T-cell receptor (TCR) T-cell therapies are adoptive cell therapies in which patient cells are engineered to express TCRs targeting specific cancer antigens and infused back into the patient. Since TCR recognition depends on antigen presentation by the human leukocyte antigen system, TCRs can respond to intracellular antigens. Cancer/testis antigens (CTAs) are a large family of proteins, many of which are only expressed in cancerous tissue and immune-privileged germline sites. Melanoma-associated antigen A4 (MAGE-A4) is an intracellular CTA expressed in healthy testis and placenta, and in a range of cancers, including esophageal, head and neck, gastric, ovarian, colorectal, lung, endometrial, cervical, bladder, breast and prostate cancers
soft tissue sarcomas
urothelial and hepatocellular carcinomas
osteosarcoma
and melanoma. This expression pattern, along with the immunogenicity and potential role in tumorigenesis of MAGE-A4 make it a prime target for TCR T-cell therapy. We outline the preclinical and clinical development of TCR T-cell therapies targeting CTAs for treatment of solid tumors, highlighting the need for extensive preclinical characterization of putative off-target, and potential on-target but off-tumor, effects. We identified ten clinical trials assessing TCR T-cell therapies targeting MAGE-A4. Overall, manageable safety profiles and signals of efficacy have been observed, especially in patients with advanced synovial sarcoma, myxoid/round cell liposarcoma, ovarian, head and neck, and urothelial cancers, with one TCR T-cell therapy approved by the US Food and Drug Administration in August 2024. We also review the limitations, and strategies to enhance efficacy and improve safety, of these therapies, and summarize related immunotherapies targeting MAGE-A4.