Cancer and Immunotherapies


Cancer is uncontrolled growth of cells in the body which may lead to organ failure and death. The body responds to uncontrolled cell growth in several ways, one of which is to deploy white blood cells of the immune system to detect, attack, and destroy the cancerous cells. It has been known for quite some time that the immune system can be manipulated to control cancer. In 1891, the American surgeon William Coley undertook the first systematic study of immunotherapy for cancer, using first live bacteria, then heat-killed bacterial toxins to stimulate the immune system to attack and resolve bone cancers.

Although initially successful, Coley’s toxins as they were known, were eventually replaced by chemotherapy and radiation therapy, which were considered to have more consistent effects. Recently, immunotherapy for blood cancers (liquid tumors) has experienced a renaissance, led by clinical researchers such as Carl June and Steve Rosenberg who have developed methods for isolating, expanding, and engineering cancer-killing cells from leukemia patients and infusing them back to destroy their cancers, with durable remissions stretching many years for a large number of the initial cohort of patients.

Ex-vivo gene therapy is typically used to impart cancer specificity on the patient’s own white blood cells used for these innovative treatments. The target cell population are often T cells, although other cell types such as NK cells are also showing promise in early clinical trials. Each T cell has a unique T cell receptor (TCR) which allows it to recognize antigen on the target cell. However, this is a complicated process involving the processing of molecules into small fragments displayed on the outside of cell surface by membrane-bound MHC (major histocompatibility complex) molecules, which may bind a given TCR in a process called antigen recognition, which is at the heart of adaptive immunity.

Cancer cells may evade immune recognition by this system, but many leukemia’s and lymphomas express CD19, a surface antigen. In an attempt to engineer an artificial receptor for recognizing CD19, the binding fragments from an anti-CD19 antibody was joined with transmembrane and signaling domains from other T cell molecules, and the CAR (chimeric antigen receptor) T cell therapy was born.

The chimera, originally a monstrous fire-breathing creature from Greek legends, a lion with a goat’s head and a snake for a tail, here represents a CAR that is composed of domains from different proteins, in effect giving the CAR-expressing T cell powers of a mighty chimera to slay the cancer cells that it may encounter in the recipient’s body. Although some cancers return (often lacking the CD19 which was originally targeted by the therapy), the advent of CAR T cell therapy has revolutionized medicine by providing up to 90% complete response as a last resort against some leukemia’s and lymphomas which have resisted conventional therapies.

At least two different CAR T cell therapies have been submitted for biologics license application and are up for FDA approval in 2017/2018 to treat several lymphomas and leukemia’s expressing CD19. Many more CAR T (many of them targeting molecules other than CD19) and engineered TCR therapies are being developed in the wake of these early, promising results, encouraging a new age for gene and cell therapy. According to some researchers, the development of genetically-modified T-cell therapies for cancer has had the most clinical impact of all gene therapies.

Alternatively, gene therapy approaches may be designed to directly kill tumor cells using tumor-killing viruses, or through the introduction of genes called suicide genes into the tumor cells. Scientists have generated viruses, called oncolytic viruses, which grow selectively in tumor cells as compared to normal cells. For example, an expanding number of human viruses such as measles virus, vesicular stomatitis virus (VSV), retrovirus, adenovirus, and herpes simplex virus (HSV) can be genetically modified to grow in tumor cells and destroy them, but grow very poorly in normal cells, thereby establishing a therapeutic advantage. Oncolytic viruses may be deployed to penetrate deep into tumors to deliver a genetic payload that destroys cancerous cells. Several viruses with oncolytic properties are naturally occurring animal viruses (Newcastle Disease Virus) or are based on an animal virus such as vaccinia virus (cow pox virus or the small pox vaccine).

A few human viruses, such as coxsackievirus A21 are similarly being tested for these properties. In addition, oncolytic viruses can be genetically modified (i.e. GM-CSF DNA transfer) so as to enhance immunogenicity (e.g., HSV). The combination of selective oncolytic cell death with release of danger-associated molecular-patterns and tumor-associated antigens with heightened immunogenicity has been shown to enhance both local and systemically beneficial effects. Currently, multiple clinical trials are recruiting patients to test oncolytic viruses for the treatment of various types of cancers.

More information regarding clinical trials can be found on the Finding a Clinical Trial page

2018
21st Annual Meeting
May 16 - 19 | Chicago
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