The issue
In 2017, Achilles Therapeutics approached the MHRA to discuss
quality, non-clinical, clinical and regulatory aspects of ATL001,
an advanced therapy medicinal product consisting of autologous
clonal neoantigen reactive T cells derived from patients’
tumour-infiltrating lymphocytes. The proposed initial indication
was for the treatment of non-small cell lung cancer.
By sequencing a patient’s own tumour, comparing it to the
germline DNA of the patient and applying bioinformatics
algorithms, it is possible to identify tumour-specific mutations.
Additionally, independently, human leukocyte antigen-typing of
the germline blood sample is performed. All of this information
is then integrated to predict which of the mutations will be the
most likely candidates.
The corresponding neoantigen peptides are manufactured and
cultured with antigen presenting cells, which can process them
for presentation to T cells. Using these clonal neoantigen
peptides (to specifically expand clones of tumour-infiltrating
lymphocytes) enhances the number of tumour-infiltrating
lymphocytes able to recognise such neoantigens and to target the
cells that express them. This is effectively an anti-cancer
treatment that is specific to the individual patient and should
specifically target all cancer cells as the clonal neoantigens
are contained within each and every cancer cell.
How the MHRA helped
Advanced therapies, such as ATL001, are complex products and
their development has for many years been hampered by myriad
scientific, technical and manufacturing challenges. The MHRA’s
scientific assessors advised that this type of therapy, i.e. not
only personalised but also autologous and does not involve any
gene modification, needed new thinking, especially regarding the
non-clinical support.
The MHRA also gave advice on the manufacturing of the product and
clinical advice on the protocol design. Advice on the protocol
allowed for endorsement of aspects such as eligibility criteria,
safety monitoring and engagement of a Data Safety Monitoring
Committee. This also assisted the MHRA to conduct a timely review
at the time of submission of the application.
‘The MHRA demonstrated an excellent understanding of the
challenges that would be faced when bringing a novel therapeutic
combining attributes of autologous cell therapy with highly
personalised and exquisite antigen targeting to patients’ said
Sean Russell, Director of Regulatory Affairs at Achilles
Therapeutics. ‘Early engagement with MHRA through scientific
advice enabled us to prospectively agree the frameworks of not
only the non-clinical package, but also areas of manufacturing
and the clinical trial design that would ultimately be part of a
clinical trial application. We were able to align with the
assessors on the areas that were going to be most critical when
it came to the review of the application and hence focus our
efforts accordingly.’
Outcomes
Through close collaboration with the MHRA, Achilles Therapeutics
has managed to take its investigational clonal neoantigen-based
therapy from a concept into the clinic in less than three years
obtaining MHRA approval in January 2019 to begin first-in-human
trials in both lung cancer and melanoma.
The MHRA’s Licensing Director, Dr Siu Ping Lam, said:
‘The MHRA’s Clinical Trials Unit has a strong reputation for
providing high calibre scientific advice, particularly to support
First Time in Human clinical trials. This example is a
demonstration of our pragmatic, scientific approach and flexible
regulatory application, in support of innovation via early
engagement and early clinical trial approval. It is further
evidence of the MHRA’s standing as a world-leading innovative
regulator.’
