Carbonic Anhydrase IX: A Renewed Target for Cancer Immunotherapy

Abstract

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.

Keywords: antitumor monoclonal antibodies; carbonic anhydrase; chimeric antigen receptor; clear cell renal cell cancer; hypoxic tumors; immune checkpoint inhibitors; immunotherapies.

Figure 1

Schematic representation of first, second, third, or fourth generations of chimeric antigen receptors (CAR). CARs are hybrid receptors that comprise an antibody-derived extracellular binding domain selected against a molecular target, usually in the form of a single-chain variable fragment (scFv), and a hinge/transmembrane domain fused to an intracellular signaling domain responsible for activating T cells. First-generation CARs have only one CD3ζ chain in the intracellular domain for activating T cells. Second- and third-generation CARs harbor one and two additional intracellular co-stimulatory domains, respectively. Fourth-generation CARs are CARs of second- or third-generation designed to induce expression of transgenic products constitutively or by induction, such as cytokines or monoclonal antibodies.