A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Abstract

Harnessing an antitumor immune response has been a fundamental strategy in cancer immunotherapy. For over a century, efforts have primarily focused on amplifying immune activation mechanisms that are employed by humans to eliminate invaders such as viruses and bacteria. This "immune enhancement" strategy often results in rare objective responses and frequent immune-related adverse events (irAEs). However, in the last decade, cancer immunotherapies targeting the B7-H1/PD-1 pathway (anti-PD therapy), have achieved higher objective response rates in patients with much fewer irAEs. This more beneficial tumor response-to-toxicity profile stems from distinct mechanisms of action that restore tumor-induced immune deficiency selectively in the tumor microenvironment, here termed "immune normalization," which has led to its FDA approval in more than 10 cancer indications and facilitated its combination with different therapies. In this article, we wish to highlight the principles of immune normalization and learn from it, with the ultimate goal to guide better designs for future cancer immunotherapies.

Keywords: B7-H1; PD-1; PD-L1; cancer; immunotherapy; normalization.

Figure 1.. FDA-Approved Cancer Immunotherapies and Their Indications under the Categories of the Immune Enhancement versus Immune Normalization

All FDA-approved cancer immunotherapies are illustrated. These cancer immunotherapies are divided into two categories. The immune enhancement category (IFNs, IL-2, anti-CTLA-4, cancer vaccine, and CAR-T cells) is listed in the left panel with the first approval of type I IFN for the treatment of hairy cell leukemia in 1984. The immune normalization category (anti-PD-1/PD-L1 mAbs) is listed in the right panel with the first approval of anti-PD-1 mAb nivolumab in 2014. Approved disease indications are listed in the middle panel.

Figure 2.. Illustration of the Immune-Normalization versus Immune-Enhancement Approaches

Using proper flow and drainage of a pipeline as a comparison for the antitumor immune response. The flow of the pipeline can be insufficient when a blockade impairs flow, as the antitumor immune response can be insufficient when there is an immune impairment. The immune enhancement approach is illustrated as an increase in flow or pressure to return to proper function/flow with the risk of breaking the pipe (adverse effects). In contrast, the immune normalization approach would be to identify and try to unblock this specific blockage and restore the flow.

Figure 3.. Tumor Immunity in the Microenvironment Classification

Four different TME groups with potential implications for mechanism and therapy have been identified according to B7-H1 (PD-L1) expression and the presence of TILs in tumor biopsies: I, B7-H1-negative tumors without TILs, considered immunological ignorant because immune cells do not accumulate at the tumor site, II, B7-H1-positive tumors with TILs, considered a paradigm of adaptive resistance of tumors mediated by the B7-H1/PD-1 pathway, III, B7-H1-negative tumors with TILs, considered a situation of tolerance because TILs are present, but they do not induce B7-H1 expression in the tumor microenvironment through IFN-γ production, and IV, B7-H1-positive tumors without TILs, considered as a scenario of intrinsic induction of B7-H1 expression in tumor cells through oncogenic pathways that may be susceptible to be targeted. Groups I, III, and IV can be converted into group II through different strategies, synergizing with the action of anti-PD therapies that are more effective in the presence of TILs and B7-H1 expression.