Neoadjuvant checkpoint blockade for cancer immunotherapy

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.

Fig. 1.. Two potential mechanisms for the enhancement of systemic antitumor T cell immunity after neoadjuvant PD-1 blockade.

PD-1 blockade could result in the “in situ” expansion of tumor-specific T cell clones already within the tumor microenvironment (left). This expansion and activation is largely driven by PD-L1– and PD-L2–expressing dendritic cells in the tumor. Tumor-specific tumor-infiltrating lymphocytes (TILs) may represent naïve T cells or T cells that have already been “primed” to tumor antigen (84) before PD-1 pathway blockade. In addition, tumor antigen–containing DCs originating in the tumor pick up tumor antigens and traffic to the tumor-draining lymph nodes, where they present antigens either ineffectively or in a tolerogenic fashion to tumor-specific T cells. PD-1 blockade could act at this point, enhancing productive stimulation of tumor-specific T cells or partially reversing tolerance induction. Activated T cells enter the circulation by way of efferent lymphatics and then egress into tissues.

Fig. 2.. Immune-mediated tumor regression.

(A) Representative photomicrograph from a definitive surgical resection specimen from a patient with NSCLC responding to neoadjuvant immunotherapy. Hematoxylin and eosin staining was used, with 100× original magnification. HEV, high endothelial venule. (B) Schematic of the tumor bed immunoarchitecture, displaying features consistent with both T cell– and B cell–mediated local antitumor immune responses. The regression bed—the area where the tumor used to be—is characterized by hallmarks of tissue repair and wound healing, such as neovascularization and proliferative fibrosis.(C) Percent RVT using irPRC is calculated by the surface area of the RVT/surface area of the tumor bed. The tumor bed surface area includes RVT + tumor-associated stroma + necrosis + regression bed. Schematics show examples of 100, 50, 10 (MPR), and 0% (pCR) RVT.