Current Challenges in Cancer Immunotherapy: Multimodal Approaches to Improve Efficacy and Patient Response Rates

Abstract

Cancer immunotherapy is a promising innovative treatment for many forms of cancer, particularly melanoma. Although immunotherapy has been shown to be efficacious, patient response rates vary and, more often than not, only a small subset of the patients within a large cohort respond favourably to the treatment. This issue is particularly concerning and becomes a challenge of immunotherapy to improve the effectiveness and patient response rates. Here, we review the specific types of available immunotherapy options, their proposed mechanism(s) of action, and the reasons why the patient response to this treatment is variable. The potential favourable options to improve response rates to immunotherapy will be discussed with an emphasis on adopting a multimodal approach on the novel role that the gut microbiota may play in modulating the efficacy of cancer immunotherapy.

Figure 1

Forms of Immunotherapy. Currently available immunotherapy treatment options include (1) monoclonal antibodies, (1) adoptive immunotherapy, (3) vaccines, and (4) correcting a dysregulated immune system. These forms of immunotherapy are designed to either actively target a specific antigen on the tumor or enhance the host's immune system.

Figure 2

Mechanism of Immune Checkpoint Inhibition. MHC present antigens to the T-cell receptor in order to active T cells (1). Through interactions with the CD80 on tumor cells and the CD28 on T cells, T cells can be deactivated (2). Additionally, CTLA-4 competes with CD80 to deactivate T cells as well (3). Lastly, PD-L1 binds to the PD-1 receptor on T cells to deactivate T cells (4). Tumor cells employ the use of these mechanisms in order to prevent T cells from clearing malignant cells. By using inhibitors that prevent this interaction from occurring, T-cells remain active after identifying tumor cells and can clear them from the host. Abbreviations: CD; cluster of differentiation, CTLA-4; cytotoxic T-lymphocyte associated antigen-4, MHC; major histocompatibility complex, PD-1; programmed death-1, PD-L1; programmed death ligand-1, TCR; T-cell receptor.

Figure 3

Mechanism of Action of Cancer Vaccines. As illustrated, cancer vaccines are administered through an intradermal injection (1) with adjuvants that activate dendritic cells (2). Immature dendritic cells take up the antigen; typically this antigen is uniquely expressed on tumor cells (3) and presents the antigen to CD4 cells (4) and CD8 cells (5). CD8 cells are then activated to seek out the antigen on the surface of tumor cells (6). Abbreviations. CD: a cluster of differentiation and MHC: major histocompatibility complex.

Figure 4

Overview of the factors contributing to varying response rates to immunotherapy and methods to overcome these barriers. Variations in immunotherapy response rates range from specific individual immune system diversity to the broad influence of the composition of the gut microbiota and are shown in red boxes. The proposed methods to overcome these barriers are indicated in green boxes. The gut microbiota can have overarching effects on patient response to immunotherapy due to the influence of the gut microbiota on the composition and function of the immune system.