Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/ijms23105448
Keywords
adoptive T cell therapy; hypoxic tumors; immune checkpoint blockade; CAR T; solid tumors; T cell exhaustion; co-stimulatory domains; CD28; 4-1BB; CD137
Funding
- Sao Paulo Research Foundation/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Brazil [2018/17656-0, 2018/25541-8, 2018/14034-8]
- National Institute for Science and Technology in Oncogenomics and Therapeutic Innovation FAPESP [2014/50943-1]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [465682/2014-6]
- CNPq [143179/2021-7]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES PROSUP) [88887.509747/2020-00, 88887.5141742020-00]
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This study found that CD28-based anti-CAIX CAR PBMCs cells, releasing anti-PD-L1 IgG, showed superior antitumor effects in vivo, especially under the influence of PD-L1 via ICB. The exhaustion status of CD4 T cells, in addition to CD8 T cells, was critical for the efficacy of CAR T cells. These findings offer exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors using anti-CAIX CAR T cells.
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.
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