The Horse Before the CAR-T

If you had not heard of Tom Long before this week, chances are you will know who he is now and know his story.  Tom, an Australian actor, was diagnosed with multiple myeloma (a blood cancer) seven years ago.  After all conventional treatments including stem cell transplants and other trial drugs failed, Tom was fortunate to be accepted into a clinical trial in Seattle, USA that commenced in April this year.

The trial was a Chimeric Antigen Receptor T cell (CAR-T) therapy.  This immunotherapy involved removing Tom’s own immune cells (T lymphocytes) from his blood, engineering the cells to express a receptor targeted to his own myeloma cancer cells and injecting the engineered cells back into Tom, where it was hoped that they would multiply and turbo charge an attack on his cancer cells.  Fast forward three months later and Tom has returned to Australia with no evidence of myeloma in his bone marrow.

Immunotherapy is now referred to as the ‘fifth pillar’ of cancer treatment.  In 2018, the FDA approved 17 new drugs for haematological malignancies. Significantly, none of these new drugs were for chemotherapeutic agents rather they were immunotherapy drugs and monoclonal antibodies.

CAR-T history

The development of CAR-T therapy reflects basic discoveries in immunology, a long history of research in understanding the human immune system and development of genetic engineering tools.  CAR-T therapy is the translation of this cumulative scientific and clinical knowledge.

  • The first generation chimeric T cells were developed around 1993 but were not clinically effective1
  • Further research and engineering including fusion with co-stimulatory molecules saw a second generation of CAR-T cells that were retained in the body and had the potential for clinical use2
  • In 2002, a group at Memorial Sloan Kettering (MSK) developed a CAR-T cell that was active and shown to target and kill prostate cancer cells in vitro
  • In 2003, human CD19 directed CAR-T cells were shown to kill leukaemia cells in a mouse model. This proof of concept saw further research focused on CD19 as a target and the development in manufacturing viable CAR-T cells
  • In 2009, MSK published a method for manufacturing CD19 CAR-T cells
  • In 2012, a young patient (Edith Whitehead) with relapsed Acute Lymphoblastic Leukaemia (ALL) was successfully treated in a clinical trial with CAR-T cells
  • In August 2017, Tisagenlecleucel marketed as Kymriah® was the first CAR-T cell (CD19 directed) therapy to receive FDA approval (developed by UPenn in collaboration with Novartis)
  • Kymriah® was approved by the TGA in Australia in December 2018 for the treatment of relapsed or refractory paediatric/young adults with ALL and for adult patients with diffuse large B cell lymphoma
  • In March 2019, the Australian Federal Government announced $80 million towards a facility at the Peter MacCallum Cancer Centre for the manufacture of CAR-T cells in Australia.
CAR-T Patenting Activity

The patent landscape reflects the evolution of technologies and technical trends.  In our own patent searching the key term ‘CAR-T Cell Therapy’ first appeared in patents dated from 2011, consistent with CAR-T therapy being an emerging technology and only very recently approved for clinical use in limited applications.

However, there are earlier patents that cover CAR-T cells or engineered cell constructs that were precursors to the CAR-T cells.  For example:

  • 2002 patent application filed by City of Hope Research Centre titled “Chimeric immunoreceptor useful in treating human cancers’
  • 2008 patent granted to MSK for a CAR-T that combines an activation signaling region (CD3 zeta), a costimulatory signaling region (CD28) and a binding element for specific interaction with a selected target.

The patenting activity related to CAR-T cell inventions and the top patent applications are shown below3.  The increase in patenting activity from around 2013 appears to correlate with the translation of the technology into the clinic and commercial interest in the technology.  The top applicants correlate with those researchers/institutes that have been pioneers in CAR-T research.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

This emerging immunotherapy: CAR-T is showing great promise in the clinic and has been life saving for patients like Tom Long but there is a horse before the CART and that is the long investment in good science and its translation to the clinic.

 

Author

Amanda Jones

Patent Attorney and Director of the Snowdome Foundation (not for profit dedicated to accelerating new treatments for blood cancer patients)

 

Footnotes

  1. Wezmann Institute engineer T cell with first chimeric molecule, a portion of an antibody fused to a part of a T cell
  2. In 1998, Dr Sadelain and colleagues from MIT show that introduction of CD28 (co-stimulatory molecule) in engineered T cells allows them to persist and remain active in the body
  3. Nature Biology | Vol 37 | April 2019 | 370-376
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