In recent years, immunotherapy has led to substantial advances in cancer therapy. In particular, the immune checkpoint inhibitors — PD-1/PD-L1 and CTLA-4 inhibitors — have revolutionized treatment for certain hematologic malignancies and solid tumors. To date, the U.S. Food and Drug Administration (FDA) has approved immunotherapies for more than 15 cancer indications.
However, widespread use of immune checkpoint therapy to treat cancers is hampered by unpredictable response rates and immune-related adverse events. To address these challenges, combination therapies are increasingly being studied as a strategy for improving response and overcoming resistance. In this post, we provide an introduction to cancer immunotherapy, exploring its immunological basis and the fundamental principles guiding development of new treatments.
Goal of cancer immunotherapy
Put simply, the role of the immune system is to distinguish “self” from “non-self.” Protecting the self and fighting the non-self requires a delicate balance of attacking invaders without attacking the self and causing an autoimmune response.
To further complicate the issue, the immune system may recognize cancer as self and develop tolerance to cancer cells. Moreover, tumors employ a variety of methods to overcome host immunity. The goal of immunotherapy is to manipulate the balance and bend the immune system curve to eliminate cancer while avoiding autoimmunity.
Characteristics of an ideal target
Ideal targets for cancer immunotherapy should have the following features:
- Selective expression on malignant cells or non-vital tissue
- A functional protein
- Ability to break tolerance and help the immune system recognize the cancer as non-self
The primary goal of cancer immunotherapy is to stimulate a patient’s suppressed immune system so that it can launch a sustained attack against tumor cells. Given the tumors have various mechanisms of evading host immunity, there is a wide range of potential cancer immunotherapy approaches:
- Monoclonal antibodies. These are artificial versions of large proteins which have a unique antigen specificity that allows them to bind to cancer cells or target the tumor microenvironment. Immune checkpoint inhibitors fall into this category.
- These are immune modulators that are naturally produced by many cell types. Certain cytokines can directly enhance of suppress T-cell responses against cancer cells.1
- Cancer vaccines. This involves the use of a vaccine to encourage the body to develop antibodies that target tumor cells. These vaccines may contain whole cancer cells, parts of cancer cells, or purified antigens that enhance the immune response against the cancer. A variety of approaches have been investigated for cancer vaccines, ranging from peptide- or immune cell-based to virus- or even DNA-based.
- Cell-based immunotherapy. Unlike other approaches which are designed to stimulate an immune response, cell-based immunotherapies contain intrinsic anti-tumor properties. Adoptive T-cell transfer, such as chimeric antigen receptor (CAR) T therapy, and therapeutic tumor-infiltrating lymphocytes fall into this category.
Rationale for combination therapies
The interactions between cancer and the immune system are complex and involve a series of stepwise events that has been referred to as the Cancer-Immunity Cycle. The multitude of both stimulatory and inhibitory factors involved in the cycle offers a wide range of potential therapeutic targets, some examples of which are highlighted in Figure 1.3
Figure 1. Intervening in the Cancer-Immunity Cycle3
The complexity of the immune response to cancer also provides a strong rationale for combination therapies. Examples of combination treatments may include:
- Immunotherapy/Immunotherapy. Two immunotherapies targeting different immune checkpoints
- Immunotherapy/Chemotherapy. Direct killing of tumor cells with chemotherapy may help activate the immune system, potentially leading to an additive effect for immunotherapy
- Immunotherapy/Targeted therapy. For example, anti-VEGF therapy may stimulate the immune system and inhibit tumor vascularization, creating a possible synergistic effect with immunotherapy
Mechanisms of resistance
Resistance to immunotherapy may be primary (failure to response) or secondary (relapse after successful treatment). Approaches for optimizing response and minimizing resistance to cancer immunotherapies include developing biomarkers to assist with patient selection, altering the tumor microenvironment and educating healthcare practitioners to check for delayed response using irRECIST criteria.
Another mechanism of resistance to immunotherapy is the escape phenomenon whereby tumors evade T-cell recognition. This can occur due to tumor secretion of immunosuppressive cytokines or immune system exhaustion, where tumor growth is too fast for the immune system to keep up or when immune checkpoints are upregulated.
This complex, dynamic relationship between cancer and the immune system has given rise to the age of immuno-oncology and a new era of cancer treatment that brings unique challenges and opportunities.
 Ventola CL. Cancer Immunotherapy, Part 1: Current Strategies and Agents. PT 2017/42(6):375-383.
 Zugazagoitia J, et al. Current challenges in cancer treatment. Clin Ther 2016;38(7):1551-1566.
 Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39(1):1-10.