Next-Generation Immunotherapies to Improve Anticancer Immunity

Abstract

Checkpoint inhibitors are widely used immunotherapies for advanced cancer. Nonetheless, checkpoint inhibitors have a relatively low response rate, work in a limited range of cancers, and have some unignorable side effects. Checkpoint inhibitors aim to reinvigorate exhausted or suppressed T cells in the tumor microenvironment (TME). However, the TME contains various other immune cell subsets that interact to determine the fate of cytotoxic T cells. Activation of cytotoxic T cells is initiated by antigen cross-presentation of dendritic cells. Dendritic cells could also release chemokines and cytokines to recruit and foster T cells. B cells, another type of antigen-presenting cell, also foster T cells and can produce tumor-specific antibodies. Neutrophils, a granulocyte cell subset in the TME, impede the proliferation and activation of T cells. The TME also consists of cytotoxic innate natural killer cells, which kill tumor cells efficiently. Natural killer cells can eradicate major histocompatibility complex I-negative tumor cells, which escape cytotoxic T cell-mediated destruction. A thorough understanding of the immune mechanism of the TME, as reviewed here, will lead to further development of more powerful therapeutic strategies. We have also reviewed the clinical outcomes of patients treated with drugs targeting these immune cells to identify strategies for improvement and possible immunotherapy combinations.

Keywords: B cells; DC; NK cells; combination immunotherapy; neutrophils.

FIGURE 1

Major types of cancer immunotherapies. (A) Immune Checkpoint blockade therapy utilizing antibodies targeting CTLA-4 or PD-1/PD-L1 pathway have demonstrated promising results in a variety of malignancies. Additionally, recent studies have identified many other immune checkpoint markers, such as LAG3, TIM3 or TIGIT that could also be targeted. (B) Tumor Antigen Targeting Antibodies are laboratory generated, designed to target specific tumor antigens, usually conjugated with a specific drug. Currently the development of polyspecific antibodies (bi- and tri-specific antibodies) has the advantages by targeting multiple tumor antigens, to more precisely and effectively eradicate cancer cells. (C) Recombinant Cytokines (e.g., IL-2, IL-18, IL-6, IFNγ, GM-CSF) can induce, mediate and regulate the immune response by improving antigen priming, facilitating T cell proliferation and survival or enhancing their cytolytic activity. (D) Therapeutic Vaccines made of laboratory modified cancer cells, parts of cells, or pure antigens elicit an immune response against tumor-specific or tumor-associated antigens. (E) Oncolytic viruses (OVs) in the forms of native or engineered viruses can be used to selectively target and kill cancer cells. Advancements of genetic engineering enable successful editing of viral genome of many species to augment antitumor activity and attenuate pathogenicity, but also to express specific cytokines that favor immune cell recruitment and activation or to produce co-stimulatory molecules on tumor cells to facilitate the generation of T-cell activating signals. (F) CAR T cells and Adoptive Cell Therapy (ACT) are personalized cancer strategies relying on the collection of immune cellular components from patient, expansion and/or genetically modification of those cells in vitro and injection them back to the patient to achieve a therapeutic response. Combination strategies involving the immunotherapies described above as well as combinations including both standard of care chemotherapy or radiation treatment options are also actively being tested in both preclinical models and in the clinical setting.

FIGURE 2

Schematic overview of immune cell-mediated anticancer therapies based on dendritic cells (DCs), natural killer (NK) cells, B cells, and neutrophils applied within clinical trials. (A) DC-related antitumor immunotherapies include the DC vaccine loaded with tumor antigen, STING agonist, TLR agonist, and anti-CD47 antibodies. (B) NK cell-related antitumor immunotherapies include treatment with a superagonist, cytokine-activated NKs, anti-CD19 chimeric antigen receptor-NK, combination of haNK with anti-CD20 antibody, application of anti-NKG2A antibody, and NK-based CD16-IL15-CD33 TriKEs. (C) B cell-related antitumor immunotherapies include treatment with anti-CD40 antibody. (D) Neutrophil-related antitumor immunotherapies include CXCR1/2 inhibitor, CCR5 inhibitor, anti-TRAIL-R2 agonist antibody, anti-C5aR agonist antibody, treatment with IFNγ, anti-TGFβ neutralizing antibody, TGFβ receptor kinase inhibitor, arginase 1 inhibitor, recombinant arginase 1, and anti-CD47 antibody. These strategies can be combined with other therapies such as anti-PD-L1 antibody. The antitumor effect (marked as a red dashed arrow) or inhibitory interaction (marked as a black line) is indicated within the figure.