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About
The purpose of this study is to assess wether it is safe and feasible to treat patients with tumor infiltrating lymphocytes that have been silenced for PD-1, using CRISPR-Cas9.
Full description
In this study the investigators will treat patients with advanced (inoperable) or metastatic melanoma with tumor infiltrating lymphocytes (TILs) in combination with lymphodepleting chemotherapy and high-dose interleukin-2. The TILs are harvested from a patient tumor and expanded a thousand-fold in a laboratory over approximately 6 weeks before being infused back into the patient. This is a well known and tried treatment regimen, often called TIL-therapy or TIL-ACT. In this study the investigators will add CRISPR-Cas9 modification to the production process of the TILs to silence the expression of PD-1 on the surface of the infused cells. The aim of this study is to demonstrate wether treatment with these PD1-deficient TILs (CRISPR-TILs) is safe and feasible.
Enrollment
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Volunteers
Inclusion criteria
Histologically confirmed inoperable or metastatic melanoma (stage IIIc or IV).
Progressive disease after standard treatment with anti-PD-1 check-point inhibition or combination of aforementioned with anti-CTLA-4 check-point inhibition.
Age: 18 - 75 years at the time of signed Informed consent.
ECOG performance status of ≤1 (Appendix 2).
Is fit for tumor resection and has at least one lesion (> 1 cm3) available for surgical resection for manufacture of TIL. (Unless TILs are already available through metastasectomy prior to enrollment in this study, as described in step one under study design)
At least one measurable parameter in accordance with RECIST 1.1 -criteria (excluding the lesion to be resected).
LVEF assessment with documented LVEF ≥50% by either TTE or MUGA.
Sufficient organ function, including:
Signed statement of consent after receiving oral and written study information
Willingness to participate in the planned controls and capable of handling toxicities.
Subject must receive CRISPR-TIL as the next therapy following tumor resection unless bridging therapy is administered:
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. WOCB must also agree to refrain from egg donation, storage, or banking during these same time periods. The following are considered safe methods of contraception:
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
Subject has received or plans to receive the following therapy/treatment prior to tumor resection (TR) or lymphodepleting chemotherapy (LDC):
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.
Patients with metastatic ocular/mucosal or other non-cutaneous melanoma. Unknown primary melanoma is eligible.
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.
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 clinical or radiologic CNS progression for at least 2 months.
The following patients will be excluded because of their inability to receive high-dose interleukin-2 (See appendix 5):
Known hypersensitivity to one of the active drugs or one or more of the excipients.
Severe medical conditions, such as severe asthma/COLD, significant cardiac disease, and poorly regulated insulin-dependent diabetes mellitus among others.
Creatinine clearance (eGFR) < 70 ml/min*.
Acute/chronic infection with HIV, hepatitis, and syphilis among others.
Severe allergies or previous anaphylactic reactions.
Active autoimmune or immune-mediated disease that has not yet resolved. Subjects with the following will be eligible:
Pregnant women and women breastfeeding.
Subjects deemed unlikely to fully comply with protocol requirements by the study investigator.
Primary purpose
Allocation
Interventional model
Masking
10 participants in 1 patient group
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Central trial contact
Inge Marie Svane, MD, phd, prof; Joel E Sohlin, MD
Data sourced from clinicaltrials.gov
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