Cell & Gene Therapy
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Matt Hewitt
The Quest to Find a Cell Therapy for Autoimmune Diseases
How CAR T cells and other cell types are being used to study cell therapy for autoimmune diseases.
Earlier this month, University of Pennsylvania (UPENN) researchers reported on the long-term results of leukemia patients treated with the Chimeric Antigen Receptor (CAR) T cell therapy CTL-019 which eventually became Kymriah, noting that two patients treated with this personalized therapeutic continue to be cancer-free 10 years after treatment. “Now we can finally say the word “cure” with CAR T cells,” Dr. Carl June, the UPENN scientist who pioneered the treatment, told The New York Times .
It’s a cliché but true that CAR T therapeutics and cell therapies in general have shifted the treatment paradigm in cancer. For the first time we are seeing increased use of the “C” word, cure rather than remission. The curative potential of cell therapies has solidified their future. There are now multiple commercial approvals for CAR T therapies against hematological cancers with more on the horizon. Even with a number of approved therapies there continues to be interest in developing the next generation of cell therapies against blood cancer. We are also seeing a shift towards increasing effort in developing cell therapies, across multiple modalities, against solid tumor cancers.
Research in Cell Therapy for Autoimmune Diseases
If we view the cell therapy field and it’s advances as a 400M dash (as of this writing Carvykti is now approved against Multiple Myeloma), where we currently are with indications approved in oncology represents not even the midway point. CAR T cells and other cell types are being used as therapeutic platforms for studying and developing cell therapy for autoimmune diseases, including some for which there are few if any treatments available. These diseases typically are ailments where a patient’s normal tissues are mistaken targets of humoral (B-cell) and/or adaptive (T-cell) immune responses. As an example, cell therapy may prove a promising alternative in the treatment of systemic lupus erythematosus (SLE), where autoantibodies produced by B cells—the same cells targeted by the currently approved CAR T therapies—lead other immune cells to attack various tissues. In addition to lupus, other research into cell therapy for autoimmune diseases includes rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, and a host of other ailments.
Cells Types Used in Cell Therapy Research
There are four key strategies to study cell therapy for autoimmune diseases based on four cell types, all in different stages of development:
- Activated T cells. Last year, it was reported that CAR T cells modified to recognize CD19 were used by a German team to treat a patient with SLE for the first time. The treatment, given to a 20-year-old woman with severe and refractory SLE, induced rapid clinical remission of severe and refractory disease, with no notable adverse effects, the researchers reported.
- Regulatory T cells (Tregs). Tregs, which form the main line of defense against autoimmune diseases, are another exciting avenue of research in cell therapy for autoimmune diseases, but not without challenges. These therapies are typically autologous in nature, using a patient’s own cells, where the Tregs are re-engineered, then infused. They have been tested in clinical trials with mixed results. The primary concern with Treg cell therapies is the durability of the response. If Tregs don’t offer a durable response, then patients will require repeated Treg infusions raising the complexity and therapeutic cost. Additionally, Tregs can be challenging to manufacture consistently which again increases the complexity of using them as cell therapy for autoimmune diseases. However, some companies are pursuing a new class of genetically engineered T reg cell transplant which they hope will improve the performance of the Tregs by tailoring them to meet their targets. To do this they are employing CRISPR and CD19 CAR T cell technologies.
- B cells. Depletion therapies, which are designed to destroy autoimmune producing B cells, are already approved for the treatment of some diseases. Rituximab, for instance, is a chimeric monoclonal antibody targeted against CD20, a surface antigen present on B cells. It works by depleting normal as well as pathogenic B cells while sparing plasma cells and hematopoietic stem cells However, while this approach eliminates autoantibodies made by short-lived plasma cells that are continually derived from B cells, they do not affect long-lived plasma cells, so the disease continues to persist. To eradicate pathogenic humoral immunity, researchers are now looking at ways to attack or replace long-lived plasma cells, with some early promising findings in animals .
- Mesenchymal stem cells. MSCs are adult stem cells that can morph into a variety of cell types. MSCs were first identified five decades ago and explored in cell therapy for autoimmune disease. Because they can be used for allogeneic transfer with minimal risk of rejection, hopes were high that they could be harnessed for treatments. However, results in the clinic have been disappointing , primarily because their heterogeneity impedes the isolation and culture of high-quality cells for transfer, and their popularity has waned.
Advances in Cell Therapy for Autoimmune Diseases
Many of these cell types are being leveraged by companies, with some therapies in early phase clinical trials. Scientists from the University of Pennsylvania —which pioneered CAR T therapy—recently established the concept of chimeric autoantigen receptor (CAAR) T therapy in laboratory models of mucosal pemphigus vulgaris, a prototypical B cell-mediated autoimmune disease that results in blistering and breakdown of skin and mucosa. The condition is caused by an autoantibody response to the skin protein, desmoglien 3. Cabaletta Bio, a Philadelphia biotech, is now partnering with UPENN to develop a (CAAR) T cell therapy to MPV, and its candidate is now in Phase 1 trials. TeraImmune, which has a Treg therapy specific to Hemophilia A in Phase 1 trials, is nearing the clinic with one for multiple sclerosis. And Sangamo Therapeutics is planning the first clinical trial, in the UK and US, for a CAR Treg for kidney transplant patients to prevent Graft vs. Host Disease.
Though small biotech’s and startups largely make up this industry now, Big Pharma is interested in exploring cell therapy for autoimmune diseases. Gilead recently announced it is partnering with the startup Kyverna Therapeutics to help develop cell therapy for autoimmune diseases such as lupus nephritis, systemic sclerosis, and inflammatory myopathies. Kyverna’s anti-CD19 CAR-T developed for B-cell driven autoimmune diseases is expected to reach the clinic this year.
The need for cell therapies for autoimmune diseases is staggeringly large. According to the US National Institutes of Health, about 23.5 million Americans suffer from an autoimmune disease, of which there are about 80 known types. While autoimmune diseases do not kill as many people as cancer, the quality of life is not good. Finding long-term solutions would be a big advance for many patients.
This is an occasional series on trends in cell and gene therapies. Check out Matt’s recent post about decentralized manufacturing in cell therapy production.
