CISH Inactivated TILs in the Treatment of NSCLC
- Conditions
- Metastatic Non Small Cell Lung CancerStage IV Non-small Cell Lung CancerSquamous Cell Lung CancerCarcinoma, Non-Small-Cell LungAdenocarcinoma of LungLarge Cell Lung Cancer
- Interventions
- Biological: CISH Inactivated TIL
- Registration Number
- NCT05566223
- Lead Sponsor
- Intima Bioscience, Inc.
- 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).
- Detailed Description
Tumor Infiltrating Lymphocytes (TIL) have shown efficacy in certain cancers, principally in melanoma, but also in non-small cell lung cancer (NSCLC). Combination cell surface checkpoint inhibitor therapy has also been employed in an attempt to enhance the efficacy of these cell therapies. Genetic engineering of T cells to further increase anti-tumor activity is now possible.
CISH (Cytokine-induced SH2 protein) is a novel intra-cellular immune checkpoint and an important negative regulator of T-cell signaling and function. The inhibition of CISH in mouse anti-tumor lymphocytes results in a marked increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice.
Additionally, data in genetically-engineered, neoantigen-specific human T cells in which CISH was inhibited, showed enhanced TCR functional avidity and increased ability of these T cells to detect cancer specific mutations and mount robust polyfunctional cytokine immune responses against their cognate cancer antigens. Thus, these T cells appear to have a significant advantage in inducing anti-tumor responses compared to wild-type anti-tumor lymphocytes.
The researchers have developed and optimized a CRISPR/Cas9 based strategy for precise and efficient genetic engineering in primary human T-cells without sacrificing cell viability or function, allowing for inhibition of a heretofore undruggable intracellular checkpoint.
Thus, in this protocol, the researchers propose to inhibit the gene encoding the intracellular checkpoint target CISH in TIL from patients with metastatic NSCLC whose tumors are PD-L1 negative or positive in order to evaluate the safety and efficacy of genetically engineered T cell therapy in the setting of novel checkpoint inhibition .
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 70
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description CISH CRISPR TIL / Phase I Arm CISH Inactivated TIL Dose Escalation/Expansion Cohort Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +escalating doses of CISH inactivated TIL + high-dose aldesleukin CISH CRISPR TIL plus pembrolizumab / Phase I Arm CISH Inactivated TIL 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 CISH CRISPR TIL plus pembrolizumab / Phase I Arm Pembrolizumab 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 CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort Fludarabine 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 CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort CISH Inactivated TIL 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 CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort Cyclophosphamide 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 CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort CISH Inactivated TIL 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 CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort Aldesleukin 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 CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort Pembrolizumab 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 CISH CRISPR TIL / Phase I Arm Fludarabine Dose Escalation/Expansion Cohort Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +escalating doses of CISH inactivated TIL + high-dose aldesleukin CISH CRISPR TIL / Phase I Arm Cyclophosphamide Dose Escalation/Expansion Cohort Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +escalating doses of CISH inactivated TIL + high-dose aldesleukin CISH CRISPR TIL plus pembrolizumab / Phase I Arm Fludarabine 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 CISH CRISPR TIL plus pembrolizumab / Phase I Arm Cyclophosphamide 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 CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort Cyclophosphamide 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 CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort Aldesleukin 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 CISH CRISPR TIL / Phase II Arm PD-L1 Negative Cohort Pembrolizumab 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 CISH CRISPR TIL / Phase II Arm PD-L1 Positive Cohort Fludarabine 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 CISH CRISPR TIL / Phase I Arm Aldesleukin Dose Escalation/Expansion Cohort Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +escalating doses of CISH inactivated TIL + high-dose aldesleukin CISH CRISPR TIL plus pembrolizumab / Phase I Arm Aldesleukin 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
- Primary Outcome Measures
Name Time Method Phase I: Safety and Initial Efficacy 11 months Safety by type, incidence, severity, seriousness, and relation of study treatment of AEs, DLTs, and laboratory abnormalities. Initial efficacy per RECIST v1.1
Phase II: Objective Response Rate (ORR) 3.5 years RECIST v1.1
- Secondary Outcome Measures
Name Time Method Clinical Benefit Rate 2-5 years Percentage of combined patients who achieve complete response, partial response and stable disease
Progression Free Survival (PFS) 2-5 years Kaplan-Meier estimate
Overall Survival (OS) 2-5 years Kaplan-Meier estimate
Toxicity Incidence 2-5 years Incidence of targeted toxicities events
Duration of Response (DoR) 2-5 years Length of time that target lesion(s) continue to respond to treatment without growing or spreading
Tumor Growth Change 2-5 years Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST v1.1 criteria
Trial Locations
- Locations (2)
Masonic Cancer Center, University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States