Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy.
Christopher Aled Chamberlain, Eric Paul Bennett, Anders Handrup Kverneland...
https://pubmed.ncbi.nlm.nih.gov/35141398Actively Recruiting
Phase 1
Age: 18Years - 75Years
All Genders
ID06783270
T-cell Therapy with CRISPR PD1-edited Tumor Infiltrating Lymphocytes for Patients with Metastatic Melanoma
Led by Inge Marie Svane · Updated on 2025-01-20
10
Participants Needed
1
Research Sites
52 weeks
Total Duration
On this page
AI-Summary
What this Trial Is About
Researchers are investigating a new treatment for patients with advanced or metastatic melanoma, a type of skin cancer. This study evaluates whether it is safe and feasible to use tumor infiltrating lymphocytes (TILs) that have been genetically edited to silence the PD-1 gene using CRISPR-Cas9 technology. The goal is to see if these modified immune cells can be safely infused back into patients and how well this approach works compared to traditional TIL therapy. Participants will receive TILs harvested from their tumors, which are then expanded in the lab over about six weeks. These TILs are modified using CRISPR-Cas9 to silence PD-1 before being infused after lymphodepleting chemotherapy with cyclophosphamide and fludarabine-phosphate. Following infusion, patients may receive up to six doses of high-dose interleukin-2. This treatment is given intravenously and follows a well-known TIL therapy regimen with the added CRISPR modification. During the study, participants will undergo tumor removal surgery, lab processing of TILs, chemotherapy, and TIL infusion. Researchers will monitor safety and feasibility from surgery through infusion over 5 to 10 weeks, and then track treatment-related side effects for three months. They will also assess tumor response up to 12 months after treatment using scans. Participants will have regular evaluations to measure heart, organ function, and overall health, and will be followed until the study ends in 2028.
CONDITIONS
Brief Title
T-cell Therapy with CRISPR PD1-edited Tumor Infiltrating Lymphocytes for Patients with Metastatic Melanoma
Who Can Participate
Age: 18Years - 75Years
All Genders
Eligibility Criteria
You may qualify if you...
- Histologically confirmed inoperable or metastatic melanoma (stage IIIc or IV).
- Progressive disease after anti-PD-1 or combined anti-PD-1 and anti-CTLA-4 checkpoint inhibition treatment.
- Age between 18 and 75 years at consent.
- ECOG performance status of 1 or less.
- Fit for tumor resection with at least one lesion larger than 1 cm3 suitable for surgery or already available TILs.
- At least one measurable tumor according to RECIST 1.1 excluding lesion to be resected.
- Left ventricular ejection fraction (LVEF) of 50% or higher by echocardiogram or MUGA.
- Adequate organ function including ANC ≥ 1,500/μl, leucocyte count above lower normal limit, platelets 100,000–700,000/μl, hemoglobin ≥ 6.0 mmol/l, eGFR > 70, bilirubin ≤ 1.5× upper normal limit (up to 2.5× with liver metastasis), liver enzymes ≤ 2.5× upper normal limit (up to 5× with liver metastasis), alkaline phosphatase ≤ 5× upper normal limit, lactate dehydrogenase ≤ 5× upper normal limit, coagulation APPT < 40 and INR < 1.5.
- Signed informed consent.
- Willing and able to participate in planned controls and manage toxicities.
- CRISPR-TIL is the next therapy after tumor resection unless bridging therapy is given with required washout.
- Women of childbearing potential must have negative pregnancy test and agree to effective contraception; males must use double-barrier contraception or abstain.
You will not qualify if you...
- Recent cytotoxic chemotherapy, small molecule/tyrosine kinase inhibitors, immune therapy, prior T-cell or gene therapy, corticosteroids > 10 mg prednisone equivalent, investigational treatments, or radiation within specified washout periods before tumor resection or chemotherapy.
- Prior malignancies except certain treated cancers without disease for 2 years.
- Metastatic ocular/mucosal or non-cutaneous melanoma; unknown primary melanoma allowed.
- Unresolved toxicity above Grade 1 from previous cancer treatments except stable or irreversible Grade 2.
- More than 2 CNS metastases or symptomatic CNS lesions larger than 1 cm or with edema.
- Conditions preventing high-dose interleukin-2 including heart arrhythmias, LVEF < 45%, severe lung disease.
- Known allergies to study drugs or excipients.
- Severe medical conditions like severe asthma, cardiac disease, or poorly controlled diabetes.
- eGFR below 70 ml/min except with dose adjustment.
- Active infections including HIV, hepatitis, syphilis.
- Severe allergies or history of anaphylaxis.
- Active autoimmune or immune diseases not resolved except certain stable conditions.
- Pregnant or breastfeeding women.
- Unlikely to comply with study requirements.
AI-Screening
AI-Powered Screening
Complete this quick 3-step screening to check your eligibility
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Your Study Journey
Screening
Duration - 2 to 4 weeks
Participants are screened for eligibility to participate in the trial.
1 visit (in-person)
Run-in Period
Duration - 5 to 10 weeks
Tumor infiltrating lymphocytes (TILs) are harvested from the participant's tumor and expanded in the laboratory with CRISPR-Cas9 modification to silence PD-1 over approximately 5 to 10 weeks.
Multiple visits over the expansion period
Treatment
Duration - Approximately 2 weeks
Participants receive lymphodepleting chemotherapy followed by infusion of CRISPR-PD1 modified TILs and up to 6 doses of high-dose interleukin-2.
Several inpatient visits during chemotherapy, infusion, and interleukin-2 dosing
Follow-up
Duration - Up to 12 months
Participants are monitored for safety and response to treatment including evaluations up to 12 months after infusion.
Regular follow-up visits including a 3-month evaluation and 12-month evaluation scan
Trial Site Locations
Total: 1 location
1
CCIT-DK
Herlev, Capital Region, Denmark, 2730
Actively Recruiting
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Research Team
J
Joel E Sohlin, MD
I
Inge Marie Svane, MD, phd, prof
How is the study designed?
Study Type
INTERVENTIONAL
Masking
NONE
Allocation
NA
Model
SINGLE_GROUP
Primary Purpose
TREATMENT
Number of Arms
1
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