Going with the Flow: Circulating Tumor-Reactive Lymphocytes Stream into Cancer Therapy

Adoptive cell therapy (ACT), best exemplified to date by chimeric antigen receptor T-cell, engineered T-cell receptor, and tumor-infiltrating lymphocyte (TIL) therapy, has emerged as a transformative approach in cancer immunotherapy. The broad application of ACT in solid tumors, however, has been limited due to several challenges, such as tumor antigen heterogeneity, the suppressive tumor microenvironment, and T-cell exhaustion. TIL therapy harvests and expands tumor-reactive T cells from excised tumors for reinfusion, now a clinical reality, despite complex manufacturing logistics. Circulating tumor-reactive lymphocytes (cTRL) are naturally occurring T cells with antitumor reactivity that are found at low levels in the peripheral blood of patients with cancer. cTRLs are among a group of T cells that possesses unique phenotypic characteristics, allowing them to circulate between the bloodstream and tumor sites, including distant metastases, to provide systemic and local immune surveillance. Preclinical studies have demonstrated that cTRLs possess potent antitumor activity in vitro and in vivo. When compared with corresponding TILs, cTRLs show less exhaustion, enhanced cell fitness, and a greater concentration and diversity of tumor-specific T-cell clonotypes, suggesting that cTRLs may be well-suited for ACT. Whereas cTRLs are typically rare cells in peripheral blood, recent advances in cTRL detection and purification methods now enable the efficient isolation and scalable production of these cells for therapeutic applications. In this review, we highlight the biological characteristics of cTRLs, their role in cancer surveillance and therapy, and the preclinical and clinical evidence showcasing their potential for development as a therapeutic option for patients with cancer.