Harnessing the immune system to improve cancer therapy

Abstract

Cancer immunotherapy uses the immune system and its components to mount an anti-tumor response. During the last decade, it has evolved from a promising therapy option to a robust clinical reality. Many immunotherapeutic modalities are already approved by the Food and Drug Administration (FDA) for treating cancer patients and many others are in the pipeline for approval as standalone or combinatorial therapeutic interventions, several also combined with standard treatments in clinical studies. The two main axes of cancer immunotherapeutics refer to passive and active treatments. Prominent examples of passive immunotherapy include administration of monoclonal antibodies and cytokines and adoptive cell transfer of ex vivo "educated" immune cells. Active immunotherapy refers, among others, to anti-cancer vaccines [peptide, dendritic cell (DC)-based and allogeneic whole cell vaccines], immune checkpoint inhibitors and oncolytic viruses, whereas new approaches that can further enhance anti-cancer immune responses are also widely explored. Herein, we present the most popular cancer immunotherapy approaches and discuss their clinical relevance referring to data acquired from clinical trials. To date, clinical experience and efficacy suggest that combining more than one immunotherapy interventions, in conjunction with other treatment options like chemotherapy, radiotherapy and targeted or epigenetic therapy, should guide the way to cancer cure.

Keywords: Cancer immunotherapy; checkpoint inhibitors; dendritic cells (DCs); monoclonal antibodies (mAbs); peptide vaccines.

Figure 1

Cancer immunotherapy approaches are classified into passive and active. Passive immunotherapy includes the use of tumor-specific mAbs, cytokines and adoptive cell transfer, whereas active immunotherapy refers to peptide, DC or allogeneic whole cell vaccines, checkpoint inhibitors and oncolytic viruses. DC, dendritic cell.

Figure 2

Schematic representation of important signals mediating T cell, APC and tumor cell interactions. During the activation phase (left), T cells interact with APCs and receive signal 1 (MHC/tumor epitope-TCR) and signal 2 (B7-CD28). Activated T cells express the inhibitory molecule CTLA-­4, which is blocked by ipilimumab, thus allowing their constant activation. During the effector phase (right), activated T cells migrate to the tumor, where their TCR recognizes tumor epitopes in the context of MHC molecules. Pembrolizumab and nivolumab block the checkpoint molecule PD-1 and, consequently, its interaction with the inhibitory regulator PD-­L expressed by tumor cells. As a result, T cells overcome tumor-induced suppression. APC, antigen presenting cell; MHC, major histocompatibility complex; TCR, T cell receptor; CTLA­-4, cytotoxic T lymphocyte-associated protein 4; PD-1, programmed cell death protein 1; PD-L, PD-1 ligand.

Figure 3

The PUSH and PULL approach could optimize anti-cancer immunity. Suitable tumor antigen-selection stimulates anti-tumor-reactive immune responses, which can be further boosted by several approaches (e.g., by co-stimulatory molecules; PUSH). Robust anti-cancer responses generated can be subsequently enhanced and sustained by blocking negative regulators (e.g., CTLA-4; PULL), leading to highly effective cancer immunotherapy interventions.