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:

Major approaches

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.[1] Given the tumors have various mechanisms of evading host immunity, there is a wide range of potential cancer immunotherapy approaches:

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.[3] 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

Cancer Immunity Cycle infographic
Figure Source: Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39(1):1-10.

The complexity of the immune response to cancer also provides a strong rationale for combination therapies. Examples of combination treatments may include:

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.

[1] Ventola CL. Cancer Immunotherapy, Part 1: Current Strategies and Agents. PT 2017/42(6):375-383.

[2] Zugazagoitia J, et al. Current challenges in cancer treatment. Clin Ther 2016;38(7):1551-1566.

[3] Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39(1):1-10.