T-cell Therapy with CRISPR PD1-edited Tumor Infiltrating Lymphocytes for Patients with Metastatic Melanoma

NCT06783270 | Recruiting Phase 1

• 2 other identifiers: MM23182023-510417-25-01
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Melanoma Metastatic

Keywords

TIL-therapy; TIL-ACT

Outcome Measures

Primary Outcomes (2)

• Feasibility

  Assess feasibility measured by the number of subjects who undergo surgery and successfully undergo CRISPR-TIL infusion

  From surgery to CRISPR-TIL infusion (5-10 weeks)

• Incidence rate of treatment-emergent adverse events

  Determine the safety and tolerability measured by the incidence rate of grade 3 treatment-emergent adverse events and serious adverse events by severity and their relationship to the CRISPR-TIL infusion.

  From admission to 2nd evaluation (3 months after CRISPR-TIL infusion)

Secondary Outcomes (1)

• Objective response rate

  From treatment until the 12 months evaluation scan.

Study Arms (1)

Autologous CRISPR-PD1 modified tumor infiltrating lymphocytes

EXPERIMENTAL

Tumor infiltrating lymphocytes expanded ex vivo from an excised tumor and treated with CRISPR-Cas9 to effectively silence the PD-1 coding gene in the T-cells. This is given as an intravenous infusion after lymphodepleting chemotherapy using cyclophosphamide and fludarabine-phosphate and followed by up to 6 doses of high-dose interleukin-2 infusions.

Biological: TIL therapy

Interventions

TIL therapy BIOLOGICAL

Compared to traditional TIL-therapy, this study will include silencing of the PD-1 coding gene in the TILs using non-viral CRISPR-Cas9 prior to the rapid expansion protocol.

Autologous CRISPR-PD1 modified tumor infiltrating lymphocytes

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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
• 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)

You may not qualify if:

• 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.
• 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.
• 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):
• History of coronary revascularization

Sponsors & Collaborators

• Inge Marie Svane: lead

Study Sites (1)

CCIT-DK

Herlev, Capital Region, 2730, Denmark

RECRUITING

Related Publications (1)

• Chamberlain CA, Bennett EP, Kverneland AH, Svane IM, Donia M, Met O. Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy. Mol Ther Oncolytics. 2022 Jan 10;24:417-428. doi: 10.1016/j.omto.2022.01.004. eCollection 2022 Mar 17.

  PMID: 35141398 BACKGROUND

Related Links

• CTIS registration

Central Study Contacts

Joel E Sohlin, MD

CONTACT

+4538689198; joel.emanuel.sohlin@regionh.dk

Inge Marie Svane, MD, phd, prof

CONTACT

+4538682131; inge.marie.svane@regionh.dk

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, professor, center leader

Study Record Dates

• First Submitted: December 13, 2024
• First Posted: January 20, 2025
• Study Start: December 16, 2024
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: January 20, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)