CAR-T Cancer Treatment: Part 3, When Breakthroughs Converge

Triple Technology to Engineer a Potent Anti-cancer Weapon, Part 3

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(click here for Part
1 or Part
2)

Medical breakthroughs usually occur when science and industry collide through combinations of various disciplines. Right now, we are on the verge of witnessing a potential medical breakthrough for the treatment of cancer as three discoveries converge:

1. Invention of CAR-T (Carl June, a scientist from University of Pennsylvania, pioneered CAR-T technology. Dr. June started treating cancer patients with it in 2010. In 2017, U.S. FDA approved the first two CAR-T medicines for the treatment of blood cancers)
2. Introduction of Checkpoint
   Inhibitors (Bristol-Myers’s Opdivo and Merck’s Keytruda were approved by FDA for the treatment of cancer in 2014/2016, respectively. Since then, the agency has approved these medicines for the treatment of various types of cancer)
3. Discovery of CRISP-Cas9 gene
   editing (In 2012, Jennifer Doudna, Emmanuelle Charpentier and Feng Zhang were credited for this eureka moment, as these scientists independently discovered CRISPR-Cas9 technology and predicted its significant potential. Jennifer (University of California, San Francisco), Emmanuelle Charpentier (Max Planck Institute) and Feng Zhang (Massachusetts Institute of Technology, MIT) were the inventors, respectively, of the technologies given rise to three emerging biotech companies: Intellia Therapeutics, CRISPR Therapeutics and Editas Medicine).

“Chimeric Antigen Receptor T cell therapy” (CAR-T) is a gene therapy designed to harness the potency of antibodies and T-lymphocytes into one single medicine for the treatment of cancer. CAR-T therapy could be viewed as a “living anti-cancer drug” as the medicine itself consists of a living cell, which is genetically engineered as a pharmaceutical “chimera” to find and destroy cancer cells (see Parts 1/2 of these series). Gene editing tools, such as CRISPR-Cas9, could be utilized to generate more effective CAR-T medicines (Figure 1).

Figure 1. Gene editing to engineer a “CAR-T
medicine”. 

Source: “T-cell tweaks to target tumors”. Nature 2017, 543:48-49

1. Traditional CAR-T Design. Traditional CARs (shown in yellow) are inserted at a random location into the genome (DNA) of T cells. If the CAR-T is expressed constitutively (constant synthesis), the cells often enter a state called “exhaustion” (become inactive). 
2. Use of CRISPR-Cas9. Gene-editing tool CRISPR–Cas9 used to replace the cell’s TCR-encoding gene (TCR – “natural T-cell receptor”, shown in green) with a CAR-T encoding sequence (shown in yellow). 
3. Gene-edited CAR-T. CRISPR–Cas9-edited T cells express only one type of TCR, the CAR-T (shown in yellow and red), providing better anti-tumor responses than traditional CAR T cells. The natural TCR (green) has been removed.

Click here to read Part 1 or Part 2 of this series on the revolutionary advances happening in the science of cancer treatment.