Cancer immunotherapy: Strategies for personalization and combinatorial approaches

Abstract

The results of recent clinical trials using novel immunotherapy strategies such as immune checkpoint blockade and adoptive T-cell therapy approaches including CAR T-cell therapy have clearly established immunotherapy as an important modality for the treatment of cancer besides the traditional approaches of surgery, radiotherapy, and chemotherapy or targeted therapy. However, to date immunotherapy has been shown to induce durable clinical benefit in only a fraction of the patients. The use of combination strategies is likely to increase the number of patients that might benefit from immunotherapy. Indeed, over the last decade, the characterization of multiple immune resistance mechanisms used by the tumor to evade the immune system and the development of agents that target those mechanisms has generated a lot of enthusiasm for cancer immunotherapy. But a critical issue is to determine how best to combine such agents. This review will focus on novel immunotherapy agents currently in development and discuss strategies to develop and personalize combination cancer immunotherapy strategies.

Keywords: Cancer; Immune checkpoint; Immunotherapy; Personalized; T cells.

Figure 1

Categories of cancer immunotherapy agents. Cancer immunotherapy agents may be broadly categorized into those that target the tumor and those that activate immune cells. Sub‐classes of agents within each group are shown. Ab, antibody.

Figure 2

Combination immunotherapy strategies to enhance function of effector T cells (Teffs). Examples of agents targeting tumor or immune cells in the tumor microenvironment that may be used in combinations to enhance function of antitumor Teffs are shown. Certain chemotherapeutic agents such as doxorubicin and radiation therapy may cause immunogenic tumor cell death and cause release of tumor neo‐antigens in an inflammatory microenvironment and promote Teff activation. Monoclonal antibodies and targeted therapies against the tumor may also induce a ‘vaccine‐like’ effect by inducing immunogenic tumor cell death. Agonistic antibodies targeting costimulatory molecules or antagonistic antibodies targeting co‐inhibitory molecules on Teffs could be used alone or in combination to augment Teff function. Agents targeting regulatory T cells (Tregs) may either inhibit their immunosuppressive function or cause depletion of Tregs from the tumor microenvironment. Agents targeting myeloid cells including macrophages (MΦ), myeloid derived suppressor cells (MDSC), and dendritic cells (DC) may either skew their polarization to inflammatory state that promotes Teff activation or cause their depletion from the tumor microenvironment. Combination therapies with these agents are expected to be complementary and/or synergistic and may significantly improve clinical efficacy and outcome of cancer immunotherapy in the future.

Figure 3

Strategy for personalized cancer immunotherapy. A potential strategy for development of personalized cancer immunotherapy is to establish the baseline ‘immunogenicity score’ of each tumor using a panel of biomarkers that assess both the tumor intrinsic and tumor extrinsic factors that affect antitumor immunity. Tumors with ‘high score’ may be highly immunogenic and may be treated with monotherapy with one of the cancer immunotherapy agents. Tumors that have ‘low score’ may be immunologically inert and may need to be primarily treated with targeted therapies, monoclonal antibodies, or re‐directed T cell therapies such as CAR T cell therapy or bi‐specific antibodies. Tumors with ‘intermediate immunogenicity score’ may need to be treated with combination immunotherapy strategies and the precise combination approach may be determined by the dominant immune resistance mechanism elucidated by the biomarker analysis.