Multicenter phase I/IIa study using T-cell receptor gene therapy in metastatic melanoma

Prior preclinical and clinical studies have provided proof for a beneficial
effect of T lymphocytes in melanoma and other tumor types. Preclinical mouse
models have shown that tumor reactivity can be endowed on non-reactive T cells
by the transfer of T cell receptor (TCR) genes. Three phase I studies, using
TCRs specific for melanoma antigens, have shown persistence of gene modified
cells and a moderate clinical effect.
In this phase I/IIa study we will investigate the safety and efficacy of TCR
gene therapy in patients with advanced (uveal) melanoma.

To study the safety of the adoptive transfer of autologous T cells modified
with a Mart-1 specific TCR in advanced stage (uveal) melanoma patients with
disease progression upon standard cancer therapy. In addition, the toxicity
according to CTC version 4.0 and response rate according to RECIST 1.1 will be
documented.
To study the efficacy of this treatment strategy in inducing tumor-specific T
cell immunity as measured by the presence of Mart-1 specific T cells in
peripheral blood samples on several time points following adoptive transfer.
To study the objective response rate in this patient population.
To study whether the infusion of MART-1 specific TCR (1D3 HMCys) transduced T
cells will lead to systemic release of inflammatory cytokines.
To study the progression-free survival and overall survival.

HLA-A2 positive patients will undergo leukapheresis to obtain T cells for
transduction with a Mart-1 specific TCR (1D3 HM Cys). Patients will receive a
non-myeloablative lymphocyte-depleting preparative regimen consisting of
cyclophosphamide (30 mg/kg/day x 2 days i.v.) and fludarabine (25 mg/m2/day IV
x 5 days). Following this regimen, patients will receive an intravenous
adoptive transfer of a maximum of 2.5 x 10^10 transduced T cells.
Supportive care consisting of blood or platelet transfusions is given until
spontaneous hematopoietic recovery occurs. A complete assessment of evaluable
lesions will be conducted 4 weeks after cell infusion and periodically after
that to obtain best objective response by RECIST.
At the first time point of documented response and/or at time of (proven)
progression after treatment additional tumor biopsies will be taken for HLA
expression and melanoma antigens expression.
Besides safety and efficacy, special focus will be on logistics and timing:
planning of leukapheresis, admission to the hospital for start of chemotherapy,
timing of transduced T cell infusion, and release from hospital.

Eligible patients will undergo leukapheresis to isolate autologous T cells.
These T cells will be transduced with a retroviral vector encoding the 1D3 HM
Cys TCR, and subsequently expanded during short-term ex vivo culture. Upon
pre-treatment with nonmyeloablative chemotherapy, patients will receive the
adoptive transfer of autologous, TCR transduced T cells.

Patients with metastatic (stage IIIc-IV) melanoma have an extremely poor
prognosis with a median survival of 9 months. In the past 30 years little if
any improvement in survival has been reached despite the development of many
new drugs and/or treatment options. Recently, however, two new drugs have been
approved by the FDA for the treatment of metastatic melanoma based on survival
benefit. Vemurafenib, an oral mutated BRAF inhibitor induces a response rate in
about 50% of patients. Unfortunately, the median duration of this response is
between 5-6 months. Eventually, all tumors will become resistant to
vemurafenib. Ipilimumab, a fully human monoclonal antibody is directed against
CTLA4 on activated T-lymphocytes, has shown to augment melanoma-specific
immunity. Ipilimumab induces objective responses in 10% of patients. However,
at two years and beyond about 20% of patients are still alive. Despite these
important new developments, there is still lots of room for improvement of the
treatment of stage IIIc-IV melanoma patients.
Adoptive transfer of TCR gene modified cells is a promising new treatment
modality and an effective strategy to create a large pool of tumor reactive T
cells and has shown clinical responses in three recent trials (13-45%).
Although this treatment and toxicity has been demonstrated to be well
manageable, common toxicities from non-myeloablative chemotherapy (transient
bone marrow suppression requiring red cell and platelet support, increased
chance of bacterial, viral and fungal infections, requiring antibiotics) may or
will occur. Due to the infusion of Mart-1 specific T cells, patients may
develop signs of melanoma associated autoimmune diseases such as vitiligo,
hearing loss and uveitis. The latter two, which are the more serious side
effects, have been shown to respond promptly to local corticosteroid treatment.
However, the fact that these patients may have a substantial chance of durable
objective responses, which otherwise would not occur, justifies for the burden
and possible toxicities.