Immunotherapy

Personalized Medicine’s Quest to Utilize the Patient’s Own Immune System

The immune system is an elaborate network of cells and organs that protect the body from infection.  The immune system is also part of the body’s innate disease-fighting capability to treat cancer.  With cancer, part of the problem is an ineffective immune system. The immune system recognizes cancer cells as foreign and up to a point can get rid of them or keep them in check.  Cancer cells are very good at finding ways to hide from, suppress, or wear out the immune system and avoid immune destruction.  The immune system may not attack cancer cells because it fails to recognize them as foreign and harmful.

Our immune systems work around the clock protecting our bodies from “foreign” substances such as bacteria, and viruses.  We know that this immune “surveillance” also protects us from cancer, by recognizing a cell that has become cancerous as something foreign. When this surveillance system fails, cancers begin to grow.

Precision Immunotherapy seeks to utilize a person’s own immune response to treat their cancer.  The goal of immunotherapy is to help the immune system recognize and eliminate cancer cells by either activating the immune system directly, or by inhibiting mechanisms of suppression of the cancer.

Stimulating the immune system to attack unwanted substances in the body is not a new concept; vaccines, which have traditionally been used to prevent infectious diseases such as measles and the flu, work in this way. What is new, is applying this idea to cancer treatment with the development of precision immunotherapies that stimulate the immune system to attack a specific individuals cancer.

Antigens Are The Key!

All cells including cancer cells have unique proteins or bits of protein on their surface called antigens. Specific antigens that are present in abundance on a cancer cells surface distinguish them from normal cells.  A person’s normal cells carry “self-antigens” that are unique to that individual. Cells with self-antigens are typically not a threat. Invading germs, however, do not come from within the body, so they do not carry self-antigens. Instead, they carry “nonself-antigens.” Cancer cells may also have “nonself” antigens that distinguish them as foreign. The immune system is designed to identify cells with nonself-antigens as harmful and respond appropriately.

Immunotherapies work in two ways: First, they alert the immune system that cancer-specific antigens—or antigens that are abundantly present on cancer cells—are foreign. Second, immunotherapies stimulate the immune cells to attack cells that have these antigens on their surface.

Immune cells called dendritic cells start to “eat” the invaders and their nonself-antigens. This process causes the dendritic cells to transform into antigen-presenting cells (APCs). These APCs expose the invader cells to the primary immune cells of the immune system the B and T-lymphocytes. These cells can recognize the invading cells and work to destroy them; . B-cells work rapidly to produce antibodies, and T-cells are activated then multiply into an army equipped with the necessary weapons to defeat the invader.

Some cancers however are able to evade our immune system. Spontaneous mutations in the genes of a cancer cell cause the cells to be altered in such a way that they are not recognized by our bodies as something foreign. Cancer cells can also produce substances or proteins that can shield them from the immune system.

Kinds of Immunotherapy

General types of immunotherapy include interferon, interleukin, and colony stimulating factors (cytokines), which generally activate the immune system to attack the cancer. These general immunotherapies however are not specific and their activation of the immune system can cause severe side effects by attacking normal cells along with cancer cells.  Immunotherapy treatment of cancer has progressed considerably over the past 30 years and has evolved from a general to more precisely targeted immunotherapy treatment. Examples of precision immunotherapy include checkpoint inhibitors, CAR T cells, and vaccines.

Immune Checkpoint Inhibitors

Immune checkpoint inhibitor drugs are currently the most widely used and publicized precision immunotherapy treatment. A patient’s cancer  cells can express molecules that activate PD-1 or CTLA-4 inhibitory “receptors” on their “T-cells” or other cells in the immune system.  When these receptors are activated on the T-cells, they are prevented from attacking the cancer cells and evade the immune response.  Checkpoint inhibitor drugs that block PD-1, PD-L1, or CTLA-4 work to “release the brakes” allowing the cancer cells to be detected and attacked by T-cells.

Chimeric Antigen Receptor (CAR) T-cell Immunotherapy

In CAR T-cell therapy, a patents immune systems T-cells are collected and reprogrammed in the laboratory to recognize and attack a patient’s cancer cells. Once the T-cells multiply and reach a certain number in the laboratory (usually hundreds of millions to billions), they are re-infused into the patient.  The infused T-cells then circulate throughout the body, attacking the patient’s cancer cells.  The key step is to genetically modify a patient’s T-cells to express a CAR that is designed to target an antigen protein expressed on the cell surface.  As a result, the reprogrammed T-cells, or CAR T-cells, make protein that find and attach to antigens on cancer cells to help destroy the cancer cells.  CAR-T-cells appear promising for the treatment of B-cell acute lymphoblastic leukemia (ALL) and other hematologic malignancies.

CTL019 CAR T-cell Therapy-engineers a patient’s own T cells to teach them to recognize and attack myeloma cells. CTL019 is designed to attack myeloma stem cells, a cell type that can give rise to many more myeloma cells. A pilot study reported that this approach was safe and feasible.

BCMA CAR T-cell Therapy-teaches T cells to recognize myeloma cells through a protein called B-cell maturation antigen (BCMA). This approach was reported to have promise in treating myeloma in patients who had already failed other therapies. There are several ongoing trials with BCMA as a target.

Vaccines

Cancer vaccines work to reeducate the body’s immune system to recognize cancer as foreign and trigger an active immune response against the cancer.  A vaccine is designed to stimulate a response by the immune system against specific targets, or antigens. When cells in the immune system perceive the antigen, which is part of the vaccine, they multiply to fight it off.

Vaccines can be either preventive or therapeutic. The cervical cancer vaccine Gardasil®, is a preventive vaccine. It prevents cervical cancer in women by providing protection against several strains of the human papillomavirus, including those responsible for causing many cases of cervical cancer.

Therapeutic vaccines, by contrast, are designed to stimulate the cells of the immune system to kill cancer cells, stop a tumor from growing, or stop a tumor from coming back.  Although experimental vaccines to treat cancer have been around for more than 20 years most are currently available only in clinical trials.

Provenge® (sipuleucel-T) was the first “dendritic cell” vaccine approved by the U.S. Food and Drug Administration. Its intended use is for the treatment of metastatic, hormone-refractory prostate cancer. Provenge is custom-made for each patient. First, a patient’s immune cells are collected and exposed to a protein that is found in most prostate cancers, linked to an immune-stimulating substance. Next, the patient’s own cells are returned to the patient to stimulate an immune response against the cancer.