15 June 2021
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It might be trite to observe, but as the human body is formed of cells, diseases and malignancies of the human body are fundamentally cellular in nature. Cells may be damaged, diseased, or defective, and recovery requires that they are repaired, replaced, or regenerated. Whether removal of the disease-causing agent is effected through drugs or the body’s own immune system, the damage caused by a disease must be addressed, and throughout medical history prognosis has ultimately depended on the body’s ability to repair itself on the cellular level. However, recent advances in modern medicine have allowed physicians to intervene in this process directly for the first time.

Cellular transplantation

Cell therapy – where new, healthy cells are introduced into a patient’s body to replace or augment cells that are diseased or absent – traces its origins back as early as 1968, where bone marrow was transplanted into patients with cancers of the blood, such as leukaemia, following destruction of their diseased cells through chemotherapy or radiation. Despite the risks of complications from the invasive procedure, bone marrow transplants have significantly increased the prognosis of leukaemia patients since their widespread adoption.

Other tissues also lend themselves to cell transplant. For example, cartilage at joints can wear away over time, particularly in the knee, resulting in significantly impaired mobility. Spherox, first offered in the UK in 2018, addresses this through cell transplant. In this approach, a small cartilage biopsy sample is obtained from the patient, cultivated to form spherical clusters of cartilage-generating cells called chondrocytes, and transplanted into the knee to regenerate damaged cartilage. The “autologous” nature of the cells – the fact that they are obtained from the patient in question – removes the need for complex tissue type matching and the risks of transplant rejection inherent with donor or “allogeneic” transplants.

A similar approach has also been utilised for treating defects of the skin. GintuitTM is an allogeneic sheet-like graft containing skin cells, which is used to treat gum recession. Advantageously, skin cells can be harvested relatively painlessly when compared to the previous approach of removing tissue from the palate. Meanwhile, Castle Creek Biosciences, long-time producers of allogeneic skin cell product Azficel-T (Laviv) have begun to develop similar treatments for a range of skin diseases. Interestingly, oral, and dermatological conditions are easy to monitor compared to internal applications, meaning that these areas are likely to continue to lead the way on advanced cellular transplant therapies.

Stem cells – a renewable resource

A major obstacle for transplantation cell therapy is obtaining enough cells. Furthermore, direct donation is only possible for cell types which are easily accessible, essentially limiting the number of conditions that can be treated in this way. Some of these issues can be overcome with stem cells. These are unspecialised cells that, unlike most, can divide, multiply, and develop into other functional cell types. This may be performed outside the body, allowing large quantities of cells to be generated from a small sample. Two main types of stem cells are being explored in the context of cell therapy: pluripotent stem cells (which can form a large number of cell types) and tissue-specific stem cells (which have a limited number of eventual cell fates). Stem cell therapies have revolutionised the field, and the market is projected to reach USD 401 million by 2026 from USD 187 million in 2021.

Newer approaches use stem cells from a variety of origins. In 2018, Takeda’s Alofisel, a therapy where adipose-derived mesenchymal stem cells (MSCs) are expanded and used in the treatment of Crohn’s disease, became Europe’s first approved allogeneic stem cell therapy. Umbilical cord blood, rich in haematopoietic stem (HSC) and progenitor (HPC) cells, is useful in treating a variety of disorders from blood and bone marrow cancers, to sickle cell anaemia. Cord blood is collected after the baby is delivered and the cord is cut, and many parents now choose to cryopreserve the cord blood shortly after birth, either for donation (whereby it is processed into products such as Allocord and Hemocord) or “banking” as autologous stem cells in case their child should need it in later life. Holoclar uses a particular type of eye stem cell, called a limbal stem cell, to repair the cornea after injury. It therefore is an autologous alternative to corneal transplant, restoring sight.

So far, stem cell-based therapies are limited to tissue types with diffuse, uniform structures, due to the challenge of recreating the highly ordered tissue microenviroments required for normal development. As technology to create tissue scaffolds develops, stem cell therapies may eventually be used to regenerate large, complex tissues and organs in situ, increasing their clinical usefulness significantly (see our blogs Collagen scaffolds – the future of tissue engineering? and The future of organ transplantation: growing organs from scratch?).

However, as cell therapy matures as a field, and as scientists are well versed at manipulating and modifying cells in the laboratory so as to introduce new traits, the question arose – why not do the same with harvested therapeutic cells?

Orchard Therapeutics’ Strimvelis is an autologous stem cell treatment used to treat adenosine deaminase deficiency – a severe genetic disorder that results from a defective adenosine deaminase (ADA) gene. Bone marrow-derived stem cells are purified and CD43-enriched, expanded, and then transduced with a gamma retrovirus containing a functional version of the ADA gene and then reinfused into the patient. These cells take root in the person's bone marrow, replicating and creating cells that mature and create normally functioning adenosine deaminase protein. Other therapies utilising modified autologous stem cells include Zynteglo, for the treatment of beta thalassaemia, and LentiGlobin (bb1111), for treating sickle cell disease, both of which aim to “repair” dysfunctional versions of the patient’s gene.

The ability to modify a patient’s cells in this manner could one day provide therapies for countless undertreated genetic diseases. However, the success of this depends on stable, safe, and reliable vectors for the modification of stem cells, as well as mastering their enrichment and expansion. Innovators working in this field may find that their platforms for transformation, culture, and differentiation have widespread applicability, meaning that developers are able to license their technology to groups working on many different diseases. Indeed, given the regulatory network that is arising around cell therapies, methods of ensuring and measuring quality control may prove especially valuable in the long run, especially if these become industry standard.

CAR-T and next-generation therapy

A new class of therapies not only modifies cells to restore normal function but introduces entirely new properties not seen in nature. The cells are modified in the laboratory to express a chimeric antigen receptor (a CAR), a synthetic receptor that recognises a target antigen that is found on cancer cells. When expressed in a T-cell, these “CAR-T” therapies modify the immune cells into “living drugs” which hunt down cancer cells and destroy diseased tissues in a patient (see our blog Fighting cancer with CAR-T therapies).

Many CAR-T therapies on the market target CD19, a B-cell marker that is overexpressed on malignant tumours arising from these cells. CD19-related cancers are typically blood cancers, which are especially suited to treatment with CAR-T. Approved by the FDA in 2017, Yescarta (Kite Pharma), a treatment for large B-cell lymphoma, and Kymriah (Novartis), approved for use against B-cell acute lymphoblastic leukemia, have been swiftly followed by Breyanzi (Bristol-Meyers Squibb) and Tecartus (Kite Pharma), the latter of which is now offered under the NHS to mantel cell lymphoma patients. Interestingly, these therapies all use autologous T-cells, meaning that the treatments are personalised for each patient, making CAR-T therapy currently an expensive procedure. As CAR-T therapies advance, it may one day be possible to develop allogeneic therapeutics which work “off the shelf” for a multitude of patients, reducing costs and increasing availability (see our blog T cell engagers - dark horses of immunotherapy).

Whilst most CAR-T therapeutics currently on the market are directed against blood cancers, as these are easily treated by intravenous infusion of CAR-T cells into the blood stream, in the future solid tumours may also be targeted in this manner. Indeed, innovators may discover that CAR-T directed against solid tumours avoid the crowded patent landscape present in the CD19 space. The challenge so far remains actually bringing CAR-T into contact with solid tumour cells, both at the periphery and throughout the tumour microenvironment, but promising early results against breast, colon and pancreatic cancers suggest that this may one day be achievable. Developing novel delivery mechanisms for CAR-T therapeutics could therefore be as productive a field of research as designing new CARs themselves.

Conclusion

As cell therapies continue to develop, they have the potential to provide advanced therapies for myriad diseases. It could well be that, within our lifetimes, cellular therapies become routine for all manner of diseases, as physicians learn to repair and rebuild the body at the fundamental level. Significant challenges remain in increasing the reliability, effectiveness, and scope of available cellular treatments, whilst reducing their cost and clinical complexity. However, with so much to gain, and with so many lives at stake, the question is not whether these obstacles will be overcome, but when.

Andrew is an Associate and Patent Attorney at Mewburn Ellis. Working in our life sciences team, Andrew is experienced in drafting and prosecuting patent applications for local and international clients. Primarily, he works with clients who are early innovators in their fields, such as universities and start-ups, and his work covers a range of technical areas. He also has extensive experience with Freedom to Operate (FTO) projects where, in addition to providing infringement opinions and patent landscape analysis, he coordinates teams handling larger projects for multinational organisations.
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