Making Sense of Recent Gene Therapy News in Cancer

This past week was an historic one for role of gene therapy in oncology – seeing two major events unfold. The first event was the acquisition of Kite Pharmaceuticals by Gilead Sciences for $12 billion. Why did Gilead pay $12 billion for a company with no approved drugs? Kite Pharma is a developer of cancer gene therapies using CAR (Chimeric Antigen Receptor) and TCR (T Cell Receptor) approaches to engineer T lymphocytes. Today, this is the hottest field in oncology. Kite has submitted an NDA for a CAR therapy against B Cell lymphoma and expects to hear from the agency by November of 2017. The second was the approval by FDA of Novartis’ Kymriah, a CAR therapy for an aggressive form of leukemia. With the unfolding of these events, gene therapy, only a hype two years ago, became a reality in the fight against cancer. Both Novartis and Kite Pharma are developing gene therapies that make use of genetically engineered T lymphocytes. Novartis Kymriah contains patient T cells modified with an antibody-like molecule called CAR targeting a specific cancer antigen on the surface of the tumor cell. Kite Pharma is developing gene therapies using both CAR and TCR approaches. The TCR approach engineers a new T Cell receptor onto the T cell and recognizes a specific antigen peptide bound to major histocompatibility complex (MHC). With the expectations for gene therapy treatments very high, this is just the beginning of the race to cure cancer.

Kite Pharma and Novartis are not the only players working on CAR and TCR gene therapies. Juno Therapeutics is also developing gene therapies using the same approach, however has fallen behind Kite Pharma. Both CAR and TCR rely on harvesting T cells from the patient, engineering them with modified CAR or TCR or enriching them with engineered CARs/TCRs, and transferring them back to the patient to fight the tumor. CARs are part antibody and can go after targets on the surface of a wide variety of tumor cells. TCRs involve genetic manipulation of T cells to make them more potent and can only target certain cells because they rely on T cell recognition. However, unlike CARs, TCRs can target antigens both within tumor cells and on the tumor cell surface.  A major drawback to both of these approaches is that very few antigens have been identified that are only specific to tumors. These engineered T cells will attack any cell containing the antigen resulting in cytotoxicity effects. The initial CAR therapies from Novartis, Kite, and Juno all target CD19, which is a protein found on the surface of B cells. As more data becomes available, clinicians will be closely monitoring the cytotoxity effects of these treatments.

As CAR based therapies becomes mainstream, KOLs in the field are already looking to gene editing technologies as stand alone or in combination with CARs. Novartis was the first to come out with an approved CAR therapy and hasn’t wasted time in partnering with Intellia Therapeutics to utilize UC Berkeley’s  CRISPR/Cas 9 (clustered, regularly interspaced, short palindromic repeat/CRISPR-associated-9) gene editing approach to modify T cells (Doudna and Charpentier, 2014). CRISPR/Cas9 is a gene editing tool discovered in bacteria effective in responding to invading pathogens such as viruses. It consists of two molecules: a RNA guided DNA endonuclease called CAS9 and a 20 base long guide RNA within a longer RNA scaffold called CRISPR. The sequence in the guide RNA is complementary to a sequence in the target DNA. This allows Cas9 which is attached to the guide RNA access to the same DNA sequence and make a cut across both DNA strands. The cell then initiates repair of the damaged DNA and in the process introduces a mutation. Another company Editas Genomics has also laid claim to this technology and is in a legal battle with UC Berkeley over CRISPR/Cas9 IP.

CRISPR/Cas9 has been adopted widely due to its ease of use and simplicity however it is unclear that it has recognition selectivity to ensure single site specificity. To over come this, two other gene editing tools are being evaluated due to their higher gene targeting specificity. These include the use of Zinc Finger Nucleases (ZFNs) by Sangamo Therapeutics and transcription activator-like effector nucleases (TALENs) by Cellectis. Both of these technologies use custom DNA-binding Domains (DBDs) to recognize specific DNA sequences. DBDs allow nucleases to target sequences and introduce double stranded breaks and knockout genes as a result of frame shift mutations. Pfizer recently announced collaboration with Sangamo for Hemophilia gene therapy. The higher specificity to the target gene of interest in ZFNs and TALENs is due to the longer sequence of the DBDs compared to shorter guide RNA sequence in CRISPR. Cellectis has been partnering the use of TALENS to Agro-businesses. While TALENs are easier and less costly to engineer than ZFNs, early data indicate that ZFNs may be easier to deliver. It has also been reported that ZFN proteins are able to cross cell membranes which may end up providing ZFNs an advantage over TALENs by reducing side effects associated with delivery vectors.

Irrespective of which approach eventually wins the gene therapy/editing race, it is clear that the number of options and approaches to treating cancer have increased significantly. It is unlikely that a single approach will treat all varieties of tumor. For current cancer treatments, the autologous nature of CAR and TCR gene therapies is going to prevent availability of these treatments to the masses based on Novartis’ Kymirah’s $475,000 price tag. However, it does come with the advantage of no immunogenicity since the T cells are from the patient. One thing is for certain there is going to be room for allogenic treatments in an effort to reduce cost and time of CAR/TCR production. There are several players in the oncology gene therapy space now. Bellicum and Zio-Pharm have developed approaches to reduce cytotoxicity. Others include Bluebird Bio, Adaptimmune, and Oxford Biomedica to name a few. The need for high specificity tumor antigen targets, greater accuracy in gene editing, and cost effective approaches to mass production will create room for many more players. And what about the ethical repercussions for gene editing? That is another story.