CAR-T cell therapies – T cells tagged with chimeric antigen receptors – have only been on the market for a couple of years, but have already been hailed as a game changer in the treatment of some cancers, and even possibly a cure.
The FDA approved Novartis’ Kymriah (tisagenlecleucel) in August 2017 for the treatment of acute lymphoblastic leukemia (ALL), with a second approval in May 2018 for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Kite Pharma (now part of Gilead Sciences) picked up an approval for Yescarta (axicabtagene ciloleucel) for second-line treatment of DLBCL in March 2017. Over 80 percent of children and young adults treated with Kymriah® in clinical trials experienced remission, and a similar percentage of trial patients who received Yescarta® experienced either a complete or partial response. Data on the long-term results with these drugs continues to be collected.
So far, the focus of CAR-T approaches has primarily been on liquid tumors, despite around 90% of cancers globally being solid tumors. Indeed, according to a review in Nature Reviews Drug Discovery, of the 364 ongoing oncology CAR-T clinical trials, more than half were in hematological cancers. This is, at least in part, because of the challenges raised by solid tumors, such as the establishment of an immunosuppressive microenvironment, the heterogeneity of tumor antigens, and the difficulties of delivering cell therapies to the tumors. Drug developers are seeking to overcome such challenges with a variety of approaches. These include “armoring” the CAR-T cells, targeting more than one antigen, combining treatment with checkpoint inhibitors, and delivering the cells directly to the tumors.
CAR-T cells are genetically engineered to produce artificial receptors that can guide them to diseased target cells. This means, in theory, that CAR-T-based therapeutics aren’t just limited to oncology. Indeed, several companies and research institutions are developing potential CAR-T treatments for non-cancer indications, from heart disease to viral infection.
For example, researchers at the University of Pennsylvania’s Abramson Cancer Center, the institution behind the discovery of Kymriah, are investigating CAR-Ts in the treatment of cardiac fibrosis, a type of scarring of the heart. The team identified fibroblast activation protein (FAP) as a marker for the fibrotic cells, and engineered CAR-Ts against FAP to remove the activated fibroblasts responsible for the damage. When tested in mice with heart disease caused by high blood pressure, the CAR-T therapy reduced cardiac fibrosis and showed improvements in heart function.
Philadelphia-based Cabaletta Bio is also using expertise from the University of Pennsylvania to develop engineered T cell therapeutics for B cell-mediated autoimmune disease. These will use chimeric autoantibody receptors (CAARs) to target only disease-causing B-cells, sparing normal B cells. The initial target is mucosal pemphigus vulgaris (mPV), an autoimmune condition where painful blisters form on the skin and mucosa, with a clinical trial expected to begin in 2020. Other CAAR-T programs at Cabaletta Bio include myasthenia gravis and hemophilia A.
CAR-T therapies may have potential in another B-cell-linked autoimmune disease, systemic lupus erythematosus (SLE). Researchers at the University of Tennessee Health Science Center created CD19-targeting CAR-T cells to deplete auto-antibody producing B cells. This treatment reduced lupus symptoms in mice, improved the health of their kidneys, spleens and skin compared to controls, and helped them to live longer.
In addition, TxCell, now acquired by Sangamo, has developed a slightly different CAR-T tactic to treat chronic organ transplant rejection. TX-200 is made of regulatory T cells (Tregs) linked with a CAR that binds to the HLA-A2 protein on the surface of a transplant. The treatment, which aims to help the body tolerate the graft, is expected to move into clinical trials by the end of 2019. Sangamo also plans to develop next-generation autologous and allogeneic CAR-Treg therapies for the treatment of autoimmune disease.
Yet another example is being developed for HIV. HIV infection is no longer the death sentence that it once was, and drug treatment can drive viral load down to almost undetectable levels. However, these treatments have been linked with increases in cancer, cardiovascular and neurological diseases, and can shorten lifespan. CAR-T therapies that target HIV-infected cells are showing signs of hope for a new treatment.
Lentigen, a Miltenyi Biotec company, is working on a multispecific CAR-T approach that targets different surface HIV antigens. These “duoCARs” reduced HIV titers by more than 97% in a mouse model, and may deplete the reservoirs of dormant HIV-infected immune cells in humans, potentially leading to a functional cure. Clinical trials are planned for 2020.
CAR-T treatments, however, also come with limitations. For instance, their use has been linked to some potentially severe side effects, including cytokine release syndrome, neurological symptoms, and low white and red blood cell count. In addition, they are only suitable for treating conditions where diseased or damaged cells express disease-specific antigens on their surface.
Beyond the science, the economics of treatment are going to be complex. The list price of Kymriah is $475,000. While a study funded by the Boston-based Institute for Clinical and Economic Review (ICER) deemed this high price to be cost-effective for cancer, if CAR-T treatments are developed for more — and more prevalent — diseases, how will society be able to afford them?