Inclusion Criteria:
- - All the criteria listed in the following need to be met before patient inclusion.
1. Histologically confirmed inoperable or metastatic melanoma (stage IIIc or IV).
2. Progressive disease after standard treatment with PD-1 check-point inhibition or
combination of aforementioned with CTLA-4 check-point inhibition.
3. Age: 18
- - 75 years at time of signed Informed consent.
4. ECOG performance status of ≤ 1 (Appendix 2).
5. Is fit for tumor resection and has at least one lesion (> 1 cm3) available for
surgical resection for manufacture of TIL.
6. At least one measurable parameter in accordance with RECIST 1.1 -criteria
(excluding lesion to be resected).
7. LVEF assessment with documented LVEF ≥50% by either TTE (transthoracic
echocardiography) or MUGA (multigated acquisition scan).
8. Sufficient organ function, including:
- - Absolute neutrophil count (ANC) ≥ 1.500 /µl.
- - Leucocyte count ≥ lower normal limit.
- - Platelets ≥ 100.000 /µl and <700.000 /µl.
- - Hemoglobin ≥ 6.0 mmol/l.
- - eGFR > 70 ml/min*
- S-bilirubin ≤ 1.5 times upper normal limit (Exception: Subjects with liver
metastasis ≤ 2.5 × ULN)
- ASAT/ALAT ≤ 2.5 times upper normal limit (Exception: Subjects with liver
metastasis ≤ 5.0 × ULN)
- Alkaline phosphatase ≤ 5 times upper normal limit.
- - Lactate dehydrogenase ≤ 5 times upper normal limit.
- - Sufficient coagulation: APPT<40 and INR<1.5.
- - * In selected cases it can be decided to include a patient with an eGFR < 70 ml/min
with the use of a reduced dose of chemotherapy.
9. Signed statement of consent after receiving oral and written study information 10.
Willingness to participate in the planned controls and capable of handling toxicities.
11. Subject must receive T-cell therapy as the next therapy following tumor resection,
unless bridging therapy is administered:
- - Bridging therapy is discouraged.
However, if in the opinion of the Investigator,
the subject requires immediate therapy after tumor resection, the subject may
receive bridging therapy for the period during which the subject is awaiting the
manufacture of TIL-infusion product. Bridging therapy may be a continuation of
the therapy the subject was receiving prior to tumor resection or may be a new
therapy.
- - Following this bridging therapy, the subject must adhere to the mandatory washout
periods (exclusion criterion 1) and must continue to have measurable disease
prior to receiving T-cell therapy.
12. Age and Reproductive Status:
- - Women of childbearing potential (WOCBP) must have a negative urine or serum
pregnancy test AND must agree to use an effective method of contraception
starting at the first dose of chemotherapy for at least 12 months.
WOCBP must
also agree to refrain from egg donation, storage, or banking during these same
time periods. The following are considered safe methods of contraception:
- - Hormonal anticonception (birth control pills, spiral, depot injection with gestagen,
subdermal implantation, hormonal vaginal ring and transdermal depot patch)
- Intrauterine device.
- - Surgical sterilization.
- - Surgical sterilization of male partner with verification of no sperm after the
procedure.
- - Menopause (for more than 12 months) o Male subjects must be surgically sterile or
agree to use a double-barrier contraception method or abstain from sexual activity
with an WOCBP starting at the first dose of chemotherapy and for 6 months thereafter.
Male subjects must also agree to refrain from sperm donation, storage, or banking.
Exclusion Criteria:
- - Patients will be excluded if they meet one of the criteria's listed below.
1. Subject has received or plans to receive the following therapy/treatment prior to
tumor resection (TR) or lymphodepleting chemotherapy (LDC):
- - Cytotoxic chemotherapy: Washout period 3 weeks before TR and LDC.
- - Small molecules/TKI: Washout period 1 week before TR and LDC.
- - Immune therapy (monoclonal AB therapy, CPI and biologics): 2 weeks before TR
and LDC.
- - Prior T-cell therapy, including gene therapy using an integrating vector.
- - Corticosteroids at dose equivalent > 10 mg prednisone or any other
immunosuppressive therapy.
2 weeks before TR and LDC. Note: Use of topical
steroids is not an exclusion.
- - Investigational treatment: 4 weeks or 5 half-lives, whichever is shorter
before TR and LDC.
- - Radiation to the pelvis and/or multiple bones containing ≥ 25% of bone
marrow: 4 weeks before TR and LDC.
- - Whole brain radiotherapy or brain stereotactic radiosurgery: 4 weeks before
TR and LDC.
- - Radiotherapy to the target lesions: 3 months prior to TIL-infusion.
A lesion
with unequivocal progression post-radiotherapy may be considered a target
lesion.
2. A history of prior malignancies. Patients treated for another malignancy can
participate if they are without signs of disease for a minimum of 2 years after
treatment. Subjects with curatively treated ductal carcinoma in situ (DCIS or
LCIS) breast cancer for which they are taking hormonal therapy is acceptable.
Resectable squamous or basal cell carcinoma of the skin is acceptable.
3. Patients with metastatic ocular/mucosal or other non-cutaneous melanoma. Unknown
primary melanoma is eligible.
4. Toxicity from previous anti-cancer therapy must have resolved to ≤ Grade 1 or
baseline prior to enrollment (except for non-clinically significant toxicities
e.g., alopecia, vitiligo).
Subjects with Grade 2 toxicities who are deemed stable or irreversible (e.g.,
peripheral neuropathy) can be enrolled.
5. Patients who have more than 2 CNS metastases or who have any CNS lesion that is
symptomatic, greater than 1 cm in diameter or show significant surrounding edema
on MRI scan will not be eligible until they have been treated and demonstrated no
clincal or radiologic CNS progression for at least 2 months.
6. The following patients will be excluded because of inability to receive high dose
interleukin-2:
- - History of coronary revascularization.
- - Patients with clinically significant atrial and/or ventricular arrhythmias
including but not limited to: atrial fibrillation, ventricular tachycardia,
2o or 3o heart block.
- - Documented FEV-1 less than or equal to 60% predicted value for patients
with: A prolonged history of cigarette smoking (greater than 20 pack years),
large tumor burden in the lungs or Symptoms of respiratory distress.
7. Known hypersensitivity to one of the active drugs or one or more of the
excipients.
8. Severe medical conditions, such as severe asthma/COLD, significant cardiac
disease, poorly regulated insulin dependent diabetes mellitus among others.
9. Acute/chronic infection with HIV, hepatitis, syphilis among others.
10. Severe allergies or previous anaphylactic reactions.
11. Active autoimmune or immune-mediated disease that has not yet resolved. Subjects
with the following will be eligible:
- - Immune-mediated AEs secondary to immunotherapy which has resolved to ≤ Grade
1 off steroids;
- Hypothyroidism, Type I diabetes, adrenal insufficiency, or pituitary
insufficiency that are stable on replacement therapy;
- Disorders such as asthma, vitiligo, psoriasis, or atopic dermatitis that are
well controlled without requiring systemic immunosuppression;
- Other stable immune conditions that do not require prednisone higher than 10
mg/day or their equivalent dose for other corticosteroid agents may be
acceptable with the agreement of the Sponsor.
12. Pregnant women and women breastfeeding.
13. Subject who, in the opinion of the Investigator, will be unlikely to fully comply
with protocol requirements.
