It’s not untypical for an emerging cancer treatments to be dubbed “revolutionary” or “game-changing”, but stepping beyond cliché, chimeric antigen receptor T-cell (“CAR-T”) therapy can rightly be said to have shifted the expectations of both oncologists and cancer patients and precipitated new thinking within public and private healthcare systems as to how 21st century medicines should be valued (and paid for).

The potential of CAR-T therapy was first established in otherwise untreatable haematological cancers, specifically the those arising from aberrant B-cells: B-cell precursor acute lymphoblastic leukaemia (ALL) in children and several forms of adult lymphoma. Although the unprecedented (and durable) response rates achieved in patients who had previously failed available treatments were accompanied by common and severe side effects (due largely to the massive release of cytokines caused by non-specific T-cell activation), the CAR-T therapies Kymriah® (Novartis) and Yescarta®(Gilead) received FDA approval in August 2017 and May 2018, respectively.

The CAR-T therapy pipeline now encompasses investigational treatments for a variety of haematological cancers and solid tumour types. A recently updated analysis from the Cancer Research Institute identified 568 CAR-T therapies across all stages of development (a 40% increase over 2018)1. A non-exhaustive search of the NIH ClinicalTrials database identified nine CAR-T therapy Phase III studies recruiting patients with acute myeloid leukaemia, multiple myeloma and metastatic pancreatic cancer, as well as those with B-cell malignancies2.

Setting aside the essential contribution of advances in cancer biology, viral vector development and cell product manufacture, CAR-T therapy is deceptively simple: T-cells are isolated from the patient’s blood, then genetically engineered to express a receptor specific for a target molecule expressed by cancer cells, followed by expansion of the transformed cells to therapeutic dose levels and infusion back into the patient. Engineered T-cells then embark on their search and destroy mission, with receptor contact triggering tumour elimination and expansion of the CAR-T cell population.

The principle underlying CAR-T therapy- targeted elimination of disease-causing cells – has application outside of cancer treatment. Autoimmune diseases occur when constituents of normal tissues become the mistaken targets of adaptive immune responses. Autoantibodies play a major role in pathology and the depletion of B-cells by therapeutic antibodies such as rituximab is of benefit in severe rheumatoid arthritis and other autoimmune conditions but results in elimination of both autoantibody-producing and useful B-cells alike, compromising resistance to infection.

CAR-T therapy offers a more nuanced approach. University of Pennsylvania researchers (including Michael Malone, a Kymriah® co-inventor) first established the concept of “CAAR-T” therapy (the extra “A” stands for “autoantigen”) in laboratory models of mucosal pemphigus vulgaris, a severe autoimmune condition which results in blistering and breakdown of skin and mucosa and is caused by an autoantibody response to a skin protein, desmoglein 3 (Dsg-3). By engineering T-cells to express Dsg-3, the Penn team were able to successfully attract and eliminate anti-DsG-3 antibody-producing B-cells3.

CAAR-T proof of concept has since been extended to myasthenia gravis (MG). A minority of MG sufferers produce antibodies against MuSK, a key enzyme present in muscle tissue. Laboratory studies have established that MuSK-expressing CAAR-T cells can eliminate anti-MuSK B-cells4. “Plain vanilla” CAR-T therapy directed against CD19, the B-cell marker targeted by both Kymriah® and Yescarta® resulted in sustained improvement of lupus symptoms in a mouse model of the disease5.

Investors and industry are taking notice. Cabaletta Bio, a Penn spin-out, has attracted $88m in venture funding and is aiming for a $100m IPO to move its early candidate therapies into clinical development. Sangamo acquired TxCell in July 2018 for €72m on the strength of a CAR-T platform based on engineered regulatory T cells (“Treg”) which may prove to be capable of dampening down the autoimmune responses resulting Crohn’s disease, multiple sclerosis and solid organ transplant rejection. Quell Therapeutics hopes to be able to bring engineered Treg cells to bear in transplant rejection and autoimmune disease and launched with €40m Series A funding in May this year.

CAR-T is not the only flavour of cell-based immunotherapy with potential in autoimmune disease. Dendritic cells (DCs), best known for their role in antigen presentation, a property exploited in experimental cancer vaccines, are also potent inducers of Treg cells. Both autoantigen-specific and non-antigen specific “tolerogenic” DC approaches are in clinical development as therapies for rheumatoid arthritis, multiple sclerosis, Type I diabetes and transplant rejection6. Mesenchymal stem cells are also Treg inducters and have the advantage of being readily isolated from fatty tissue or cord blood, opening the prospect of “off the shelf” treatments. Early studies in rheumatoid arthritis patients have hinted at clinical improvement.

CAR-T cancer therapy uptake has been constrained by high drug and total treatment costs and slow procurement of comprehensive reimbursement. Future C(A)R-T and other cell-based autoimmune disease therapies may benefit from advances in manufacture, leading to lower drug costs and their highly specific modes of action might minimise expensive to treat adverse events. While few of the one hundred or so autoimmune conditions7 are adequately managed, novel therapies will need to show significant benefit over established and emerging small molecule and biologic treatments. The first marketing submissions are likely to address the rarer autoimmune conditions or defined subsets of sufferers with well-characterised autoantibody responses.

On the other hand, the commoner autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis represent complex and chronic conditions, with relatively high direct and indirect lifetime treatment costs. For example, around 20-25% of rheumatoid arthritis patients never achieve satisfactory disease control from existing treatments, with the majority being of working age when first diagnosed8. The prospect of long-term, treatment free remission or even stable disease allowing a return to economic activity might conceivably justify the use of high-ticket cell-based treatments.



1 The global pipeline of cell therapies for cancer. Yu JX, Hubbard-Lacey VM and Tang J. Nature Reviews Drug Discovery, Published online: May 30th 2019; doi:10.1038/d41573-019-00090-z 2

2 Accessed 16th October 2019

3 Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Ellebrecht CT et al. Science 08 Jul 2016;353 (6295):179-184 doi: 10.1126/science.aaf6756

4 Caballetta Bio Form S1/A SEC filing 16th October 2019

5 Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Kansal R et al. Sci. Transl. Med. 11, eaav1648 (2019) online March 6th 2019. doi:10.1126/scitranslmed.aav1648.

6 Tolerising cellular therapies: what is their promise for autoimmune disease? Mosanya CH and Isaacs JD. Ann Rheum Dis 2019;78:297–310.

7 According to the not for profit American Autoimmune Related Diseases Association

8 Diagnosis and management of rheumatoid arthritis. A review. Aletaha D and Smolen JS. JAMA. 2018;320(13):1360-1372 doi:10.1001/jama.2018.13103



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