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. In this
study we will be treating patients who already progressed on the standard
treatment lines.
In 2011 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. After this pilot study we treated 22
patients, who were more heavily pre-treated with immunomodulating therapies. In
total 6/22 patients showed clinical benefit. From the treatment of 32 patients
with interferon-alpha and T-cells we concluded that this combination is well
tolerated by our study population.


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-reactiveT cells and that
ipilimumab-refractory patients may benefit from subsequent ACT plus nivolumab
treatment.

To evaluate the safety and toxicity of ACT and low-dose IFN-alpha plus
nivolumab according to CTCAE 4.0 criteria. Toxicity grade 3 or less and SAE
related to treatment but that do not result in treatment termination are
considered acceptable for continuation of the study.

Secondary objectives include:
* To evaluate of the clinical response according to RECIST 1.1 criteria and
immune related response criteria (irRC), overall survival (OS),
progression-free survival (PFS) and quality of life. Clinical benefit is
defined as Stable Disease (SD), Partial Response (PR), or Complete Response
(CR).
* To study the potential working mechanisms of the different treatment compounds
* To establish a possible prognostic biomarker profile
* To perform immunomonitoring on the infusion product
* To analyse potential correlations between the clinical response and
hypothesis related immune parameters

The ACTME study is an investigator initiated, single center phase I/II clinical
trial for patients with progressive unresectable stage III or stage IV
melanoma.

Eligible patients will undergo surgery, to obtain material of a melanoma
metastasis. This material will be used to culture tumor infiltrating
lymphocytes (TIL) for the ACT. Before the start of nivolumab, imaging will be
performed (CT and/or MRI), to define target lesions according to RECIST 1.1.
Two weeks after surgery patients will start with an initial 2 cycles of
nivolumab 2-weekly. In the meanwhile the TILs will be cultured.
After an initial 14 days of culturing the obtained TILs will be expanded to
large numbers required for infusion using the so called rapid expansion
protocol. Once enough TILs have been cultured the patients will start with low
dose daily subcutaneous IFN-alpha injections (3 million IU/day) seven days
before the first TIL infusion and continue with IFN-alpha injections for a
total of eleven weeks. Three infusions of TILs will be administered
intravenously with an interval of three weeks. At the day of the first TIL
infusion the patients will also receive nivolumab, which will be continued
every 2 weeks until progressive or intolerable toxicity for up to two years. At
week 9 after the first cycle of three TIL infusions plus nivolumab, the tumor
response will be evaluated by CT and/or MRI and will be described according to
RECIST 1.1 and immune response criteria (irRC).
An additional cycle of TIL infusions in combination with IFN-alpha and
nivolumab will be administered after the first cycle of TIL infusions unless
disease progression or complete response is observed during the evaluation of
CT/MRI scans at week 9. In patients with a complete regression of all
metastases after one cycle of three TIL infusions, additional cycles of TIL
infusions are not considered necessary to remain the state of complete clinical
remission. After the first cycle of three TIL infusions, when possible, surgery
or a biopsy of another metastasis will be performed to culture more TIL and to
compare biological and immunological markers before and after treatment.

Eligible patients will undergo surgery to obtain a melanoma metastasis. Prior
to the start of nivolumab treatment imaging will be performed. The imaging
performed before nivolumab treatment is started will be used to define the
lesions at baseline. 75 ml of blood will be drawn before the start of nivolumab
and before the start of low-dose IFN-alpha. Two weeks after surgery patients
will start with nivolumab infusions and will receive 2 courses 2-weekly before
cultured TILs are given, three infusions 3-weekly.
During every visit for TIL infusion physical examination, vital signs, CBC
differential and blood chemistry will be performed and 50ml of blood will be
drawn.
During one cycle patients will have approximately 12 visits in the hospital, of
which only one requires hospitalisation for 24 hours. If the treatment results
in an initial clinical response/disease stabilization without indications of
SAE related to treatment, the purpose is to give one additional cycle of three
TIL infusions similar to the first cycle to obtain further clinical benefit.
Quality of life is already measured in this group of patients by the Dutch
Melanoma Treatment Registry as standard of care. We will analyse this data
without further burdening the patients.
Side effects of nivolumab are largely known from clinical trials and clinical
practice. Treatment-associated side effects of higher grade (grade 3 or 4)
according to the common terminology criteria for adverse events (CTCAE) are
relatively rare. However, new immune-mediated side effects can occur and affect
the skin, liver (hepatitis), kidneys (nephritis), gastrointestinal tract
(diarrhea and colitis), lungs (pneumonitis) and endocrine organs
(hyperthyroidism, hypothyroidism and hypophysitis).
TIL infusions may induce melanoma associated autoimmune diseases such as
vitiligo and uveitis. Uveitis can be managed adequately with topical
corticosteroid treatment, vitiligo in most cases is permanent but is related to
a better response to treatment.
Possible side effects of interferon-alpha include leucopenia, fever, chills,
myalgia, headache, diarrhea and alopecia. But as described by Verdegaal and
colleagues the treatment with the combination of tumor specific T cell and
low-dose interferon-alpha, similar to the dose used in our current study, is
well tolerated.
In our 32 patients treated with low-dose IFNa in combination with TIL, there
were no TIL related adverse events and five patients had an IFN-alpha induced
grade 3 leukopenia, which was transient and seemed to be related to a better
response.
As we mentioned previously in a personal communication with other investigators
combining ACT (with toxic lymphodepleting chemotherapy and IL-2) with anti-PD1,
the PI stated that they did not observe any toxicity that was substantially
different from either TIL therapy or PD1 antibody monotherapy.
We also contacted researchers in Pittsburgh, who investigated the combination
of anti-PD1 treatment and high-dose Peginterferon alpha, and concluded that
this combination was well tolerated with no dose limiting toxicities.

Patients with unresectable stage III or stage IV melanoma have a poor prognosis
with a median survival of 6-9 months without treatment. In our study we include
patients who failed on all regular treatment options, meaning their median
survival will be even less. The chance to obtain a further improvement in
clinical benefit in these patients, partially justifies for the burden and
possible toxicities.
Even though this study mainly focusses on safety and toxicity of a new
combination of treatments, nivolumab is already registered for the treatment of
metastatic melanoma and treatment with adoptive T-cell transfer and low-dose
IFN-alpha has shown promising results in our 32 treated patients. In our study
design we have tried to minimalize the extra burden for the patients, by
combining treatment dates and moments at which blood will be drawn.