| Autor: |
Katri Sofjan, Sharon Lin, Sol Shenker, Caroline Dugopolski, Leila Williams, Karrie Wong, Christopher Wrocklage, Mallory Brady, Hugh S. Gannon, Frank Stegmeier, Robert A. LaMothe, Tracy VandenBerg, Noah Tubo, Micah J. Benson, Tianlei Xu, Nicholas John Colletti, Michael R. Schlabach, Louise Cadzow |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Journal for ImmunoTherapy of Cancer, Vol 9, Iss Suppl 2 (2021) |
| ISSN: |
2051-1426 |
| Popis: |
BackgroundAdoptive cell therapy with ex vivo expanded tumor infiltrating lymphocytes (TIL) offers a potentially curative treatment for cancer. However, the immunosuppressive tumor microenvironment limits the effectiveness of TIL therapy. To address this medical need, we used our Immune-CRISPRomics® Platform to perform a series of genome-wide CRISPR/Cas9 screens to identify targets enhancing the ability of T cells to infiltrate and kill solid tumors in an in vivo setting. These screens identified SOCS1 as a top target that restrains T cell anti-tumor immunity. Based on these findings, we developed KSQ-001, an engineered TIL (eTIL) therapy created via CRISPR/Cas9-mediated editing of SOCS1 for the treatment of solid tumors.MethodsGenome-wide CRISPR/Cas9 screens were conducted in in vitro primary human T cells and TIL cultures and in in vivo primary mouse OT1 and PMEL-TCR-Tg T cells in syngeneic tumor models. The efficacy of surrogate murine KSQ-001 (mKSQ-001), in which the SOCS1 gene is inactivated by CRISPR/Cas9 in OT1 or PMEL-TCR-Tg T cells, was evaluated in both the B16-Ova and CRC-gp100 syngeneic tumor models, with memory formation and efficacy evaluated both in the presence and absence of cyclophosphamide-mediated lymphodepletion. KSQ-001 was manufactured from human TIL using SOCS1-targeting sgRNAs selected for therapeutic use based on potency and selectivity, with KSQ-001 characterized for in vitro function and in vivo anti-tumor efficacy.ResultsUpon adoptive transfer of a single dose into solid tumor-bearing hosts, mKSQ-001 was found to robustly enhance anti-tumor efficacy and eradicate tumors in 7/10 mice in the PD1-sensitive OT1/B16-Ova model and to drive responses in the PD-1 refractory PMEL/CRC-gp100 syngeneic tumor model. mKSQ-001 also showed a ten-fold increase in anti-tumor potency in vivo compared to unengineered T-cell product and established durable anti-tumor memory by persisting in the form of T central memory cells detectable at high frequency in the peripheral blood of complete responder mice. In the setting of lymphodepletion, mKSQ-001 also displayed heightened anti-tumor potency, accumulation, and memory formation in comparison to inactivation of PD-1. Importantly, human KSQ-001 displayed a transcriptional signature indicative of increased anti-tumor function, produced increased amounts of pro-inflammatory cytokines, exhibited a hypersensitivity to IL-12 signaling, and demonstrated increased anti-tumor function both in vitro and in vivo solid tumor models.ConclusionsBased on insights from our Immune-CRISPRomics® platform and demonstrated efficacy across multiple preclinical tumor models, we have developed KSQ-001, a novel eTIL therapy. These preclinical data support clinical testing of KSQ-001 in a variety of solid tumor indications. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
