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

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Adoptive cell therapy (ACT) shows promise for cancer immunotherapy but faces limitations in solid tumors.
• Challenges include tumor-antigen heterogeneity, a suppressive tumor microenvironment, and T-cell exhaustion.
• Tumor-infiltrating lymphocyte (TIL) therapy is a clinical reality but involves complex manufacturing.

Purpose of the Study:

• To review the biological characteristics and therapeutic potential of circulating tumor-reactive lymphocytes (cTRLs).
• To highlight cTRLs as a promising alternative for ACT in solid tumors.
• To discuss advancements in cTRL detection, purification, and scalable production.

Main Methods:

• Review of preclinical and clinical evidence on cTRLs.
• Analysis of cTRL phenotypic characteristics and antitumor activity.
• Comparison of cTRLs with TILs regarding exhaustion and cell fitness.

Main Results:

• cTRLs possess potent in vitro and in vivo antitumor activity.
• cTRLs exhibit less exhaustion, enhanced cell fitness, and greater T-cell diversity compared to TILs.
• Recent advances enable efficient isolation and scalable production of cTRLs.

Conclusions:

• cTRLs are naturally occurring T cells with significant antitumor reactivity.
• cTRLs demonstrate superior characteristics for ACT compared to TILs.
• cTRLs represent a viable therapeutic option for patients with solid tumors, with ongoing development for clinical application.