Putting The CAR-T Before The Horse

In The WEEKLY by Emily Burke

THE STORY BEHIND CAR-T

The hottest cancer therapy in the pipeline — chimeric antigen receptor therapy (CAR-T) — got a big boost last month when an FDA advisory panel unanimously recommended approval of the treatment for children and young adults with a severe form of leukemia who have run out of other options. Developed by Novartis (Basel, Switzerland), this elegant hack of the immune system is one of many horses in the race for a FDA approval, with Kite Pharmaceuticals (Los Angeles, CA) and Juno Therapeutics (Seattle, WA) rounding out the pack. Let’s take a moment to review these revolutionary therapeutics and understand how they attack cancer.

TERM OF THE WEEK: KILLER T-CELLS

CAR-T therapy is modeled after a cell in the immune system known as the killer T-cell. The job of a killer T-cell is exactly what the name implies — to kill dangerous cells. They target diseased cells in the body via their receptors: each one has a uniquely shaped receptor, and will recognize its intended target because the shape of its receptor “matches” or fits into a uniquely shaped surface protein found only on diseased cells. Once the Killer T-cell “docks” onto its target, it injects an enzyme which triggers death. The result: no more bad cells.

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WHY CAR-T?

In theory our immune system should recognize the unique proteins presented on all diseased/cancerous cells; however there are two main reasons this doesn’t always happen:

  1. Early on in the tumor development, the cell composition is similar enough to healthy tissue that it can be overlooked by the immune system.
  2. Later as a tumor progresses, it releases chemical signals that suppress the immune response, helping it to evade detection. This trickery is known as the tumor microenvironment and once again the dangerous cancer cells can pass by undetected.

So what’s a scientist to do?!  Figure out a way to train killer T-cells to ALWAYS recognize and destroy cancer cells… enter CAR-T.

HOW TO TRAIN AN IMMUNE SYSTEM

Killer T-cells are “trained” to go after early and late stage cancer by having their physical structure altered. This alteration is accomplished by fusing an antibody with the receptor of a killer T-cell to create a chimeric molecule — or the “C” in CAR-T.

Training day begins by having killer T-cells drawn out of a patient’s body and isolated in the lab. Next, scientists deliver a gene to the T-cells that encodes the chimeric receptor. This receptor consists of two parts:

  • A targeting domain: This is the part of the chimeric receptor that will be outside of the T-cell. It is composed of an antibody that will recognize and dock onto a unique surface protein of the patient’s cancer.
  • An activation domain: This part of the receptor will be triggered once the targeting domain is engaged. It will signal to the killer T-cell to:
    1.  Stay alive.
    2. Make copies of itself.
    3. Release signaling molecules called cytokines. Cytokines are chemical signals that activate other white blood cells to join the fight against the tumor.
    4. Kill the target cell.

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The T-cell/antibody hybrid is now a CAR-T therapeutic. It is then multiplied in the lab and infused back into the patient’s body. Once inside, the CAR-T locks onto its cancer target, replicates, sends out cytokines, and kills the designated cancer cells. The CAR-T will continue to replicate and kill any and all cancer cells recognized by the initial antibody component, with the goal of eliminating the disease.

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WHAT’S IN A NAME?

Chimeric antigen receptor therapy broken down:

  • Chimeric: Composed of components from two distinct parts, such as an antibody and a killer T-cell.
  • Antigen: A protein that is recognized by an antibody, such as a protein on the surface of a tumor cell.
  • Receptor: A protein that is embedded in a cell membrane and transmits signals to itself in response to being activated, for example a T-cell receptor transmits signals to the T-cell when it docks onto its target.
  • Therapy: A treatment meant to manage or cure a disease.

As these therapies begin to move from clinical trials into clinical practice, the treatment of cancer will truly be revolutionized, offering new hope to patients and their families.