Emerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies

Abstract

Checkpoint blockade has formally demonstrated that reactivating anti-tumor immune responses can regress tumors. However, this only occurs in a fraction of patients. Incorporating these therapies in more powerful combinations is thus a logical next step. Here, we review functional roles of immune checkpoints and molecular determinants of checkpoint-blockade clinical activity. Limited-size T cell-infiltrated tumors, differing substantially from "self," generally respond to checkpoint blockade. Therefore, we propose that reducing tumor burden and increasing tumor immunogenicity are key factors to improve immunotherapy. Lastly, we outline criteria to select proper immunotherapy combination partners and highlight the importance of activity biomarkers for timely treatment optimization.

Keywords: cancer immunotherapy; immune checkpoint blockade; immunotherapy-based combinations; tumor immunology.

Figure 1. Differences between CTLA-4 and PD-1 immune inhibitory pathways

Schematic representation of CTLA-4 and PD-1 molecular functions. Different outcomes of these molecular pathways in tumor-bearing hosts may be mechanistically explained at least at 4 levels: expression pattern and localization, expression kinetic during T-cell activation, partner phosphatases in the downstream signaling pathway, and metabolic effects. TCR, T-cell receptor; MHC, major histocompatibility class molecules; FAO, fatty acid oxidation; Treg, regulatory T cell.

Figure 2. T-cell molecular pathways regulated by CTLA-4 and PD-1

Upon TCR and CD28 engagement, CTLA-4 is rapidly up-regulated and binds with high affinity to B7 molecules. This leads to the CTLA-4 cytoplasmic tail recruitment of tyrosine phosphatases (SHP-1, SHP-2 and PP2a) that switch off TCR/CD28 downstream signaling pathways, otherwise promoting cell proliferation, differentiation, motility, acquisition of effector functions and glycolysis. On the other hand, PD-1 engagement induces LCK to phosphorylate its cytoplasmic tail with the consequent recruitment of tyrosine phosphatases (in particular SHP-2), which, besides down-regulating TCR/CD28 activation, reduces phosphorylation of PD-1 itself. PD-1 downstream signaling pathway also leads to Cpt1a up-regulation and promotes fatty acid oxidation (FAO).

Figure 3. Strategy to interfere with tumor fitness for potentiating cancer immunotherapy

(A) A growing tumor is the result of multiple levels of adaptation in a relatively unfavorable environment. In order to develop and spread, malignant cells need to acquire survival/proliferation advantage, which is typically conferred by mutations in oncogenes/tumor-suppressor genes (cellular fitness), evade immune surveillance (immune fitness) and gain preferential access to nutrient (metabolic fitness). (B) Potentiating immune control of tumor growth, for example with immune checkpoint blockade, has shown efficacy in a limited number of patients. Therapeutic anti-tumor immune responses require that a sufficient amount of activated tumor-specific killer T cells are mobilized toward the tumor. As immune effector cells and tumor cells rely on the same glycolytic metabolism, immune cells need to gain metabolic advantage to sufficiently expand and efficiently eradicate the tumor. To this end, the use of anti-neoplastic agents to reduce tumor burden by directly interfering with tumor growth may favorably combine with immunotherapy, in particular if these anti-cancer treatments have positive immune modulatory effects. At the same time, improving tumor immunogenicity may facilitate immune recognition and clearance of malignant cells.

Figure 4. Improving checkpoint blockade activity in rational therapeutic combinations

Examples of available anti-neoplastic agents and immunotherapies to exploit in combination with checkpoint blockade based on the rationale discussed in the article.

Figure 5. Selection and optimization of immunotherapy-based combinations

Proposed strategy to improve combination of anti-neoplastic and immunotherapeutic treatments based on their reciprocal levels of activity against tumors of different stage and immunogenicity. The extent of tumor invasion is expected to inversely correlate with immunogenicity and/or immune functions. De-bulking potential of standard anti-neoplastic treatments is generally stronger against limited diseases than disseminated tumors. Given that reducing tumor burden may facilitate long-lasting protective immunity, it is logical to combine therapies with the maximal de-bulking potential in each case with the immunotherapy (ImmunoTx) that can best complement such activity toward sustained anti-tumor responses. This approach would also ensure that immunotherapy is appropriately dosed to limit the occurrence of immune-related adverse events. The possibility to monitor the biological and therapeutic performance of the selected combination would allow for timely and patient-specific treatment optimization. ICB, immune checkpoint blockade.