Topalian et al. reviewed results of neoadjuvant (presurgical) PD-1 blockade in earlier stage cancer, focusing on emerging biological mechanisms, trial designs, response evaluation, and immune-related tumor pathology. Neoadjuvant PD-1 inhibition enhanced antitumor T cell immunity by direct DC priming of T cell responses, intratumorally and in tumor-draining LNs, and expanding additional sub-dominant tumor-specific T cell clones. In neoadjuvant trials of several different tumor types, histologically measuring immune-mediated tumor regression, coupled with the rich correlatives from the resected tumor tissue, may provide early surrogate markers.
Contributed by Katherine Turner
ABSTRACT: Cancer immunotherapies that target the programmed cell death 1 (PD-1):programmed death-ligand 1 (PD-L1) immune checkpoint pathway have ushered in the modern oncology era. Drugs that block PD-1 or PD-L1 facilitate endogenous antitumor immunity and, because of their broad activity spectrum, have been regarded as a common denominator for cancer therapy. Nevertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing research efforts are focused on improving patient outcomes. Using anti-PD-1 or anti-PD-L1 treatment against earlier stages of cancer is hypothesized to be one such solution. This Review focuses on the development of neoadjuvant (presurgical) immunotherapy in the era of PD-1 pathway blockade, highlighting particular considerations for biological mechanisms, clinical trial design, and pathologic response assessments. Findings from neoadjuvant immunotherapy studies may reveal pathways, mechanisms, and molecules that can be cotargeted in new treatment combinations to increase anti-PD-1 and anti-PD-L1 efficacy.