Intro
Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a revolutionary approach in the treatment of hematologic malignancies. However, despite its success in blood cancers, CAR-T therapy continues to face significant barriers when applied to solid tumors. This blog explores how single domain antibodies, such as VHHs (derived from camelids) and VNARs (from sharks), are transforming CAR-T therapy and helping to overcome longstanding challenges in solid tumor treatment.

The Challenges of CAR-T in Solid Tumors
Traditional CAR-T cells rely heavily on single-chain variable fragment (scFv) antibodies, which often struggle with:

• Tumor antigen heterogeneity

• Antigen escape mechanisms

• Limited infiltration and persistence in the tumor microenvironment

• Potential off-target toxicity and immunogenicity

These challenges have slowed progress in extending CAR-T therapy to broader cancer types, particularly in solid tumors like lung, breast, and pancreatic cancers.

Enter the Single Domain Antibody: VHHs and VNARs

Single domain antibodies—also known as nanobodies—are the smallest functional antigen-binding fragments derived from heavy-chain-only antibodies. Their unique properties make them powerful tools in immunotherapy:

• Smaller size → Better tissue penetration

• High stability → Resilient in harsh tumor microenvironments

• Strong affinity and specificity → Effective targeting of elusive tumor antigens

• Low immunogenicity → Reduced risk of immune rejection

• Modular design → Easier to engineer into multi-target CAR formats

These characteristics make VHHs and VNARs ideal candidates to replace or supplement scFvs in CAR-T designs.

Strategic Advantages in Solid Tumor Targeting
Nanobody-based CAR constructs offer the potential to:

• Identify and bind unique or hidden tumor antigens with precision

• Combat tumor antigen escape by creating multi-specific CARs

• Improve CAR-T cell persistence and activity in immunosuppressive environments

• Enable bispecific or logic-gated CAR designs to reduce off-tumor effects

Future Outlook
The integration of VHHs and VNARs into CAR-T therapies signals a new wave of innovation in cancer treatment. By overcoming current limitations, nanobody-enhanced CAR-T platforms may unlock effective, safe, and scalable solutions for patients with solid tumors—an area of high unmet medical need.

As more preclinical and clinical studies explore these next-gen CAR constructs, single domain antibodies could play a critical role in expanding the success of CAR-T therapy beyond blood cancers and into the broader oncology landscape.

Reference: Biomarker Research