Cancer is a highly complex disease, which is mainly caused by the overgrowth of malignant cells and altered immune response. Traditional cancer therapies include surgery, radiotherapy, chemotherapy, and targeted therapy, but none can completely cure cancer. Immuno-oncology is a relatively new form of cancer therapy that can control and kill tumor cells by stimulating or restoring the immune system. Current forms of cancer immunotherapy include immune checkpoint inhibitors, T-cell therapy, cancer vaccines, oncolytic virus therapy, and monoclonal antibodies. Combining these effective therapies can significantly enhance efficacy, leading to a durable antitumor immune response. This article discusses the common immunotherapy approaches used in clinical practice and analyzes current challenges in this field.
History of Immuno-Oncology
After more than a century of development, immuno-oncology is now one of the most successful tumor treatment strategies. In the 1890s, William Coley investigated the potential of immuno-oncology and successfully treated cancer by injecting bacteria into tumors. In the 1980s, there were new methods for treating cancer, such as adoptive cell therapy, targeted antibodies, and cancer vaccines. In 1989, the first chimeric antigen receptor (CAR) was generated. CAR-T cell therapy was used by Carl June to cure a patient with leukemia in 2012. In the 1990s, PD-1/L1 inhibitors were discovered and these are now the most widely applied type of immunotherapy. Recently, immune checkpoint inhibitors such as ipilimumab, nivolumab, and atezolizumab have been approved by the Food and Drug Administration (FDA) for the treatment of cancer.
Types of Cancer Immunotherapy
Over the years, immunotherapy has demonstrated strong potential in the treatment of cancer, with the promising approaches including adoptive cell therapies (ACT), immune checkpoint inhibitors, bispecific T cell engagers, and therapeutic cancer vaccines. These approaches share a common mechanism of action, which is to protect against tumor antigens by stimulating the T cell-based immune response (Figure 1).
Figure 1. Major types of immunotherapy.
Adoptive Cell Therapy
Adoptive cell therapy is a passive method of immunotherapy. Four major models of adoptive cell therapy include tumor-infiltrating lymphocyte (TIL) therapy, engineered T cell receptor (TCR) therapy, chimeric antigen receptor (CAR) T cell therapy, and natural killer (NK) cell therapy. TIL therapy directly isolates the patient’s immune cells and expands their numbers before infusing them back into the patient. In TCR and CAR-T cell therapies, the patient’s immune cells are isolated and genetically engineered to recognize and target tumor antigens before infusing them back into the patients.
Immune Checkpoint Inhibitors
Immune checkpoints are protective factors in the immune system that prevent the overactivation of T cells, which may lead to autoimmune damage. However, these are often used by cancer cells to evade immunosurveillance. To counteract this, immune checkpoint inhibitors (ICIs) were designed to interrupt coinhibitory signaling pathways, thereby restoring T cell immune surveillance and killing tumor cells. The most widely used targets for ICIs are PD-1, PD-L1, and CTLA-4, these have demonstrated great benefit innonsmall-cell lung cancer (NSCLC), metastatic melanoma, and renal cancers.
Antibody-Drug Conjugates
Antibody-drug conjugates (ADCs) leverage the antigen-specificity of monoclonal antibodies to direct and deliver cytotoxic drugs to tumor cells. As of October 2023, there were 15 approved ADCs, with over 150 candidates in clinical trials. Studies of ADC combinations with chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted. In fact, the success of ICIs has garnered interest in exploring immune-stimulating ADC payloads such as STING agonists and TLR agonists.
Bispecific Antibodies
Bispecific antibodies (bsAbs) are a diverse family of antibodies developed from monoclonal antibodies, these can bind two different antigens or two different epitopes on the same antigen. Most bsAbs are bispecific T-cell engagers (BiTEs), which target one tumor antigen and one immune-related molecule and redirect T cells to specific tumor antigens to eliminate cancer.
Cancer Vaccines
Cancer vaccines can stimulate antitumor immunity using tumor antigens, eventually killing tumor cells. These can be either preventive or therapeutic. Preventive cancer vaccines, such as the HPV and HBV vaccines (the only two with FDA approval), prevent the development of certain cancers. Meanwhile, therapeutic cancer vaccines stimulate the development of immunity to specific tumor antigens and control tumor growth or induce tumor regression. These are mainly divided into four types: genetically engineered vaccines, tumor whole-cell vaccines, dendritic cell vaccines, and protein peptide vaccines.
Summary
Despite its long history, immuno-oncology has truly advanced only in recent decades. Here, we discuss the history and different types of cancer immunotherapy and its current challenges. To improve the therapeutic effect of cancer immunotherapy, a combination of multiple methods is effective. Biomarkers are also useful for the diagnosis, progression, and prediction of cancer. Personalized immunotherapy is also extremely valuable because of the diverse modulation pathways of anticancer immune responses and patient-specific variations.
