Serial Assessment of Circulating T lymphocyte Phenotype and Receptor Repertoire During Treatment of Non-Muscle Invasive Bladder Cancer with Adoptive T Cell Immunotherapy

Abstract

Background: Recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) are frequent despite intravesical therapy. We hypothesized that administration of an activated T cell immunotherapy (ACT) at times when immunosuppressive populations were noted to have increased in peripheral blood would prevent recurrence of disease.Method: This was an N-of-1 study. A subject with multiple primary bladder high grade urothelial carcinomas who had initially completed standard resection and chemotherapy was enrolled. ACT consisted of dendritic cells mixed with cytokine induced killer cells (DC/CIK)) which were infused intravenously 18 times over a 6 year period in response to observed increases in peripheral blood immunosuppressive CD8+/CD28- cells. Peripheral blood was analyzed for T cell phenotype by flow cytometry, T cell receptor (TCR) repertoire, and circulating tumor DNA (ctDNA) by next generation sequencing (NGS) at the time of each infusion. Standard of care cystoscopy and pelvic CT scans have been performed at routine intervals. Results: The patient’s resected bladder tumors did not express PD-1 or PD-L1. There has been no recurrence of urothelial carcinoma. Peripheral blood cytotoxic T cells and unique TCR clones increased and suppressive T cell populations decreased after DC/CIK infusions. ctDNA detected mutations in six tumor relevant genes (ARID1B, MYCN, CDH23, SETD2, NOTCH4 and FAT1) at baseline but all of them disappeared after the DC-CIK infusions.Conclusion: DC/CIK infusions were associated with beneficial changes in T cell phenotype, TCR repertoire, decreases in circulating tumor DNA and sustained recurrence-free survival.

Elevated Stratifin promotes cisplatin-based chemotherapy failure and poor prognosis in non-small cell lung cancer

“…Immunotherapy has revolutionized lung cancer treatments within the past decade, and resistance to immunotherapy, which manifests as a lack of initial response or clinical benefit to therapy or tumor progression after the initial period of response, is frequent. 12 , 13 , 14 Overcoming immunotherapy resistance is challenging because of the complex and dynamic interplay among malignant cells and the immune defense system. 15 , 16 , 17 , 18 …”