CD70: An emerging target for integrated cancer diagnosis and therapy

Abstract

CD70, which is a ligand belonging to tumour necrosis factors, exhibits aberrant overexpression among multiple hematologic and solid malignancies and has drawn extensive research enthusiasm as a target to treat and diagnose cancers. CD70-targeted immuno-PET/CT is an emerging approach for cancer diagnosis, with the potential to improve tumour detection, assist disease staging, and monitor therapeutic response. CD70-targeted therapeutic approaches, involving antibody-drug conjugates, CAR-T, CAR-NK, and monoclonal antibodies, have shown encouraging activity in preclinical models and preliminary signals of efficacy in early clinical studies. In addition to these monotherapies, increasing efforts have focused on rational combination strategies that aim to enhance antitumor efficacy, reverse immune suppression, and overcome resistance. This review comprehensively summarizes the diagnostic and therapeutic advances in CD70-targeted strategies, discusses ongoing barriers, and outlines future directions to advance CD70-targeted imaging and therapeutic strategies through mechanistic research and clinical translation. Key points CD70 is aberrantly overexpressed in diverse malignancies with limited normal tissue expression. CD70-targeted immuno-PET/CT improves tumour detection, staging, and treatment monitoring. Multiple CD70-targeted therapies, including CAR-T and CAR-NK, are under active investigation. Rational combination strategies are emerging to enhance antitumor efficacy.

Keywords: CAR‐T; CD70; combination therapy; immuno‐PET/CT; targeted therapy.

FIGURE 1

Overview of CD70‐targeted strategies in cancer diagnosis and therapy. CD70‐targeted immuno‐PET/CT has shown unique application potential in cancer diagnosis, highlighting its value as an emerging diagnostic tool. Additionally, various strategies targeting CD70 in solid and hematologic cancers are illustrated, including monoclonal antibodies (mAb), antibody‐drug conjugates, CAR‐T and CAR‐NK cell therapy. Combination therapy is receiving increasing attention for its potential to enhance therapeutic efficacy.

FIGURE 2

CD70‐targeted immuno‐PET/CT in RCC diagnosis. CD70‐targeted tracers ([¹⁸F]RCCB6 and [⁶⁸Ga]Ga‐NOTA‐RCCB6) enable the detection of CD70‐positive primary and metastatic lesion in renal cell carcinoma (RCC), as confirmed by immunohistochemistry (IHC). Compared with CD70 immuno‐PET/CT, conventional ¹⁸F‐FDG PET/CT shows limited diagnostic efficacy due to low tracer uptake in some RCC lesions and poor specificity, which may lead to missed or incorrect diagnoses. CD70‐targeted immuno‐PET/CT also shows potential in treatment monitoring and disease progression assessment.

FIGURE 3

CD70‐targeted CAR designs and strategies. A, CAR construction across five generations. The first‐generation CAR consists of four key components: the antigen recognition domain (scFv), hinge, transmembrane domain, and intracellular signalling domain. The second generation introduces a costimulatory domain to enhance T cell activation. The third generation further expands upon the second generation by incorporating two or more costimulatory domains. The fourth‐generation CAR adds cytokine secretion elements to enhance the immune response within the tumour microenvironment. The fifth generation represents the latest design, which is more complex and employs multiple mechanisms to enhance antitumor activity and improve clinical safety. B, CD70‐targeted CAR‐T strategies. The first row (from left to right) illustrates autologous CD70 CAR‐T designs derived from patient T cells. These include three types of antigen recognition domains: truncated CD27, CD70 scFv, and nanobody, combined with appropriate costimulatory domains and hinge structures to enhance CAR‐T efficacy. The middle section features tandem CAR, which combines two antigen recognition domains targeting different tumour antigens within one receptor, and dual CAR, which features two distinct CAR molecules, each with an individual antigen recognition domain, allowing the CAR‐T cell to target multiple antigens simultaneously. The right section shows 4SCAR70, a fourth‐generation CAR with multiple co‐stimulatory domains and the iCasp9 suicide gene. The second row (from left to right) includes allogeneic CAR‐T cells derived from healthy donors, featuring TCR and immune‐modulatory gene editing to improve therapeutic potential. The CD70 knockout section shows the use of CRISPR/Cas9 technology to knockout endogenous CD70 in CAR‐T cells, enhancing production efficiency and cytotoxicity. The final section displays emerging CAR designs, which include modifications like CXCR2 for enhanced migration and the ability to secrete antibodies, cytokines, or other therapeutic molecules, aiming to optimize CAR‐T cell function.

FIGURE 4

CD70‐targeted CAR‐NK strategies. The left section illustrates current fourth‐generation CD70 CAR‐NK designs that include various antigen recognition domains, transmembrane domains, and co‐stimulatory domains, integrated with IL‐15 secretion modules to enhance NK cell persistence and cytotoxicity. The right section illustrates a multiengineered CD70 CAR‐NK cell strategy derived from human induced pluripotent stem cell (iPSC), incorporating CD70 knockout to prevent fratricide, high‐affinity noncleavable CD16 (hnCD16) to augment antibody‐dependent cellular cytotoxicity, and an IL‐15Rα/IL‐15 fusion protein (IL15RF) to enhance persistence. This schematic was redrawn and conceptually adapted from the CAR‐NK strategy developed by Wang et al., and reorganized to highlight its key engineering elements.