A clinical trial to assess the safety and efficacy of genetically-engineered, neoantigen-specific Tumor Infiltrating Lymphocytes (TIL) in which the intracellular immune checkpoint CISH has been inhibited using CRISPR gene editing for the treatment of Gastro-Intestinal (GI) Cancer.
Tumor Infiltrating Lymphocytes (TIL) have shown efficacy in certain cancers, principally in melanoma. Efficacy in more common solid tumors has been demonstrated via the selection of cancer neoantigen-specific TIL. 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 lymphocytes from patients with metastatic cancers that are selected for anti-tumor activity in order to evaluate the safety and efficacy of genetically engineered T cell therapy for solid tumors in the setting of novel checkpoint inhibition.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
23
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.
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.
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.
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.
Masonic Cancer Center, University of Minnesota
Minneapolis, Minnesota, United States
Maximum tolerated dose (MTD)
Highest dose at which less than or equal to 1 of 6 patients experienced a DLT or the highest dose level studied if DLTs are not observed at any of the dose levels
Time frame: 28 Days Post IL-2
Preliminary efficacy of tumor reactive autologous lymphocytes with knockout of CISH gene in patients with refractory metastatic gastrointestinal epithelial cancers: changes in diameter
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
Time frame: Every 4 Weeks for the first three months, then every 8 weeks thereafter, up to 2 years
Safety of tumor reactive autologous lymphocytes with knockout of the CISH gene - Incidence of Adverse Events
Incidence of Adverse Events
Time frame: 2 Years or Disease Progression
Progression-Free Survival (PFS)
Progression-Free Survival (PFS) of patients with metastatic gastrointestinal cancers treated using the autologous lymphocytes
Time frame: 2 Years or Disease Progression
Overall Survival (OS)
Overall Survival (OS) of patients with metastatic gastrointestinal cancers treated using the autologous lymphocytes
Time frame: 2 Years or Disease Progression
Toxicity profiles resulting from treatment using these engineered tumor-infiltrating lymphocytes
Incidence of targeted toxicities events
Time frame: 2 Years or Disease Progression
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