Anti-CAIX BBζ CAR4/8 T cells exhibit superior efficacy in a ccRCC mouse model

Wang, Yufei; Buck, Alicia; Grimaud, Marion; Culhane, Aedín C.; Kodangattil, Sreekumar; Razimbaud, Cecile; Bonal, Dennis M.; Nguyen, Quang-Dé; Zhu, Zhu; Wei, Kevin; O'Donnell, Madison L; Huang, Ying; Signoretti, Sabina; Choueiri, Toni K.; Freeman, Gordon J.; Zhu, Quan; Marasco, Wayne A.

doi:10.1016/j.omto.2021.12.019

Cited by 23 publications

(46 citation statements)

References 65 publications

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“…Higher E:T (50 or 100:1) showed even more potent results, reaching up to 80% cytotoxicity of the same ccRCC cells. These CAR T cells could not induce cytotoxicity of CAIX negative cells, as previously tested [18,21].…”

Section: Functional Characterization and Cytotoxic Activity In Vitro ...mentioning

confidence: 60%

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

Campos¹,

Beserra²,

Pereira³

et al. 2022

Preprint

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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.

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Section: Functional Characterization and Cytotoxic Activity In Vitro ...mentioning

confidence: 60%

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

Campos¹,

Beserra²,

Pereira³

et al. 2022

Preprint

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show abstract

“…Furthermore, the ccRCC is a solid tumor, and the circulation of CAR T cells in the tumor microenvironment is also a challenge. However, the results obtained with second-generation anti-CAIX CAR T cells alone or capable of releasing immune checkpoint blockade were the most promising in the preclinical setting [51,54] and should be tested in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, anti-CAIX G36 scFv CAR T cells containing 4-1BB as a co-stimulatory domain were tested in a CD4/CD8 ratio of 2:1, leading to complete remission in an orthotopic ccRCC model in NSG mice, which remained tumor-free 72 days after CAR-T cells infusion. This powerful treatment was able to downregulate immune checkpoint genes and reduce the differentiation of regulatory T cells [54].…”

Section: Preclinical and Clinical Studies With Anti-caix Chimeric Ant...mentioning

confidence: 99%

Carbonic Anhydrase IX: A Renewed Target for Cancer Immunotherapy

Campos

Souza

Silva

et al. 2022

Cancers

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The carbonic anhydrase isoform IX (CAIX) enzyme is constitutively overexpressed in the vast majority of clear cell renal cell carcinoma (ccRCC) and can also be induced in hypoxic microenvironments, a major hallmark of most solid tumors. CAIX expression is restricted to a few sites in healthy tissues, positioning this molecule as a strategic target for cancer immunotherapy. In this review, we summarized preclinical and clinical data of immunotherapeutic strategies based on monoclonal antibodies (mAbs), fusion proteins, chimeric antigen receptor (CAR) T, and NK cells targeting CAIX against different types of solid malignant tumors, alone or in combination with radionuclides, cytokines, cytotoxic agents, tyrosine kinase inhibitors, or immune checkpoint blockade. Most clinical studies targeting CAIX for immunotherapy were performed using G250 mAb-based antibodies or CAR T cells, developed primarily for bioimaging purposes, with a limited clinical response for ccRCC. Other anti-CAIX mAbs, CAR T, and NK cells developed with therapeutic intent presented herein offered outstanding preclinical results, justifying further exploration in the clinical setting.

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“…Similar payload-based strategies are being developed using small molecules targeting CAIX for delivery of therapeutic agents [ 11 , 12 ]. Immunotherapy approaches using CAIX-targeted chimeric antigen receptor T (CAR-T) cells are also currently gaining traction, with the development of new generations of CAIX CAR-T cells resulting in the initiation of Phase I clinical trials evaluating these agents for treatment of advanced renal cell carcinoma (NCT04969354) [ 13 , 14 , 15 ]. Administration to renal cancer patients of autologous dendritic cells transduced by adenovirus with a granulocyte-macrophage colony-stimulating factor/CAIX fusion construct (DC-AdGMCAIX) elicited a CAIX-specific immune response in Phase I trials, further highlighting the potential promise of CAIX-targeted immune therapy [ 16 ].…”

Section: Immunotherapymentioning

confidence: 99%

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

McDonald¹,

Chafe

Supuran

et al. 2022

Cancers

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Carbonic Anhydrase IX (CAIX) is a major metabolic effector of tumor hypoxia and regulates intra- and extracellular pH and acidosis. Significant advances have been made recently in the development of therapeutic targeting of CAIX. These approaches include antibody-based immunotherapy, as well as use of antibodies to deliver toxic and radioactive payloads. In addition, a large number of small molecule inhibitors which inhibit the enzymatic activity of CAIX have been described. In this commentary, we highlight the current status of strategies targeting CAIX in both the pre-clinical and clinical space, and discuss future perspectives that leverage inhibition of CAIX in combination with additional targeted therapies to enable effective, durable approaches for cancer therapy.

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Anti-CAIX BBζ CAR4/8 T cells exhibit superior efficacy in a ccRCC mouse model

Cited by 23 publications

References 65 publications

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

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

Carbonic Anhydrase IX: A Renewed Target for Cancer Immunotherapy

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

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