Development of a GMP protocol for personalized adoptive T-cell therapy

Recent results have shown that immune-recognition of neoantigens (antigens
derived from mutated tumor proteins) plays a large role in the anti-tumor
T-cell response. Evidence for this has been demonstrated in immune checkpoint
blockade therapy (e.g. anti-PD1, anti-PDL1, anti-CTLA4) and adoptive T-cell
therapy where deep and durable clinical responses have been demonstrated.
In the majority of cases, neoantigens are unique to each individual*s tumor,
necessitating that therapeutic strategies to target them must be
individualized. Furthermore, neoantigens are unique therapeutic targets in that
their expression is limited only to the tumor and not to *normal* tissue. These
targets can be leveraged in the development of new immunotherapies, including
personalized adoptive T-cell therapy. In the approach proposed in this study,
autologous T-cells are activated and expanded ex vivo against a panel of
neoantigens specific to the individual patient*s tumor. These
neoantigen-reactive T-cells are then expanded to large numbers and transferred
back into the patient as an adoptive cell therapy. The current study aims to
develop a protocol by which this can be achieved, in preparation for a clinical
trial testing the safety and efficacy of the treatment.

The primary objective is to develop a cell therapy production protocol in line
with Good Manufacturing Practice (GMP) regulations by which an autologous
T-cell product is generated towards tumor-specific neoantigens. The secondary
objective is to characterize and optimize the frequency, phenotype, and
functionality of the expanded tumor-reactive T-cells.

This is a non-therapeutic intervention study that uses patient material to
optimize a protocol for personalized adoptive T-cell therapy. The protocol will
entail using autologous antigen-presenting cells (e.g. monocyte-derived
dendritic cells) that will present tumor-specific neoantigens to stimulate the
lymphocytes. All cells used in the protocol will be isolated from the apheresis
product or a 200 ml blood sample of a patient.

The blood sample taken at the screening phase of the study and the 10 ml blood
sample that will be taken at the start of the study will be combined with a
treatment-related blood draw whenever possible and should therefore not lead to
an extra burden for the patient. The 15 liter apheresis procedure is expected
to take around 2-3 hours and may cause some discomfort when inserting the
required lines. The apheresis procedure is not associated with any safety
concerns, but patients may experience some discomfort such as a dry mouth due
to a low level of citrate in their blood after the procedure. When a tumor
biopsy is taken during a routine investigation or therapeutic/palliative
surgery, this will not cause any extra burden to the patient as these
procedures were already planned as part of the treatment. When a tumor biopsy
is taken solely for the purpose of this study, this is expected to take around
30 min of the patient*s time. Patients may experience discomfort due to the
biopsy (i.e. bruising or pain) and there is a small chance of complications
(i.e. infection and/or bleeding). Therefore, biopsies will be taken only from
sites that are safely accessible. Standard procedures will be followed in case
complications occur, to assure the safety of the patient.

Protocol development is done using healthy donor material as much as possible.
However, this study can only be performed in the described study population as
the protocol will need to be confirmed to work in patient samples. In addition,
the results obtained with patient material will be required as part of the
clinical trial application to demonstrate feasibility and safety of the
procedure.