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

Author(s)

de Campos, Najla Santos Pacheco ; de Oliveira Beserra, Adriano ; Pereira, Pedro Henrique Barbosa ; Chaves, Alexandre Silva ; Fonseca, Fernando Luiz Affonso ; da Silva Medina, Tiago ; dos Santos, Tiago Goss ; Wang, Yufei ; Marasco, Wayne Anthony ; Suarez, Eloah Rabello

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 23, n. 10, p. 17-pg., 2022-05-01.

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 approximately equal to 10(8) 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 alpha/4-1BB compared to CD28-based anti-CAIX CAR peripheral blood mononuclear cells (PBMCs) 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 approximately equal to 10(7) 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, the 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 the administration of a 10(7) 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. (AU)

• FAPESP's process: 14/50943-1 - INCT 2014: on Oncogenomics and Therapeutic Inovations
• Grantee: Dirce Maria Carraro
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/14034-8 - Characterization of chromatin and transcriptional landscapes of T cells from gastric adenocarcinoma patients as a tool to discover immunotherapy targets
• Grantee: Tiago da Silva Medina
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 18/17656-0 - Next-generation immunotherapy - Chimeric antigen receptor-modified T cells targeting cancer and immune checkpoint blockade: therapeutic efficacy and molecular mechanisms of T cell exhaustion.
• Grantee: Eloah Rabello Suarez
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/25541-8 - Molecular characterization of soft-tissue sarcomas: integration of translational preclinical models and functional study of genetic alterations with clinical relevance
• Grantee: Tiago Góss dos Santos
• Support Opportunities: Regular Research Grants