The Rationale and Emerging Use of Neoadjuvant Immune Checkpoint Blockade for Solid Malignancies

Abstract

Unprecedented advances in the treatment of cancer have occurred through the use of immunotherapy, with several agents currently approved by the Food and Drug Administration (FDA) for the treatment of widespread metastatic disease across cancer types. Immune checkpoint blockade represents a particularly promising class of agents that block inhibitory molecules on the surface of T cells, resulting in their activation and propagation of an immune response. Treatment with these agents may re-invigorate anti-tumor immunity, resulting in therapeutic responses, and use of these agents currently is being studied in the adjuvant setting. Additionally, a strong rationale exists for their use in the neoadjuvant setting for high-risk resectable disease (e.g., regional nodal disease in the case of melanoma). This rationale is based on the relatively high risk of relapse for these patients, as well as on scientific evidence suggesting that long-term immunologic memory and tumor control may be superior in the setting of treatment for an intact tumor (i.e., neoadjuvant therapy) as opposed to treatment in the setting of micrometastatic disease (e.g., adjuvant treatment). The potential advantages of this approach and the current landscape for neoadjuvant immune checkpoint blockade is discussed in this report, as well as caveats that should be considered by clinicians contemplating this strategy.

Figure 1. Currently approved immune checkpoint inhibitors target immunoinhibitory interactions between T cells, antigen-presenting cells, and tumor cells

Immune activation is opposed by upregulation of immunoinhibitory molecules (such as CTLA-4 and PD-1) on T cells or their ligands (such as PD-L1) which may be subverted by tumor cells to facility immune escape. Currently approved immune checkpoint inhibitors target CTLA-4, PD-1, and PD-L1.

Figure 2

Timeline of FDA approvals of immune checkpoint blockade in (a) melanoma, (b) non-small cell lung cancer, and (c) other tumor types

Figure 2

Timeline of FDA approvals of immune checkpoint blockade in (a) melanoma, (b) non-small cell lung cancer, and (c) other tumor types

Figure 2

Timeline of FDA approvals of immune checkpoint blockade in (a) melanoma, (b) non-small cell lung cancer, and (c) other tumor types

Figure 3

Representative radiographic images of (a) a patient who achieved complete response to combination ipilimumab/nivolumab and (b) a patient who progressed on pembrolizumab

Figure 4

Study schema of phase 2 clinical trial of neoadjuvant immune checkpoint blockade for patients with high-risk resectable metastatic melanoma (NCT02519322)