Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Immune Checkpoint Blockade via PD-L1 Potentiates More CD28-Based than 4-1BB-Based Anti-Carbonic Anhydrase IX Chimeric Antigen Receptor T Cells

Version 1 : Received: 26 April 2022 / Approved: 29 April 2022 / Online: 29 April 2022 (15:14:06 CEST)

A peer-reviewed article of this Preprint also exists.

de Campos, N.S.P.; de Oliveira Beserra, A.; Pereira, P.H.B.; Chaves, A.S.; Fonseca, F.L.A.; da Silva Medina, T.; dos Santos, T.G.; Wang, Y.; Marasco, W.A.; Suarez, E.R. Immune Checkpoint Blockade via PD-L1 Potentiates More CD28-Based than 4-1BB-Based Anti-Carbonic Anhydrase IX Chimeric Antigen Receptor T Cells. Int. J. Mol. Sci. 2022, 23, 5448. de Campos, N.S.P.; de Oliveira Beserra, A.; Pereira, P.H.B.; Chaves, A.S.; Fonseca, F.L.A.; da Silva Medina, T.; dos Santos, T.G.; Wang, Y.; Marasco, W.A.; Suarez, E.R. Immune Checkpoint Blockade via PD-L1 Potentiates More CD28-Based than 4-1BB-Based Anti-Carbonic Anhydrase IX Chimeric Antigen Receptor T Cells. Int. J. Mol. Sci. 2022, 23, 5448.

Journal reference: Int. J. Mol. Sci. 2022, 23, 5448
DOI: 10.3390/ijms23105448

Abstract

The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to 10e8 CAR T cells/ Kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here we tested CD8/4-1BB compared to CD28-based anti-CAIX CAR PBMCs cells-releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a 10e7 CAR PBMCs cells/ Kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, T cell exhaustion status in peripheral CD4 T cells, additionally to CD8 was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon administration of 10e7 CAR PMBCs cells/Kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.

Keywords

adoptive T cell therapy; hypoxic tumors; immune checkpoint blockade; CAR T; solid tumors; T cell exhaustion; co-stimulatory domains; CD28; 4-1BB; CD137

Subject

MEDICINE & PHARMACOLOGY, Oncology & Oncogenics

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