February 15, 2016 (Vol. 36, No. 4)

Key Question: Is This Pie in the Sky or a Serious Proposition?

According to Stephen Ward, Ph.D., the U.K. means business when it says it has the goal of building a £10 billion ($15 billion) cell and gene therapy industry in that country.

Dr. Ward, COO of the Cell Therapy Catapult, a U.K. government initiative which assists in developing and commercializing cell therapies, made his remarks at the recent bioProcessUK conference in Cambridge, U.K.

To achieve this bold ambition, speakers at the conference discussed the technical, fiscal, and regulatory strengths of the U.K., as well as the challenges it faces in manufacturing if it is to become a global hub for cell and gene therapy production.

One of the technical highlights is the increasing development of T-cell therapies. “There is a major step change going on in the U.K. around T-cell therapies with serious money coming in to support it,” Dr. Ward said. “With the success of case studies such as the one at Great Ormond Street Hospital, which effectively cured 11-month-old Layla of drug-resistant leukemia, cell-based immunotherapies are beginning to become a reality.”

Dr. Ward then introduced three U.K.-based biotech companies that are at the crest of this wave of new therapies.

T Cells—Licensed to Kill

One of these biotech companies is Autolus, a spin-out biopharma from University College London that’s developing a portfolio of chimeric antigen receptors (CARs) for use in T-cell therapies. CARs are engineered proteins that are composed of parts from different sources. The parts include an outwardly facing antibody recognition domain, a transmembrane domain, and an inwardly facing signaling domain.

“T cells are amazing because they are constantly scanning cells in the body,” pointed out Jim Faulkner, Ph.D., head of manufacturing at Autolus. “They are totally xenophobic. If any cell is slightly different from normal, they will destroy that cell. By adding CARs to T cells to make CAR-T cells, we’re producing tumor-targeted T cells that are ‘licensed-to-kill’ cancer cells.”

However, producing CAR-T cells for large patient numbers is challenging. According to Dr. Faulkner, Autolus produces CAR-T cells by extracting T cells from patients via leukapheresis, activating the cells with cytokines, and transducing them with a viral vector. The resulting CAR-T cells are cryopreserved, shipped back to the hospital, thawed, and administered back to the patient.

“Producing these cells requires lots of manual manipulations and two weeks of work by skilled scientists working in a clean room, so this is not an industrial process,” noted Dr. Faulkner. “This is sufficient for Phase I studies, but if our therapy delivers on its promise, it could be relevant to thousands of patients globally, so we have challenges to overcome with process complexity and scalability.”

Adaptimmune, a University of Oxford spin-out biopharma, is also engineering T-cells as therapeutics. It uses a process similar to that used by Autolus. But instead of using CARs, Adaptimmune is using engineered T-cell receptors (TCRs), proteins that can target both intracellular as well as extracellular cancer target proteins. (TCRs recognize peptide fragments that are presented  in association with tissue-type molecules called human leukocyte antigens, or HLAs.)

Like Autolus, Adaptimmune uses engineenered cells instead of tumor-infiltrating lymphocytes (TILs), which are T cells that have demonstrated strong antitumor activity in patients. They are harvested, multiplied in culture, and reintroduced to patients. TILs are effective at destroying tumors but are difficult to manufacture and standardize.

Adaptimune prefers to produce T cells that express TCRs that have known affinity and specificity to destroy tumors. To do so, the company identifies higher affinity variants using phage display and validates TCR targets via mass spectrometry. It then determines if the targets are on healthy tissue using human cell lines and whole-blood assays in a package of preclinical testing. This is because Adaptimmune wants only low-risk targets because too high a potency can mean cross-reactivity with HLAs in the body and destruction of healthy cells.

This approach looks promising, and clinical trials of Adaptimmune’s T-cell therapy targeting the NY-ESO-1 cancer antigen for treating synovial sarcoma and multiple myeloma are ongoing. During bioProcessUK, the company also announced that it had initiated a Phase I/II study of NY-ESO-1 in non-small cell lung cancer patients. The program, which is part of a strategic collaboration between Adaptimmune and GlaxoSmithKline, is worth up to $350 million.

Going Viral

A critical component in producing engineered T cells is the viral vector for transducing the CAR or TCR genes into the cells. This component, said several speakers at bioProcessUK, could represent a weak link in the development of T-cell therapies. Specifically, these speakers raised the possibility that consistently manufactured viral vectors could be hard to supply in adequate amounts. A potential solution to this manufacturing problem was described by James Miskin, Ph.D., CTO at Oxford BioMedica, another University of Oxford biopharma spin-out.

According to Dr. Miskin, a pioneer in the development of lentiviral vectors, his firm begins with an adherent serum-based process. It produces the vector using single-use components and a sterile filtration step. Also, it utilizes chromatography and membrane-based bioprocessing to purify and concentrate the vector, which is then frozen.

Then the company subjects the vector to extensive internal testing. This part of the production process ensures that GMP standards are met prior to the vector’s release and subsequent application in the modification of patient T cells.

The company now has a strategic partnership with Novartis. This partnership includes a licence to OXB technology, as well as OXB in-house manufacture of the lentiviral vector that is used in Novartis’ CAR-T cell therapy, CTL019. To meet the needs of this collaboration, Oxford BioMedica has invested significantly in its process development and manufacturing capabilities and capacity.

“Initially, we made our vectors with external contract manufacturing organizations in the U.K. and in mainland Europe using our own process,” explained Dr. Miskin. “We now have GMP production capacity in-house, and we continue to invest in the further development of lentiviral vectors.

“For example, we use a dedicated custom robotic system for selecting and screening packaging and producer cell lines, and we have also developed a serum-free, next-generation process in 200 L bioreactors to scale-up production of our vectors to facilitate commercialization. Data to date suggests this will provide us with around a tenfold improvement on yield.”

Dr. Miskin added that the company is also doubling its GMP capacity, with further expansion expected to be online within the next 18 months.

“This means we are future-proofing our production process and increasing our capacity,” he said. “From a U.K. perspective, this is helping to build a high-value manufacturing sector of leading technology here.”

Using serum-free, nonadherent manufacturing techniques, Oxford BioMedica pursues in-house development of lentiviral vector-based products. The company’s facilities have received GMP certification and approval from the U.K. Medicines and Healthcare Products Regulatory Agency to manufacture bulk drug material for Investigational Medicinal Products.

Billion-Dollar Question

In addition to some promising therapeutic developments, what else does the U.K. offer? Alternatively, what does it need to help it achieve its cell and gene therapy ambitions?

A definite U.K. advantage, bioProcessUK speakers agreed, is the nation’s Medicines and Healthcare Products Regulatory Agency (MHRA). The MHRA is respected globally because of its desire and willingness to help in the introduction of innovative medicines.

More generally, the U.K. government has demonstrated its commitment to building a cell and gene therapy industry by maintaining Patent Box, a special tax regime for intellectual property revenues. In addition, the U.K. government has launched the Accelerated Access Review, which will consider how to speed up the introduction of innovative medicines in the U.K.

Innovate UK, the U.K.’s innovation agency, has committed £55 million ($78 million) to fund the building of a 7,200-square-meter Cell Therapy Catapult manufacturing center in Stevenage. Construction began in November 2015 and is due to be completed in 2017.

Despite holding these advantages, the U.K. also faces the same challenges that any supporter of a gene therapy industry must overcome. Manufacturing cell and gene therapies at scale is not an easy business. It requires investment in the right infrastructure and skilled people.

“We need to enable training at the post-doc level that interfaces with industry,” insisted Jeffrey Almond, Ph.D., a professor at the University of Oxford. “We need to have people who understand what it takes to make cell-based products and know that it is exciting to be in manufacturing.”

Another issue is being able to develop the optimum processes for efficient and profitable production. “There is great science and engineering going on in the U.K. which will lead to the successful industrialization within the cell therapy and gene therapy field,” maintained Dr. Miskin.

“Scalability is a major challenge,” stressed Dr. Faulkner. “The main enablers for success are automation, single-use technology, and sophisticated logistics.”

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