Serial TIL infusions and PD-1 blockade drive long-term clonal persistence in prostate cancer

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) offers durable responses in metastatic cancers.
• Long-term clonal dynamics and synergy with checkpoint blockade for TIL therapy are not well understood.

Purpose of the Study:

• To investigate the long-term clonal dynamics of tumor-infiltrating lymphocytes (TIL) and their synergy with anti-PD-1 therapy.
• To track the persistence and evolution of T-cell receptor (TCR) clonotypes in a patient with metastatic prostate cancer over five years.

Main Methods:

• Longitudinal high-throughput T-cell receptor (TCR) sequencing of blood and tumor samples.
• Case study of a patient with metastatic prostate cancer undergoing multiple TIL infusions and anti-PD-1 therapy.

Main Results:

• TIL-derived clonotypes persisted long-term in the blood, with expansions correlating to clinical response.
• Multiple TIL administrations improved pharmacokinetic profiles.
• Combination therapy with pembrolizumab led to re-expansion of TIL clonotypes and emergence of new clones.
• Clonotype stability was observed for up to five years post-treatment.

Conclusions:

• TIL therapy combined with PD-1 blockade demonstrates potent synergy, enhancing both infused and endogenous T-cell responses.
• Longitudinal immunogenomic monitoring is valuable for personalized immunotherapy strategies.
• Findings provide insights into long-term TIL persistence and reactivation of anti-tumor immunity.