Adoptive TIL therapy plus anti-PD1 in metastatic melanoma

Patients with unresectable stage III/IV melanoma have an extremely poor
prognosis with a median survival of 6-9 months. Despite development of new
drugs and treatment options, further improvement is still necessary. Recently,
we published the results of our clinical study in metastatic melanoma patients
that were treated by adoptive T-cell transfer (ACT) in combination with low
dose interferon-alpha. The treatment was safe and five out of ten treated
patients showed clinical benefit.
We previously showed that the majority of the T cells used for adoptive
transfer were PD-1 positive. By blocking the interaction of PD-1 and PD-L1 or
PD-L2 using the anti-PD-1 antibody nivolumab, the anti-tumor reactivity of T
cells can be strongly enhanced. We propose to enhance the clinical benefit of
ACT by combining it with nivolumab since this will enhance the
tumor-reactivity of both naturally occurring tumor infiltrated as well as
adoptively transferred T cells. Importantly, clinical efficacy of anti-PD1 in
ipilimumab-refractory stage IV melanoma patients has been reported, indicating
that these checkpoint-blocking antibodies may unleash a different set of
tumor-reactive T cells and that ipilimumab-refractory patients may benefit from
subsequent ACT plus nivolumab treatment.

1. The primary objective of this phase I/II clinical trial is to evaluate the
safety and toxicity of ACT plus nivolumab according to CTCAE 4.0 criteria.
Toxicity grade 3 or less and SAE related to treatment but that does not result
in treatment termination are considered acceptable for continuation of the
study.
2. Secondary objectives include the evaluation of the clinical response
according to RECIST 1.1 criteria and immune related response criteria (irRC)
and overall survival (OS). Clinical benefit is defined as Stable Disease (SD),
Partial Response (PR), or Complete response (CR).

Furthermore, immune related parameters will be analyzed in patient*s tumor
material, blood and serum and in the TILs used for infusion and correlations
with clinical response will be evaluated.

This is a phase I/II clinical trial.

A metastatic lesion will be removed and used to culture tumor-infiltrating T
cells and if possible an autologous tumor cell line. Seven days before the
first T cell infusion the patients will start with injections of IFN-alpha that
will be continued for twelve weeks in total. T cells will be administered as
three consecutive infusions with a three week interval. If the patient does nog
have progressive disease upon evaluation after the first cycle of three T cell
infusions a second cycle of T cell infusions plus interferon-alpha will be
administered just like the first cycle.
Four weeks before the start of the first T cell infusion the patient will start
with anti-PD1 (nivolumab) treatment every two weeks, this will be continued
throughout and between the cycles. If the patient has clinical benefit,
nivolumab treatment can be continued for up to two years.

The patients will be operated to obtain metastatic melanoma tissue that will be
used to culture tumor infiltrating T cells. Before start of therapy 75ml of
blood will be drawn for further analysis of immune parameters.
If enough tumor reactive T cells are obtained the actual treatment of the
patients wil consist of three infusions of T cells given with a three week
interval. Daily IFN-alpha injections will be initiated one week before the
first infusion and continued for a total of twelve weeks. Peripheral venous
blood will be drawn at several time points before (75 ml) and after (50 ml
each) T cell infusions to monitor the immunological response and to evaluate
chemical an hematological parameters. For the first T cell infusion patients
will be hospitalized for 24 hours in order to carefully monitor vital functions
following T cell transfer. If the first infusion of T cells is well tolerated
without any SAE, administration of the following T cells does not require
hospitalization but day care will be sufficient.
T cell infusions may induce melanoma associated auto-immune disease such as
vitiligo and uveitis, which can be managed adequately with topical
corticosteroid treatment.
Side-effects of nivolumab are largely known from clinical trials and clinical
practice. Treatment-associated side effects of higher grade according to the
common terminology criteria for adverse events are relatively rare. However,
new immune-mediated side effects can occur and can affect the skin, liver
(hepatitis), kidneys (nephritis), gastrointestinal tract (diarrhea and
colitis), lungs (pneumonitis) and endocrine organs (hyperthyroidism,
hypothyroidism and hypophysitis).
Despite recent developments with respect to new treatment options including
BRAF inhibitors (vemurafenib) and anti-CTLA4 or PD-1 antibodies (ipilimumab,
nivolumab), patients with metastatic melanoma still have a poor prognosis and
adoptive T cell therapy has been shown to be a good treatment option, resulting
in response rates up to 50%. More importantly, the obtained responses after ACT
are durable and side effects and treatment burden are limited. Experience with
TIL infusion studies, performed in three independent centers abroad (NIH,
Bethesda, USA, Sheba Hospital, Israel) and Herlev Hospital, Copenhagen,
Denmark) and at the NKI, Amsterdam, shows that the risks related to treatment
are very low. The majority of the reported adverse events are attributed to the
extensive conditioning regimen and/or high dose IL-2 applied in these
protocols. These conditioning or additional treatments are not applied in our
protocol which further enhances the safety and low risk of the treatment.
Toxicities attributable to melanoma-reactive T cells may result from reactivity
against target antigens present on non-malignant melanocytes and other
non-malignant cells. Indeed, melanocyte destruction after ACT has been reported
to result in vitiligo. The risk that additional antigens expressed on normal
cells are targeted is very low, since we showed that generated
melanoma-reactive T cells mainly recognized autologous tumor cells and not
partially HLA-matched allogenic melanoma cell lines, indicating that the
majority of T cells recognize private melanoma associated antigens.
Furthermore, toxicities related to treatment with T cells that lyse off-target
tissue has not been observed in our phase I/II trial and is also not reported
thus far in patients treated in the US, Israel and Denmark.