| Eligibility |
Inclusion Criteria:
1. Patients with locally advanced (not radically treatable) or metastatic solid tumors
with the below cancer types, who progressed after at least one standard therapy for
advanced disease, or for whom such therapy was proven to be intolerable, or is
considered inappropriate. Prior immunotherapy is allowed.
1. Breast cancer: irrespective of hormone receptor, Human epidermal growth factor
receptor 2 (HER2) status or molecular subtype.
2. Non-small cell lung cancer (NSCLC): irrespective of histological or molecular
subtypes.
3. Ovarian cancer: patients with high-grade serous ovarian cancer (HGSOC).
4. Colon cancer: irrespective of molecular subtype.
5. Other solid tumor: Patients with any other histology (any molecular subtype) with
the exception of primary brain tumors, as well as cutaneous, mucosal, and
ocular/uveal melanoma.
2. Patients who have previously undergone tumor resection or biopsy and for whom pre-REP
TILs are already available and adequate for further REP expansion. The following
conditions have to be met:
a. The Manufacturing facility / sponsor representative confirms that adequate pre-REP
material (in quantity and quality) is available to move to REP.
3. At least one lesion accessible to biopsy for translational research (TR) at baseline
and D30, without putting the patient at unusual risk. Every effort should be made to
obtain a fresh tumor biopsy upon enrolment, if previous collection of tissue is judged
insufficient for study translational endpoints. The following exceptions are accepted
for the baseline biopsy:
a. Tumor material was properly collected for all protocol translational endpoints
during harvesting surgery or biopsy for the TIL production (pre-REP) and no
intercurrent anticancer therapy has been administered since that surgery or last
biopsy. If patient has been treated with any antitumor therapy that may have altered
the tumor microenvironment at the estimation of the PI, a repeat biopsy should be
performed.
4. Male or female age = 18 to = 70 years at the time of informed consent. Patients aged
>70 will be evaluated by the investigator, and decision will be made according to
patient's status, upon agreement with the PI.
5. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) of 0 to 2.
6. Life expectancy of greater than 12 weeks.
7. Radiologically measurable disease (as per RECIST v1.1).
1. Modified RECIST should be used for mesothelioma.
2. Prostate Cancer Working Group 3 (PCWG3) criteria should be used for prostate
cancer
8. Patients with brain metastases are eligible after discussion and agreement with the
PI, provided there are no more than 3 residual metastases, that all metastases have
been treated with stereotactic radiation therapy or gamma knife therapy and are
asymptomatic. Lesions should be stable for at least 1 month, as determined by CT or
MRI evaluation after treatment and should not require steroids.
Note: Patients presenting between three and five treated and inactive brain metastases
can be considered for enrollment, after discussion and agreement with the PI.
9. Adequate viral serology defined by the following laboratory results obtained during
screening period (within 17 days prior registration).
1. Seronegative for HIV infection (anti-HIV-1/-2)
2. Seronegative for hepatitis B infection (HBsAg, total anti-hepatitis B core
antigen (HBc), anti-HBs). Exception is made in case of prior vaccination.
Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen HBsAg test and a positive anti-HBc antibody
test) are eligible, if Hepatitis B virus (HBV) DNA test is negative.
3. Seronegative for hepatitis C infection (anti-HCV): if a patient has positive
anti-HCV antibody, a negative HCV RNA need to be obtained to register the
patient.
10. Hematology
1. Absolute neutrophil count = 1.0 x 10^9 cell/L without the support of granulocyte
colony stimulating factor (G-CSF).
2. Platelet count = 100 x10 ^9 cell/L
3. Hemoglobin = 80 g/L. Subjects may be transfused to reach this cut-off.
11. Coagulation
a. International normalization ratio (INR) =1.5 times the upper limit of normal (x
ULN) unless the subject is receiving anticoagulant therapy as long as INR/PT and
partial thromboplastin time (PTT) is within therapeutic range of intended use of
anticoagulants.
i) Exception: for patients with hepatocellular carcinoma (HCC), the INR may be up to
2.2, as long as the Child-Pugh score is A6 maximum.
b. PTT or activated partial thromboplastin time (aPTT) = 1.5 x ULN unless the subject
is receiving anticoagulant therapy as long as INR/PT and PTT/aPTT is within
therapeutic range of intended use of anticoagulants.
12. Chemistry:
1. Serum Alanine transaminase (ALT)/Aspartate aminotransferase (AST) = to 3 x ULN i)
Exception: ALT/AST considered related to liver metastasis = to 5 x ULN ii)
Exception: for patients with HCC serum ALT/AST = to 5 x ULN
2. Total bilirubin =1.5 x ULN i) Exception: in patients with Gilbert's syndrome who
must have a total bilirubin =2.5 x ULN ii) Exception: total bilirubin considered
related to liver metastasis =3 x ULN iii) Exception: for patients with HCC total
bilirubin =2.3 x ULN, as long as the Child-Pugh score is A6 maximum
3. Creatinine clearance by Cockcroft-Gault formula = 40 ml/min
13. Adequate cardiovascular function, with documented left ventricular ejection fraction
(LVEF) = 45%. This parameter must be documented within 12 weeks before registration
14. Adequate respiratory function with forced expiratory volume in 1 second (FEV1) = 50%
predicted, forced vital capacity (FVC) = than 50% predicted and diffusing capacity of
lung for carbon monoxide (DLCO) = than 50% predicted corrected. Patients with lung
cancer or mesothelioma and values slightly under these limits (but >30% of predicted)
can be enrolled after discussion and approval by the trial chair. These parameters
must be documented within 12 weeks before registration
15. At the time the patient receives the NMA chemotherapy regimen (D-7):
1. =28 days must have elapsed from any chemotherapeutic cytotoxic drug
2. =28 days must have elapsed from bevacizumab, aflibercept and other
anti-angiogenic antibodies
3. =28 days or 5 half-lives (whichever is shorter) must have elapsed from a
non-cytotoxic drug including but not limited to trastuzumab, pertuzumab, and
other molecular targeted therapy (such as tyrosine kinase inhibitors), etc… i)
Note: In case of probable tumor flare upon stopping of the non-cytotoxic drug,
the investigator may decide to shorten this delay, upon agreement of the trial
chair, in a case-by-case approach.
4. =21 days must have elapsed from the last antibody therapy that could affect an
anti-cancer immune response, including but not limited to anti-CTLA4,
anti-Programmed cell death protein 1 (PD-1)), anti-Programmed death-ligand 1
(PD-L1), anti-Tumor Necrosis Factor Receptor Superfamily, member 4 (OX-40), or
anti-Lymphocyte-activation gene 3 (LAG3) antibody therapy or their combination
5. Exceptions: denosumab and biphosphonates are permitted
6. Exceptions: androgen-deprivation therapy (ADT) for prostate cancer and hormonal
therapy for breast cancer are permitted (and will be administered as SOC).
16. Patients' toxicities from previous therapies must have recovered to at least grade 1
according to NCI CTCAE v5.0, except for toxicities described below, as long as they do
not put at risk the patient's condition and do not require systemic immunosuppressive
steroids at immunosuppressive doses, including but not limited to:
- Fatigue
- Alopecia
- Skin disorders
- Stable neuropathy
- Endocrinopathies requiring replacement treatment Note: For other medical
conditions, or for any other toxicity with a higher grade but controlled by
adequate treatment, prior discussion and agreement with the trial chair is
mandatory.
Note: Patients may have undergone surgical procedures within the past 3 weeks, as long
as all toxicities have recovered to grade 1 or less.
17. For women of childbearing potential (WOCBP: sexually mature women who have not
undergone a hysterectomy and/or bilateral oophorectomy, have not been naturally
post-menopausal for at least 12 consecutive months or have a serum
follicle-stimulating hormone (FSH) < 40 milli-international units per milliliter
(mIU/ml):
1. Agreement to follow instructions for method(s) of contraception for the couple
from screening until month 6 post start of NMA chemotherapy of the study.
2. Negative pregnancy test (urine or serum) during screening.
18. For men participating in the trial and their female partners: agreement to follow
instructions for method(s) of contraception for the couple from screening until month
6 post start of NMA chemotherapy of the study.
Exclusion Criteria:
1. Patients with an active second malignancy, except for
1. non-melanoma skin cancer that has been apparently cured or successfully resected
2. carcinoma in situ as long as they have been adequately treated
3. Any malignancy that can be adequately managed expectantly without compromising
prognosis, and after PI agreement..
Patients who have a history of malignancy are not considered to have an active
malignancy if they have completed therapy since at least 2 years and are considered by
their treating investigator to be at = 30% risk for relapse.
2. Patients with known peritoneal metastases who have a recent history of intermittent
bowel obstruction (even partial), unless such obstruction has been resolved. Agreement
with the Trial Chair is mandatory.
3. Patients with leptomeningeal carcinomatosis
4. History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any
origin)
5. History of recent myocardial infarction or unstable angina, either within six months
of enrolment
6. Documented Child-Pugh score of B or C for hepatocellular carcinoma patients with known
underlying liver dysfunction
7. Active severe systemic infections within four weeks prior to beginning of NMA
chemotherapy.
8. Patient requiring regular systemic immunosuppressive therapy (for example for organ
transplantation, chronic rheumatologic disease); all immunosuppressive medications
including but not limited to steroids, mycophenolate mofetil, azathioprine,
methotrexate, thalidomide, and anti-tumor necrosis factor (TNF)-alpha agents must have
been discontinued within the last two weeks prior to starting NMA chemotherapy.
1. Note: Use of inhaled or topical steroids or corticosteroid use for radiographic
procedures is permitted
2. Note: The use of physiologic corticosteroid replacement therapy is permitted.
9. History of severe immediate hypersensitivity reaction to any of the agents used in
this study.
10. History of immediate hypersensitivity reaction to aminoglycosides (e.g. gentamicin or
streptomycin).
11. Women who are pregnant or breastfeeding because of the potentially dangerous effects
of the treatment on the fetus or infant.
12. Subjects for whom there are concerns that they will not reliably comply with the
requirements for contraception should not be enrolled into the study.
13. Any serious underlying medical condition that could interfere with study medication
and potential adverse events.
14. Any mental or other impairment that may compromise compliance with the requirements of
the study.
15. Patient participation in any other study currently receiving treatment. If the patient
is in the follow-up period, he/she may be enrolled, as far as the elapsed time since
the last previous treatment administration and the preparative regimen (NMA
chemotherapy) is respected according to Inclusion Criteria n°15).
16. Participation in a research project using radiation sources exceeding an effective
dose of 5 millisievert (mSv) with no direct benefit within the 12 last months.
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