CISH Inactivated TILs in the Treatment of NSCLC

NCT05566223 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: 2022LC001
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 2

Brief Summary

A clinical trial to assess the safety and efficacy of genetically-engineered Tumor Infiltrating Lymphocytes (TIL) in which the intracellular immune checkpoint CISH has been inhibited using CRISPR gene editing for the treatment of Metastatic Non-small Cell Lung Cancer (NSCLC).

Conditions

Carcinoma, Non-Small-Cell Lung; Metastatic Non Small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Adenocarcinoma of Lung; Large Cell Lung Cancer

Keywords

PD-L1 negative; PD-L1 positive; Adoptive Cell Therapy; Immunotherapy; Gene Therapy; CISH Checkpoint; CRISPR; Gene Edit

Outcome Measures

Primary Outcomes (2)

• Phase I: Safety and Initial Efficacy

  Safety by type, incidence, severity, seriousness, and relation of study treatment of AEs, DLTs, and laboratory abnormalities. Initial efficacy per RECIST v1.1

  11 months

• Phase II: Objective Response Rate (ORR)

  RECIST v1.1

  3.5 years

Secondary Outcomes (6)

• Progression Free Survival (PFS)

  2-5 years

• Overall Survival (OS)

  2-5 years

• Duration of Response (DoR)

  2-5 years

• Clinical Benefit Rate

  2-5 years

• Tumor Growth Change

  2-5 years

Study Arms (4)

CISH CRISPR TIL / Phase I Arm

EXPERIMENTAL

Dose Escalation/Expansion Cohort Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +escalating doses of CISH inactivated TIL + high-dose aldesleukin

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: CISH Inactivated TIL; Drug: Aldesleukin

CISH CRISPR TIL plus pembrolizumab / Phase I Arm

EXPERIMENTAL

Dose Expansion with Maintenance Therapy Cohort Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +escalating doses of CISH inactivated TIL + high-dose aldesleukin Maintenance pembrolizumab during follow-up

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: CISH Inactivated TIL; Drug: Aldesleukin; Drug: Pembrolizumab

CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort

EXPERIMENTAL

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +recommended phase II dose (from phase I) of CISH inactivated TIL + high-dose aldesleukin May include maintenance pembrolizumab during follow-up

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: CISH Inactivated TIL; Drug: Aldesleukin; Drug: Pembrolizumab

CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort

EXPERIMENTAL

PD-L1 positive is defined as tumors with a PD-L1 Tumor Proportion Score (TPS) ≥ 1%. Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +recommended phase II dose (from phase I) of CISH inactivated TIL + high-dose aldesleukin May include maintenance pembrolizumab during follow-up

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: CISH Inactivated TIL; Drug: Aldesleukin; Drug: Pembrolizumab

Interventions

Cyclophosphamide DRUG

Day -6 and Day -5: Cyclophosphamide 60 mg/kg/dose as a 2 hour intravenous infusion with Mesna 15 mg/kg/dose, 1st dose prior to Cyclophosphamide infusion then at 3,6,9 and 12 hours later.

Also known as: Cytoxan

CISH CRISPR TIL / Phase I Arm; CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort; CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort; CISH CRISPR TIL plus pembrolizumab / Phase I Arm

CISH Inactivated TIL BIOLOGICAL

Day 0 : Each bag of autologous CISH inactivated TIL for infusion will be administered intravenously (IV) on the Patient Care Unit over 10-20 minutes at assigned dose level.

CISH CRISPR TIL / Phase I Arm; CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort; CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort; CISH CRISPR TIL plus pembrolizumab / Phase I Arm

Aldesleukin DRUG

Days 1-4 : Aldesleukin at 720,000 U/kg as an intravenous infusion, every 8 -12 hours but, no more than 24 hours apart as tolerated for up to 6 doses.

Also known as: Proleukin, Interleukin-2, IL-2

CISH CRISPR TIL / Phase I Arm; CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort; CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort; CISH CRISPR TIL plus pembrolizumab / Phase I Arm

Pembrolizumab DRUG

Administered as maintenance therapy in some patients starting at first follow-up (400 mg/dose starting Day 28 /Week 4 then every 6 weeks thereafter until disease progression, unacceptable toxicity, or up to 24 months)

Also known as: Keytruda

CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort; CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort; CISH CRISPR TIL plus pembrolizumab / Phase I Arm

Fludarabine DRUG

Day -7 to Day -3 : Fludarabine 25 mg/m\^2/dose as a 1 hour intravenous infusion per institutional guidelines once a day for 5 doses beginning on Day -7. Fludarabine will be started approximately 1 to 2 hours after the cyclophosphamide on Day -6 and Day -5.

Also known as: Fludara

CISH CRISPR TIL / Phase I Arm; CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort; CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort; CISH CRISPR TIL plus pembrolizumab / Phase I Arm

Eligibility Criteria

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

You may qualify if:

• Confirmed histologic diagnosis of either PD-L1 negative or positive metastatic non-small cell lung cancer (NSCLC)
• Candidate to receive 1st line treatment with anti-PD-1/anti-PD-L1 immunotherapy in combination with chemotherapy or be within 6 months (Phase 1) or 3 months (Phase 2) of initiation of this type of systemic treatment (regardless of where such treatment was started) when the tumor resection is performed. Patients who have received adjuvant or neoadjuvant anti-PD-1/anti-PD-L1 immunotherapy and/or chemotherapy can be screened for the trial if they experienced a relapse more than 6 months from the end of their last systemic treatment. The tumor resection for investigational product manufacturing should be undertaken before the initiation of this 1st line therapy; however, patients who have already started their 1st line treatment should have these procedures performed and completed as soon as deemed clinically appropriate, but no later than 6 months (Phase 1) or 3 months (Phase 2) from the start of 1st line treatment. After documented radiographic disease progression on or following this 1st line of treatment, patients will receive investigational product as 2nd line therapy.
• Measurable disease per RECIST v1.1 with at least one lesion identified as resectable for cell therapy manufacturing (minimum volume of tumor tissue required is 1 cm\^2 as single mass or fragments) and at least one other lesion meeting the RECIST criteria for measurable disease to serve as an indicator of disease response. The location of the tumor resection and method used to obtain tumor (i.e., laparoscopy, endoscopic ultrasound, etc.) will be determined based on an individual patient's disease. Note: previously irradiated lesions with radiographic progression are not eligible for tumor resection.
• Patients who have asymptomatic and or treated brain metastases are eligible, but must be discussed with and approved by the Coordinating Investigator. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible. Patients with brain metastases must not be receiving systemic steroids (oral progestin/estrogen combinations used for contraception are an exception). Brain metastases are assessed using the RANO-BM criteria.
• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 and an estimated life expectancy of ≥ 6 months.
• Age ≥ 18 years and ≤ 70 years.
• Hematology within 14 days of study enrollment:
• Absolute neutrophil count \> 1000/mm\^3 without the support of filgrastim
• White Blood Cells (WBC) ≥ 3000/mm\^3
• Platelet count ≥ 75,000/mm\^3
• Hemoglobin \> 8.0 g/dL. Subjects may be transfused to reach this cutoff.
• Adequate organ function within 14 days of study enrollment defined as:
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0 x upper limit of normal (ULN)
• Serum creatinine ≤ 1.6 mg/dL or creatinine clearance by Cockroft-Gault ≥ 50 mL/min.
• Total bilirubin ≤ to 2.0 mg/dL, except in patients with Gilbert's Syndrome, who must have a total bilirubin ≤ 3.0 mg/dL.

You may not qualify if:

• Known oncogene driver mutations (e.g., including but not limited to, epidermal growth factor receptor \[EGFR\], anaplastic lymphoma kinase \[ALK\], reactive oxygen species \[ROS\], Kirsten RAt Sarcoma Virus G12C \[KRAS G12C\], human epidermal growth factor receptor 2 \[HER2\], neurotrophic tyrosine receptor kinase \[NTRK\], BRAF V600E, RET fusion positive, mesenchymal-epithelial transition gene exon 14 \[METex14\]) which are sensitive to targeted Food and Drug Administration (FDA)-approved therapies.
• Pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant. Women of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days of enrollment.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
• Prior treatment with any cell therapy product or organ allograft within the past 20 years.
• Patients who have had another primary malignancy within the previous 3 years.
• Concurrent opportunistic infection.
• Receipt of a live or attenuated vaccination within 28 days prior to the tumor harvest.
• Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active major medical illnesses.
• Use of systemic steroids (0 mg) within 14 days prior to tumor collection or anticipated need of systemic steroids (0 mg) within 21 days prior to investigational product infusion or anticipated any time after that infusion (oral progestin/estrogen combinations used for contraception are an exception).
• History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, aldesleukin, pembrolizumab, or dimethyl sulfoxide (DMSO).
• History of coronary revascularization or ischemic symptoms, myocarditis, congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), serious uncontrolled cardiac arrhythmia, or other clinically significant cardiac disease that may increase the risk associated with study participation, in the opinion of the investigator.
• Documented left ventricular ejection fraction (LVEF) ≤ 45%.
• History of Grade ≥ 2 pneumonitis or active interstitial lung disease/pneumonitis requiring treatment with systemic steroids.
• Documented forced expiratory volume in 1 second (FEV1) ≤ 50% or FEV1/forced vital capacity (FVC) ≤ 0.7 (6-minute walk test if unable to perform or unreliable spirometry).
• Clinically significant patient history that, in the judgment of the enrolling investigator, would compromise the patient's ability to tolerate high-dose aldesleukin.

Sponsors & Collaborators

• Intima Bioscience, Inc.: lead

Study Sites (2)

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

Masonic Cancer Center, University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Adenocarcinoma of Lung

Interventions

fludarabine; fludarabine phosphate; Cyclophosphamide; aldesleukin; Interleukin-2; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Emil Lou, MD, PhD

  Division of Hematology, Oncology, and Transplantation, University of Minnesota

  PRINCIPAL INVESTIGATOR

• Erminia Massarelli, MD, PhD, MS

  Department of Medical Oncology & Therapeutics Research, City of Hope

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2022
• First Posted: October 4, 2022
• Study Start: February 1, 2023
• Primary Completion: November 1, 2025
• Study Completion (Estimated): November 1, 2027
• Last Updated: February 23, 2026

Record last verified: 2026-02

Locations

US (2)