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

## TL;DR

A prostate cancer patient achieved long-term remission through repeated TIL infusions and PD-1 blockade, with TIL-derived immune cells persisting and expanding over five years.

## Contribution

This study reveals the long-term clonal dynamics and synergy of TIL infusions with PD-1 blockade in a prostate cancer patient.

## Key findings

- TIL-derived clonotypes persisted in blood for five years with reduced diversity and increased clonality during remission.
- Multiple TIL infusions improved therapy exposure and pharmacokinetics over time.
- PD-1 blockade after TIL infusions led to re-expansion of TIL-derived clonotypes and new clones.

## Abstract

Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) can achieve durable responses in patients with metastatic cancers, but the long-term clonal dynamics after multiple administration and synergy with checkpoint blockade remain understudied. We present a longitudinal case study of a patient with treatment-refractory metastatic prostate cancer that achieved complete and durable tumor remission over 5-years after multiple TIL infusions and anti-PD-1 therapy. We performed longitudinal high-throughput T-cell receptor (TCR) sequencing on blood and tumor samples collected over five years to track the persistence and dynamics of TIL-derived and endogenous clonotypes. TIL-derived clonotypes exhibited sustained persistence in blood, with notable clonal expansions correlating with reduced repertoire diversity, increased clonality, and observed clinical response. Multiple TIL administration increased the patient exposure to the therapy, improving its pharmacokinetics profile over time. The third TIL infusion was followed by pembrolizumab administrations, which coincided with the re-expansion of TIL-derived clonotypes and emergence of novel clones. Serial tracking revealed clonotype stability for up to five years post-treatment. Our findings provide insights into the long-term persistence and reactivation of TIL-derived immunity and illustrate the potent synergy between adoptive transfer and PD-1 blockade by enhancing both infused and endogenous tumor-reactive T cell responses, and supporting the integration of longitudinal immunogenomic monitoring in personalized immunotherapy.