Prostate Cancer: In Search of Predictive Biomarkers for Immunotherapy
Scientists are testing immune checkpoint proteins, CD8 T cell clonal expansion, mutational load, and PSA levels as predictive biomarkers for prostate cancer immunotherapy outcomes.
Immunotherapies represent an important fourth paradigm in cancer treatment, expanding treatment modalities beyond the longstanding triad of chemotherapy, surgical oncology, and radiation oncology. For some patients, including some diagnosed with prostate cancer, immune checkpoint therapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1, offer remarkable clinical responses.
Yet not all patients benefit, and these agents are associated with severe immune-related adverse events (irAEs), ranging from rash to autoimmune endocrinopathies like thyroiditis or Graves disease.
Many researchers are focusing on developing CTLA-4, PD-1 and PD-L1 expression biomarkers, reasoning that tumor or tumor microenvironment expression of these proteins might predict responses to the checkpoint blockade agents that target them.
Early research suggests that flow cytometry of peripheral blood samples for expression of PD-1 and CTLA4 is associated with clinical immunotherapy responses, according to Sumit K. Subudhi, MD, PhD, an assistant professor of genitourinary medical oncology at the University of Texas MD Anderson Cancer Center in Houston. Immune system biomarkers also show promise for predicting irAEs, his team found.
“Clonal expansion of CD8 T cells appears to predict for irAEs,” Dr Subudhi told Cancer Therapy Advisor.
Analyzing peripheral blood samples taken from men undergoing androgen deprivation therapy plus CTLA-4-targeting immunotherapy with ipilimumab for metastatic prostate cancer in 2 phase 2 clinical trials, Dr Subudhi's team found that CD8 T-cell clonal expansion in systemic circulation preceded the development of irAEs, suggesting this as a predictive biomarker useful for on-treatment monitoring.2 irAEs predicted by CD8 expansion included rash, diarrhea, and transaminitis, Dr Subudhi noted.
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“Sequencing of the T cell receptor β-chains in purified T cells revealed clonal expansion of CD8 T cells, which occurred in blood samples collected before the onset of grade 2-3 irAEs,” Dr Subudhi and colleagues reported in the Proceedings of the National Academy of Sciences.