Adoptive Cell Therapy Using Cancer Specific CD8+ Tumor Infiltrating Lymphocytes in Adult Patients With Solid Tumors — ACT  

Colorectal Cancer Clinical Trial

Official title: Phase I Randomized Open Label Trial Investigating Adoptive Transfer of CD39+CD103+CD8+ Tumor-isolated T Cells (AGX148) Alone or Combined With siRNA Modulation of PD-1 (AGX148/PH-762) in Patients With Advanced Solid Tumors

Status Recruiting

Clinical Trial Summary

The subject of this study is the adoptive transfer of selected autologous tumor infiltrating lymphocytes (TIL) after in vitro expansion for the treatment of solid tumor malignancies. The TIL selection process is based on evidence showing that CD8+ TIL which co-express both CD39 and CD103 harbor the bulk of tumor-reactivity and that the remaining CD8 TIL is mainly composed of non-tumor reactive bystander cells. All of the expanded TIL that are produced (1-40 billion are expected) will be delivered in the form of a cell suspension to the participants by intravenous infusion. It is proposed that these selected TIL will produce a more potent and efficacious treatment of late-stage cancer.

Clinical Trial Description

Our research identified a subpopulation of CD8 tumor infiltrating lymphocytes (TIL) highly enriched for tumor reactivity that can be identified and isolated based on the co-expression of CD39 and CD103. The investigators refer to this tumor-reactive cell population as DP CD8 TIL. The DP CD8 TIL can constitute as few as 2% and up to 70-80% of the CD8 TIL directly isolated from tumors, suggesting that in any given patient a substantial percentage of their CD8 TIL can be bystanders lacking tumor specificity. The CD8 DP TIL were highly enriched for cells that recognize autologous tumor as evidenced by interferon gamma production, 4-1BB upregulation and autologous tumor cell killing. The investigators also found that T cell receptors within the CD8 DP TIL population share very little overlap with the other sub-populations of CD8 TIL, suggesting that they have a distinct antigen recognition pattern.

The DP CD8 TIL express high levels of PD-1 especially when encountering tumor Ag(s) in situ. Pre-clinical experiments have shown that the potency of DP CD8 TIL can be enhanced by decreasing PD-1 checkpoint expression by incubating them with siRNA that targets PD-1. The investigators hypothesize that transient knockdown of PD-1 expression will enable DP CD8 TIL to initiate a more effective and persistent anti-tumor response without increasing toxicity. The investigators refer to DP CD8 TIL after PD-1 knockdown as DP CD8 TIL KD. Although preclinical experiments have shown the value of siRNA modulation of PD-1 in DP T cells, this strategy has not been studied in humans. The main goals of this phase I first-in-human study are to define toxicity and understand the biology and anti-tumor activity of DP CD8 TIL alone and with siRNA PD-1 modulation. Thus, the trial is designed as a randomized comparison of DP CD8 TIL and DP CD8 TIL KD with comprehensive immune monitoring as detailed below.

Lymphodepleting chemotherapy just before adoptive transfer facilitates proliferation and persistence of adoptively transferred T cells as has been demonstrated in other adoptive cellular therapy trials over the last 30 years. Similarly, interleukin-2 (IL-2) administered after adoptive transfer enhances T-cell proliferation, persistence, and cytotoxicity. The investigators have also performed pre-clinical experiments confirming the need for IL-2 after DP CD8 TIL adoptive transfer to achieve maximum antitumor effect in a human xenograft model. Cyclophosphamide and fludarabine will be given prior to adoptive transfer of the DP CD8 TIL and high dose IL-2 (600,000 IU/kg IV with a maximum of 6 doses over 6 days) will be administered starting within 24 hours of the adoptive transfer followed by subcutaneous IL-2 in dose-escalation cohorts of IL-2, 5 MIU/m2 TIW starting on day +8 for 1 weeks, 2 weeks or 3 weeks if tolerated. ;

Related Conditions & MeSH terms

• Colorectal Cancer
• Gynecologic Cancer
• HNSCC
• Lung Cancer
• Melanoma
• Urogenital Cancer
• Urogenital Neoplasms

• NCT number: NCT05902520
• Study type: Interventional
• Source: AgonOx, Inc.
• Contact: Colin J Thalhofer, PhD
• Phone: 503-215-6745
• Email: Colin.Thalhofer@agonox.com
• Status: Recruiting
• Phase: Phase 1
• Start date: June 19, 2023
• Completion date: May 19, 2026