Immunotherapies and Combination Strategies for Immuno-Oncology

Abstract

The advent of novel immunotherapies in the treatment of cancers has dramatically changed the landscape of the oncology field. Recent developments in checkpoint inhibition therapies, tumor-infiltrating lymphocyte therapies, chimeric antigen receptor T cell therapies, and cancer vaccines have shown immense promise for significant advancements in cancer treatments. Immunotherapies act on distinct steps of immune response to augment the body's natural ability to recognize, target, and destroy cancerous cells. Combination treatments with immunotherapies and other modalities intend to activate immune response, decrease immunosuppression, and target signaling and resistance pathways to offer a more durable, long-lasting treatment compared to traditional therapies and immunotherapies as monotherapies for cancers. This review aims to briefly describe the rationale, mechanisms of action, and clinical efficacy of common immunotherapies and highlight promising combination strategies currently approved or under clinical development. Additionally, we will discuss the benefits and limitations of these immunotherapy approaches as monotherapies as well as in combination with other treatments.

Keywords: adoptive cell transfer; checkpoint inhibition; chemoresistance; chemotherapy; combination therapy; immunotherapy; radiation therapy.

Figure 1

Mechanisms of anti-tumor actions of cytotoxic T- lymphocyte-associated protein 4 (CTLA-4) targeting antibodies. Interaction of CTLA-4 on T cell with B7-1 or B7-2 on antigen presenting cells (APCs) leads to inhibition of T cell activity. Disruption of this interaction with anti-CTLA-4 antibody leads to activation of T cells and subsequent tumor growth inhibition. Additionally, interaction between the Fc portion of the anti-CTLA-4 antibodies and the Fc receptors (FcR) on natural killer (NK) cells may lead to antibody dependent cellular cytotoxicity (ADCC) of T_regs leading to depletion of T_regs in mice. p:MHC = peptide:major histocompatibility complex.

Figure 2

Adoptive T cell therapy. Peripheral blood lymphocytes (PBLs) or tumor infiltrating lymphocytes (TILs) are collected and antigen-specific or non-specific expansions can be performed depending on the source of T cells and their tumor antigen reactivity. Addition of antigen specific receptors and additions/deletions of stimulatory/inhibitory receptors can be achieved with genetic engineering prior to the expansion of T cells. Once desired quantity of these cells is reached through expansion, they are reinfused into the patient.

Figure 3

Overview of the production of chimeric antigen receptor (CAR) T cells. Peripheral blood is collected, T cells are extracted via leukapheresis and apheresis. The genome of the CAR is loaded onto the T cell using transduction from vectors (usually retroviruses). Next, the novel CAR T cells are expanded and purified until they reach sufficient numbers. The quality and overall immunological tolerance are tested for 2–4 weeks before reinfusing the cells into the patient.

Figure 4

Mechanism of radiation-induced abscopal effect. Radiation damages tumor cells leading to generation of tumor antigens and neoantigens. Antigen presenting cells (APCs) can pick up these antigens, travel to draining lymph nodes, and present antigens and prime the naïve CD8⁺ T cells. The primed and activated T cells circulate to both the primary irradiated tumor and non-irradiated metastatic tumor sites and attack these tumors; hence generating the abscopal effect.