinical studies for hematological malignancies have implicated that less differentiated, CD8+-dominant CAR T cell products have greater antitumor activity. Here, we have investigated whether the differentiation status of CAR T cell products affects their antitumor activity in preclinical models of solid tumors. We explored if different activation/expansion protocols, as well as different co-stimulatory domains in the CAR construct, influence the short- and long-term efficacy of CAR T cells against HER2-positive tumors. We generated T cell products that range from the most differentiated (CD28.z; OKT3-antiCD28/RPMI expansion) to the least differentiated (41BB.z; OKT3-RetroNectin/LymphoONE expansion), as judged by cell surface expression of the differentiation markers CCR7 and CD45RA. While the effect of differentiation status was variable with regard to antigen-specific cytokine production, the most differentiated CD28.z CAR T cell products, which were enriched in effector memory T cells, had the greatest target-specific cytolytic activity in vitro. These products also had a greater proliferative capacity and maintained CD4+ T cells upon repeated stimulation in vitro. In vivo, differentiated CD28.z CAR T cells also had the greatest antitumor activity, resulting in complete response. Our results highlight that it is critical to optimize CAR T cell production and that optimal product characteristics might depend on the targeted antigen and/or cancer.
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Keywords:
solid tumor; chimeric antigen receptor (CAR); immunotherapy; cell therapy; T cell expansion; T cell persistence; HER2-positive tumors; CD4+; CD8+
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MDPI and ACS Style
Csaplár, M.; Szöllősi, J.; Gottschalk, S.; Vereb, G.; Szöőr, Á. Cytolytic Activity of CAR T Cells and Maintenance of Their CD4+ Subset Is Critical for Optimal Antitumor Activity in Preclinical Solid Tumor Models. Cancers 2021, 13, 4301. https://doi.org/10.3390/cancers13174301
AMA Style
Csaplár M, Szöllősi J, Gottschalk S, Vereb G, Szöőr Á. Cytolytic Activity of CAR T Cells and Maintenance of Their CD4+ Subset Is Critical for Optimal Antitumor Activity in Preclinical Solid Tumor Models. Cancers. 2021; 13(17):4301. https://doi.org/10.3390/cancers13174301
Chicago/Turabian StyleCsaplár, Marianna, János Szöllősi, Stephen Gottschalk, György Vereb, and Árpád Szöőr. 2021. "Cytolytic Activity of CAR T Cells and Maintenance of Their CD4+ Subset Is Critical for Optimal Antitumor Activity in Preclinical Solid Tumor Models" Cancers 13, no. 17: 4301. https://doi.org/10.3390/cancers13174301
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