Cancer Immunotherapy CME

Fundamentals of Cancer Immunotherapy CME

Mary L. "Nora" Disis, MD

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CME Information

Target Audience

This activity is intended for oncologists, hematologists, pathologists, dermatologists, and other healthcare professionals involved in the management of cancer with immune-based therapies.

Goal

The goal of this activity is to examine the potential for and current use of immune-based therapies for the treatment of cancer.

Authors and Disclosures

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Describe the different classes of immunotherapies and the mechanisms of their anticancer effects
2. Demonstrate appropriate strategies for prevention and management of adverse events associated with cancer immunotherapies
3. Evaluate the unique patterns of response that may be associated with cancer immunotherapies

 

Introduction

Treating cancer by harnessing a patient's immune system has several major advantages over other forms of cancer therapy (Table 1). For example, some cells of the immune system can respond to specific immunogenic proteins, or antigens, expressed by the tumor. This characteristic allows specificity of the immune response to cancer without excessive toxicity to normal tissues, as is seen with cytotoxic chemotherapy. Antigen-specific T lymphocytes, presumably the most important component of the immune system in mediating an antitumor response, have the capability of homing to any site of cancer even if disease deposits are located deep in tissues.^[1] Therefore, unlike other standard forms of cancer treatment, the immune response has the potential to eradicate cancer in any location. Cancer-specific T and B lymphocytes are cells that can directly induce tissue destruction and will continue to proliferate and function as long as there is antigen present to stimulate their activity. For this reason, once a robust immune response is elicited, no further immune-based treatments would be necessary. Finally, a key characteristic of an effective immune response is the generation of immunologic memory, which is the persistence of an antigen-specific immune response over many years. If the cancer antigen is sensed again, even decades after the initial diagnosis of disease, immune cells will rapidly respond, proliferate, and destroy antigen-expressing cancer cells before those cells have the chance to become re-established.

Unfortunately, the development of actual immune-based therapies for the treatment of cancer has been challenging. In large part, the challenges have been due to the nature of the immunogenic proteins that are expressed by human tumors. Over the last decade, a host of human tumor antigens have been identified as potential therapeutic targets. Some antigens expressed in tumors are viruses -- hepatitis B virus (HBV) in hepatocellular carcinoma, Epstein-Barr virus (EBV) in lymphomas and nasopharyngeal carcinomas, and human papillomavirus (HPV) in cervical cancer are just a few examples -- but most immunogenic cancer-associated proteins are normal cellular proteins (self proteins) that have become qualitatively or quantitatively altered in the malignant state as compared with their expression in normal tissues. Clinical responses to immunotherapies targeting either viral or self proteins have been reported.^[2] Immunologic targeting of a cancer-related self protein is hampered by the multiple mechanisms our bodies have of preventing autoimmunity. The inflammatory response that develops when cancer grows elicits immune system cells that are likely to turn off a destructive cancer-specific immune response because the antigens being recognized are perceived as "self." Certain types of macrophage, termed M2, will secrete cytokines that prevent T-cell proliferation.^[3] Immature myeloid cells, myeloid-derived suppressive cells, are also present in the tumor bed and can inhibit the generation of a clinically productive immune response by preventing antigen-specific T cells from functioning correctly.^[4] T cells themselves can differentiate into regulatory cells when they sense self antigens and prevent further tumor recognition via secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta, which are immune-suppressant cytokines.^[5] These are just a few of the natural defense mechanisms in place for preventing the development of autoimmune disease; unfortunately, these same mechanisms limit the tumor-specific immune response. Effective cancer immunotherapy must generate a destructive immune response as well as control tolerizing mechanisms that are in place to limit self-specific immunity.
Despite the challenges, there are several immune-based therapies that are routinely used in the treatment of cancer patients. Cancer immunotherapy is generally classified as being "active" or "passive" (Table 2). Active immunotherapy is a treatment modality that functions by stimulating the patient's own immune system to generate the cells needed to impart an antitumor effect. An example of an active immunotherapy would be a vaccine. The vaccine is administered to stimulate T or B lymphocytes to recognize and destroy the cancer. The use of nonspecific immunomodulators such as bacillus Calmette-Guerin (BCG) would also be considered active immunotherapy. After administration of BCG, it is assumed that cells of the innate immune system, present in the patients, would respond and cause inflammation that could result in the eradication of superficial bladder cancer. In the case of active immunotherapy, patients must have immune systems capable of competently responding to stimulation. For this reason, in general, active immunotherapy is not effective in patients with advanced-stage refractory disease who may have a depressed number of immune system cells able to adequately function. Passive immunotherapy provides the immune response to the patients. Monoclonal antibody therapy is considered a passive immunotherapy. Rather than stimulating a patient's own antibody response, the infusion of monoclonal antibodies provides the antigen-specific antibodies to the patient. Similarly, rather than stimulating a patient's own T cells via vaccination, adoptive T-cell therapy infuses high numbers of antigen-specific T cells into patients, thus providing immediate robust immunity to a specific target. Because patients do not have to generate their own endogenous immune response, passive immunotherapy is often used in the treatment of patients with well established and even refractory cancers. An example of adoptive T-cell therapy would be the use of donor lymphocyte infusions in the treatment of chronic myeloid leukemia (CML) that has relapsed after allogeneic hematopoietic stem cell transplant (HSCT).

The potential mechanisms of action of many cancer immunotherapies are multifactorial and often not fully understood because the immune system is a complex organization of numerous components, pathways, and interdependent interactions. The cell types involved in mediating tumor-specific immunity will define the clinical efficacy as well as the toxicities associated with targeted immune-based treatments.