CAR-T cell therapy has swept the biotech industry by storm in recent years, creating hope that it could welcome in a new age of cancer treatment. However, the remarkable success stories have come from targeting CD19, which is now considered an antigen that holds the key to a limited range of blood cancers. Presently, this hematological arena is a highly competitive therapy space that is being shared between leading CAR-T companies.
Scientists, investors and developers invariably agree that the key to longer-term success in this space depends on solving two major problems: identifying antigens other than CD19 that can be targeted with CAR-T therapy with strong efficacy and going beyond liquid cancers into solid tumor indications. CAR-T cell products to deal with solid tumors will undoubtedly offer a larger market potential.
However, it is not an easy task to identify the antigens found on the cells of solid tumors. There are reasons why CD19 is the most common target. It is seen solely on B cells, whose destruction via CAR-T therapy offers a straightforward route for treating B-cell leukemias and lymphomas. At the same time, loss of the body's B cells is not particularly problematical, because their antibody-producing function can be reinstated by injecting intravenous immunoglobulin (IVIG) to patients.
Currently, the only two non-CD19-directed CAR-T therapies are those that target CD22 in B-cell malignancies and B-cell maturation antigen (BCMA) in multiple myeloma. CD22 is structurally analogous to CD19, while BCMA is an antigen expressed on plasma cells, whose functional loss can also be replaced with IVIG.
The problem with solid tumors is that there is little evidence of CAR-T being able to overcome the numerous difficulties that exist for these to be targeted efficiently. However, both academic and commercial groups are racing against time to identify the antigens on solid tumor cells and develop suitable CAR-T cells, because it represents large market potential.
There are several reasons which make solid tumors difficult to treat using CAR-T cell therapies. Globally, solid tumors outnumber hematological tumors by 10 to one. In 2015, Novartis and PENN reported that their CART-meso failed to show any effect in patients with mesothelioma, ovarian cancer and pancreatic cancer. Moreover, there was very poor persistence of CAR-T cells in the patients.
The difficulty with solid tumors is that they are usually surrounded by a hostile, immuno-suppressive microenvironment. This environment presents many inhibitory factors that prevent CAR-T cells from reaching them. A typical CAR-T approach will not have success under these conditions. For this reason, Juno and Novartis are engaging in constructing CAR-T cells with novel designs that incorporate additional elements to boost activity within this setting. Currently, these products are in preclinical development.
Driving Forces for the CAR-T Therapy Market
With the growing demand for CAR-T therapies, CAR-T companies are proliferating. Growing numbers of these companies are supported by:
Increasing investment flowing into CAR-T cell research
Landmark approvals of CAR-T cell therapies by the U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA)
Major acquisitions within the CAR-T industry
Large IPOs within the CAR-T industry
As mentioned, 2017 was the first year that the U.S. FDA approved a CAR-T cell therapy, approving Kymriah in August 2017 and Yescarta in October 2017. Novartis produced Kymriah, a CAR-T therapy used to treat leukemia, while Gilead/Kite Pharma developed Yescarta, a CAR-T therapy for patients with lymphomas. Approvals for these products are now spreading globally, with authorizations permitted by the EU, Canada, and Australia, among others. The approval of these early CAR-T cell therapies has opened the gates for many other types of cell and gene therapies to claim respect, both from regulators, as well as from the broader scientific and medical communities.
CAR-T funding is also on the rise. At first, the trend was subtle, but the tide swelled as CAR-T therapies like Kymriah and Yescarta reached the marketplace and created a CAR-T funding craze. CAR-T start-ups have been richly funded by investors eager to get into this trending area of regenerative medicine. Following IPOs by CAR-T players Kite Pharma, Bellicum, Juno Therapeutics and Cellectis totaling over $750 million, CAR-T developer Autolus announced a $150 million IPO.
This has bought the total value of recent CAR-T initial public offerings (IPO's) to nearly $1 billion.
CAR-T Industry Deal-Making
The CAR-T industry has also witnessed aggressive deal-making in recent years. Celgene snagged Juno Therapeutics for a shocking $9 billion in January 2018 and Gilead acquired Kite Pharma for an astounding $11.9 billion in August 2017. After $20 billion of market capitalization from the CAR-T companies in 2018, the CAR-T market has continued to gain momentum.
There have also been more than a dozen CAR-T deals between pharmaceutical companies and academic institutions, with the best known being the partnership between Novartis and the University of Pennsylvania (UPenn). When Kymriah because the first CAR-T cell therapy to be approved in the U.S. in August 2017, it resulted from a 5-year collaboration between UPenn and Novartis.
CAR-T financing rounds have also proliferated. In one major example, Cellularity raised $250 million in February 2018 to support the development of placental-derived products, including T-cells that will be immune advantaged because of their derivation from the placenta. Cellularity is looking to burst a major bottleneck in the industry by deriving T-cells from a single (allogeneic) cell line, potentially positioning itself to slash the price point for CAR-T treatments. In another significant example, London-based CAR-T start-up Allogene Therapeutics entered into an asset contribution deal with Pfizer in April 2018, as well as announced a $300 million Series A round.
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