Malignant Cells
13 April 2016

Hacking Immunity: How 4 Radical Immunotherapy Techniques Work

Immunotherapy is still the new kid on the block, but cancer researchers are already pouring huge amounts of effort into this potential breakthrough methodology, which seeks to harness the body’s own immune system to fight tumors. The government is pouring in money for immunotherapy, too. It’s one of the approaches Vice President Joe Biden says his team of experts will focus on pursuing for his “moonshot” initiative to cure cancer.

You & Not You: The Problem With Cancer

A healthy immune system is already able to detect and stop some malignant cell growth. But it’s harder than tracking down viruses or bacteria, which are often marked by substances not normally found inside the human body, since cancer cells start out as perfectly normal human cells. Your immune system’s main job is to distinguish between cells that belong, and cells that don’t, which can get tricky when your own cells have gone out of control.

Cancer Cells

Cancer cells under an electron microscope.

So over the last few decades, scientists have developed a number of techniques to make your own immune system “smarter,” better able to identify and fight cancerous tumors. Collectively, these techniques are known as “immunotherapy,” although you might see the terms “biotherapy” or “biologic therapy” used elsewhere.

While each immunotherapy technique is different, they all center around solving a basic problem: how do we amplify the “foreignness” of cancer cells, without diminishing the familiarity of normal healthy cells?

Interferon: Immunity’s Jack Of All Trades

Some forms of immunotherapy give an overall boost to the immune system. Interferon, for example, a chemical produced by cells after they’ve been infected with a virus, tells neighboring cells to boost their own anti-viral defenses.

At the same time, interferon seems to activate special cells within the immune system, including natural killer, or NK, cells, which have a direct cytotoxic effect. In proximity to a foreign cell, natural killers blast the potentially-dangerous intruder with proteins, almost like a shotgun, opening small pores in the foreigner’s membrane. With the invasive cell open to the outside environment, another type of protein can penetrate its internal structure, ultimately inducing cellular death. Interferon’s third effect, one we still don’t understand fully, is to prevent viruses from replicating themselves.

Where viruses are concerned, interferon seems to do it all. For cancers, it’s not so simple. The chemicals appear to work, both directly, by attacking malignant cells (which, like viruses, are primed for proliferation), and indirectly, by boosting the immune system response of other cells, but only in the presence of certain tumors. Lymphomas and leukemia are particularly susceptible to interferon-based therapies, according to Dr. David Goldstein, an oncologist at the University of Washington, but more common cancers, including breast, colon and lung cancers, have proven largely resistant.

Monoclonal Antibodies

Other techniques are highly-targeted, introducing new laboratory-designed antibodies into the blood stream. These “monoclonal antibodies,” similar to the antibodies your body naturally produces to fend off disease, bind to specific proteins in cancer cells, with a wide range of effects.

Controlling The “On-Off Switch” Of Cancer Killers

T Helper Cell

A T helper cell

Proper immune system response relies on a vast array of white blood cells, all of which play some role in distinguishing harmful invaders from cells native to the human body.  One type of white blood cell, known as a T-cell, is equipped with a special “off switch,” a protein on its surface called PD-1. When a normal cell comes into contact with PD-1, the T-cell stays inactive. Rather than attack the other cell as foreign, the T-cell recognizes it as another component of the body. But some cancer cells can also trigger PD-1, meaning the T-cell will mistake the malignancy for a cell that should be there.

Researchers now have an answer for these cases of “mistaken identity,” a class of monoclonal antibodies that target PD-1, effectively leaving the T-cell in its “on” position all the time. A similar treatment has been shown to inactivate the protein that cancer cells use to switch PD-1 off.

Delivering Radiation Directly To Tumors

In another radical approach, doctors are using artificial antibodies to deliver radiation directly to cancer cells. Since monoclonal antibodies are designed to track down cancer cells already, scientists are using them to transport small radioactive molecules into tumors, while leaving healthy cells safe. It’s kind of like secreting a tiny bomb behind enemy lines.

This technique has already shown promise for diagnosing cancers, too. Using a special type of camera, physicians can track where the radioactive molecules gather, identifying potential tumors in a new way.

A Vaccine For Cancer?

Immunotherapy has even opened the door for potential cancer vaccines.

Immune system cells react to antigens, molecules that tip white blood cells off to the presence of foreign, and possibly dangerous, cells. Like vaccines for chickenpox or flu, the idea of a cancer vaccine rests on introducing an antigen specific to cancer cells, but before a patient has cancer. It’s a way of “training” the body’s immune system to identify potentially cancerous cells, so it can pick them out quickly when a tumor begins to develop.

We already have several preventative cancer vaccines, but they’re designed to train the immune system to recognize viruses, like the human papillomavirus (HPV), which often lead to cancer, not cancerous cells themselves. Some researchers believe that vaccines for actual cancers are possible, which would be something of a holy grail, but the realization of that possibility is still years away.

Vaccines have been developed, however, for people who already have cancer. In one promising technique, doctors remove immune cells from a patient’s body, and expose them to specific cancer antigens in the lab. Once the white blood cells are “familiar” with the look and feel of malignancy, they can be injected back into the patient to fight more effectively. That’s how Provenge, the only cancer vaccine approved in the US, works to help extend prostate cancer patient’s lives. Another method, which just went through its first successful clinical trial, involves introducing the genetic material responsible for creating cancer antigens directly to immune system cells.

Viruses Aren’t All Bad

As we’ve seen, one of the most difficult challenges in making immunotherapy a reality is getting white blood cells to recognize cancerous tumors as foreign in the first place. Antigens are the key, but some malignancies appear to hide those molecular “trademarks,” and thus their own malignancy, from plain sight. Forcing antigens into view, and stimulating an appropriate immune response, has proved difficult, but viruses may be the solution.

Viruses are sort of brilliant. They’re tiny, around one thousand times smaller than bacteria, and unlike human cells, don’t have the cellular technology necessary for sustaining life. Essentially, viruses are just DNA, but what these minuscule invaders lack, they borrow from their hosts. Viruses replicate, and they’re very good at it, by injecting their genetic information into a host cell, and recruiting your cellular machinery to manufacture new viral “body parts.” The problem with viruses comes at this point, after those viral components have been assembled into new viruses, often thousands of new viruses within a single host cell. They have to get out, and many viruses do so simply by breaking through the cell’s membrane, ultimately killing their host.

Bacteriophage

Bacteriophage: a virus that infects bacteria.

But if viruses can kill normal human cells, they can also kill cancer cells. By modifying the genetic instructions inside a virus, researchers have been able to create one that only attacks cancerous cells, leaving healthy cells alone. That fact alone could be a breakthrough with major implications, since, by contrast, chemotherapy agents kill off all rapidly-dividing cells, cancerous or not. The real trick, though, comes when the newly-replicated viruses are ready to break free from their cancerous host. When they do, a plume of cancer antigens are released from inside the malignant cell, triggering a wider immune response. And those white blood cells are now primed to identify every cancer cell marked by the same antigens. It’s a two-handed approach, which both kills cancer cells and teaches white blood cells how to recognize malignancy.

This technique, known as “oncolytic virotherapy,” is still in its early stages, but there’s already an FDA-approved therapy available for melanoma patients, Imlygic, which was approved on October 27, 2015. Check out this video to learn more about how oncolytic virotherapy works.

How Cancer Stays One Step Ahead Of Treatment

Some malignant cells, however, are able to evade even the most tenacious T-cells, by actively altering their external surfaces. It’s like camouflage and, disguised by their new texture, the tumor cells slip away, unnoticed by the body’s immune system. Researchers at Germany’s University of Bonn noticed the shocking reaction, which seems to be triggered by inflammation, while studying skin cancers for a paper published in the journal Scientific Reports. “Phenotypic plasticity” is what the scientists are calling it, since “phenotype” refers to the outward appearance of something and “plastic” can mean “able to change.”

But because immunotherapy is used to trigger an inflammatory response, the cancer cells could be altering their appearance as an adaptive answer to our attempts to destroy them. It may explain why some types of cancer seem to develop a resistance, much like bacteria do, to immunotherapy treatments.

Cancer cells have other ways of out-smarting the human immune system. Some can even create new proteins that inactivate immune cells on contact. More indirect, but no less troublesome, are the tumor cells that can force other cells within their immediate environment to secrete chemicals which inhibit immune system responses. These

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