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. The U.S. Food and Drug Administration (FDA) has approved six immunotherapies across 19 cancer types and two tissue-agnostic conditions.
But widespread use of immune checkpoint therapy to treat cancers is hampered by unpredictable response rates and immune-related adverse events. To address these challenges, researchers are increasingly looking to combination therapies as a strategy for improving response and overcoming resistance. This post provides an introduction to cancer immunotherapy, exploring its immunological basis and the fundamental principles guiding the development of new treatments.
The goal of cancer immunotherapy
Put simply, the immune system’s role 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. Immunotherapy aims 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
Major approaches
The primary goal of cancer immunotherapy is to stimulate a patient’s suppressed immune system so it can launch a sustained attack against tumor cells.[1] Given that tumors have various mechanisms of evading host immunity, there is a wide range of potential cancer immunotherapy approaches.
- Targeted antibodies, bispecific antibodies, and antibody-drug conjugates
These are artificial versions of large proteins with a unique antigen specificity that allows them to bind to cancer cells or target the tumor microenvironment. They disrupt cancer-cell activity and alert the immune system to attack the cancer. Immune checkpoint inhibitors fall into this category. - Immunomodulators
These are immune modulators naturally produced by many cell types that can manipulate the “gas pedals” and the “brakes” of the immune system. Certain cytokines can directly enhance or suppress T-cell responses against cancer cells.1 - Cancer vaccines
This modality involves using 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. Various 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 designed to stimulate an immune response, cell-based immunotherapies contain intrinsic anti-tumor properties.[2] Adoptive T-cell transfer, such as chimeric antigen receptor (CAR) T therapy and therapeutic tumor-infiltrating lymphocytes, fall into this category. - Oncolytic virus therapy
This type of therapy uses modified viruses that can infect and destroy tumor cells. Such viruses represent a promising treatment approach, as cancer cells often have impaired antiviral defenses. Additionally, oncolytic viruses can cause cancer cells to burst after infection, releasing cancer antigens and stimulating an immune response that can eliminate any remaining tumor cells nearby and potentially elsewhere in the body.
The interactions between cancer and the immune system are complex, and understanding the rationale behind different combination therapies is essential to the successful design and execution of cancer immunotherapy trials. We’ll cover this and more in Part 2 of this blog series.
Premier Research has completed more than 190 hematology and oncology clinical trials through every phase over the past five years, with more than 40 percent involving an immunotherapy component. To learn more about our oncology expertise, click here.
[1] Ventola CL. Cancer Immunotherapy, Part 1: Current Strategies and Agents. P T 2017;42(6):375-383.
[2] Zugazagoitia J, et al. Current challenges in cancer treatment. Clin Ther 2016;38(7):1551-1566.