KSQ-004EX / KSQ Therapeutics - LARVOL DELTA

Characterizing the impact of SOCS1 and Regnase-1 inactivation on tumor reactive T cells present in CRISPR/Cas9-engineered TIL (eTIL®) therapies derived from melanoma and NSCLC tumors through functional and single cell analyses (AACR 2025) - "Seeking to improve the clinical activity of TIL therapy, we developed KSQ-001EX and KSQ-004EX, two CRISPR/Cas9-engineered TIL (eTIL®) therapies wherein the genes encoding SOCS1 or SOCS1 in combination with Regnase-1 are inactivated, respectively. The majority of predTRT clones were also detected in DPs, where they preferentially aligned to effector memory and proliferating states. Further demonstrating the impact of SOCS1 and Regnase-1 edits on predTRT clones, we observed enrichment of an activated interferon-stimulated gene signature in eTIL DPs, with predTRT clones in dual-edited KSQ-004EX uniquely enriched for heightened expression of a Regnase-1 transcriptional signature.To conclude, we observe that eTIL possess reactivity against tumor through retention of TRT clones, with SOCS1 and Regnase-1 inactivation enhancing the anti-tumor functionality of TRT clones within eTIL DP."

IO biomarker • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD69 • CD8 • CXCL13 • GZMB • IFNG • IL2RA • IL7R • ISG20 • SOCS1 • TNFRSF9

Evolving therapeutic pipeline for tumor-infiltrating lymphocytes in metastatic melanoma - a review. (PubMed, Front Immunol) - "The recent U.S. FDA approval of lifileucel, a non-engineered, autologous tumor-infiltrating lymphocyte (TIL) therapy, for unresectable or metastatic melanoma represents a major milestone for cellular therapies in solid tumors...OBX-115, designed with regulatable membrane-bound IL-15 expression, eliminates the need for IL-2 infusion and has shown early clinical activity. KSQ-001EX uses CRISPR/Cas9 to inactivate SOCS1, while KSQ-004EX additionally targets Regnase-1 to enhance TIL function...TIL therapy remains among the most promising strategies in melanoma and solid tumors after immunotherapy failure. Ongoing research aims to optimize cell dose, phenotype, tumor procurement, treatment sequencing, and rational combinations to improve durable benefit."

IO biomarker • Journal • Review • Tumor-infiltrating lymphocyte • Melanoma • Oncology • Solid Tumor • IL15 • SOCS1

eCARTM-T: Dual-inactivation of SOCS1 and Regnase-1 by CRISPR/Cas9 gene editing enhances CAR-T function against solid tumors (SITC 2025) - P1/2 | "Applying this insight, we developed the engineered TIL (eTIL®) therapy KSQ-004EX, currently in a phase 1 clinical trial (NCT06598371)...These effects were sustained even when eCAR-T cells were administered at a ten-fold lower dose, indicating substantially higher in vivo potency and expansion.Conclusions Dual-inactivation of Regnase-1 and SOCS1 enhances the potency, expansion, and in vivo efficacy of eCAR-T cells in a solid tumor model, enabling durable tumor control even at reduced doses. Our results support the use of Regnase-1 and SOCS1 disruption as a potential strategy to overcome key barriers in solid tumor treatment, extending the durability and potency of CAR-T therapies beyond hematologic cancers."

IO biomarker • Hematological Malignancies • Oncology • Solid Tumor • CA9 • MSLN • SOCS1

A Phase 1/2 Study of KSQ-004EX: Autologous Tumor Infiltrating Lymphocytes, Engineered to Inactivate Genes Encoding SOCS1 and Regnase-1, in Patients with Select Advanced Solid Tumors (SITC 2025) - P1/2 | "Patients receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine prior to KSQ-004EX infusion. The protocol, ICF(s), and any participant materials will be submitted to the IRB for review and approval. Approval of both the protocol and the consent form(s) must be obtained before any participant is consented."

Clinical • Metastases • P1/2 data • Tumor-infiltrating lymphocyte • Cervical Cancer • Colorectal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • IL2 • SOCS1

SOCS1 and Regnase-1 inactivation enhances functionality and prevents exhaustion of tumor reactive clonotypes in KSQ-004EX eTIL (SITC 2025) - P1/2 | "In KSQ-004EX, the dual-inactivation of SOCS1 and Regnase-1 in TRT clonotypes enhances their anti-tumor functionality and prevents their exhaustion upon acute and chronic engagement with autologous tumor. These data support continued evaluation of KSQ-004EX in patients with solid tumors."

Oncology • Solid Tumor • CCL3 • GZMB • IFNG • SOCS1 • TNFRSF9

A phase 1/2 study of KSQ-004EX: Autologous tumor infiltrating lymphocytes, engineered to inactivate genes encoding SOCS1 and Regnase-1, in patients with select advanced solid tumors. (ASCO 2025) - P1/2 | "Patients receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine prior to KSQ-004EX infusion...The primary objective of Phase 2 is to assess the anti-tumor activity of KSQ-004EX in patients with advanced solid tumors by ORR per RECIST v1.1. This is currently a single-institution study that is actively enrolling/recruiting patients."

Clinical • Metastases • P1/2 data • Tumor-infiltrating lymphocyte • Cervical Cancer • Colorectal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • IL2 • SOCS1

KSQ Therapeutics Announces First Patient Dosed in Phase 1/2 Study for KSQ-004EX, a CRISPR/Cas9-Engineered Tumor Infiltrating Lymphocyte (eTIL) Therapy (GlobeNewswire) - "KSQ Therapeutics...announced the first patient dosed in the Phase 1/2 clinical study of KSQ-004EX, a novel CRISPR-engineered Tumor Infiltrating Lymphocyte (eTIL) therapy....The first patient treated with KSQ-004EX was enrolled by Rodabe Amaria, M.D., professor of Melanoma Medical Oncology and principal investigator of the study at The University of Texas MD Anderson Cancer Center....The Phase 1/2 clinical trial is an open-label, dose escalation study for patients with advanced solid tumors (including melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), pancreatic cancer, and cervical cancer."

Trial status • Cervical Cancer • Colorectal Cancer • Melanoma • Non Small Cell Lung Cancer • Pancreatic Cancer • Squamous Cell Carcinoma of Head and Neck

A Phase 1/2 Study of KSQ-004EX, Autologous Tumor Infiltrating Lymphocytes Engineered to Inactivate Genes Encoding SOCS1 and Regnase-1, in Patients With Select Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=141 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting | Initiation date: Mar 2025 ➔ Nov 2024

Enrollment open • Metastases • Trial initiation date • Oncology • Solid Tumor

Development of a gene editing platform for the manufacture of CRISPR/Cas9 engineered TIL (eTIL) (SITC 2024) - "Background To improve the clinical activity of Tumor Infiltrating Lymphocyte (TIL) therapy, we developed engineered TIL (eTIL®) using CRISPR/Cas9 gene editing: KSQ-001EX is a single-edit eTIL product with SOCS1 inactivated; KSQ-004EX is a dual-edit eTIL product with inactivation of both SOCS1 and Regnase-1. Robust eTIL editing efficiency was achieved while maintaining consistently high cell viability, in vitro functionality, and other process attributes. Conclusions With the goal of simplifying the manufacture of eTIL and improving sterility assurance, we report the development of a robust, scalable gene editing platform that accounts for tumor variability in the manufacture of eTIL using a next generation ExPRESS manufacturing process."

Oncology • Solid Tumor • SOCS1

KSQ-004EX: a SOCS1/Regnase-1 dual-edited eTIL therapy demonstrating enhanced anti-tumor activity (SITC 2024) - "Using ExPRESS, a feeder cell-free, next-gen eTIL manufacturing process, TIL were activated and expanded for 11 days whereupon editing of SOCS1 and Regnase-1 was performed by electroporation (EP) of CRISPR/Cas9 ribonucleoprotein (RNP) complexes. Conclusions KSQ-004EX, a SOCS1/Regnase-1 dual CRISPR/Cas9 edited TIL therapy, demonstrated enhanced anti-tumor functionality and in vivo persistence in pre-clinical animal models. These results support the evaluation of KSQ-004EX in a clinical setting in cancer patients with treatment-refractory solid tumors."

Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CCR7 • CD8 • IFNG • IL2 • SOCS1

KSQ Therapeutics Announces FDA Clearance of IND Application for KSQ-004EX, a CRISPR/Cas9 Engineered Tumor-Infiltrating Lymphocyte (eTIL) Therapy (GlobeNewswire) - "KSQ Therapeutics, Inc...announced that the U.S. Food and Drug Administration (FDA) has cleared an Investigational New Drug (IND) application for a Phase 1/2 clinical study of KSQ-004EX, KSQ’s second engineered tumor-infiltrating lymphocyte (eTIL) program....The Phase 1/2 clinical trial is an open-label, dose-escalation study for patients with select advanced solid tumors."

IND • New P1/2 trial • Oncology • Solid Tumor

A Phase 1/2 Study of KSQ-004EX, Autologous Tumor Infiltrating Lymphocytes Engineered to Inactivate Genes Encoding SOCS1 and Regnase-1, in Patients With Select Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=141 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

Metastases • New P1/2 trial • Oncology • Solid Tumor

KSQ Therapeutics and CTMC Announce Strategic Collaboration to Accelerate the Development of Novel Engineered Tumor Infiltrating Lymphocyte (eTIL) Therapies for the Treatment of Solid Tumors (Businesswire) - "KSQ Therapeutics, Inc...and MD Anderson Cancer Center, announced today a strategic collaboration to expedite the development of KSQ's two lead engineered tumor-infiltrating lymphocyte (eTIL^®) programs, KSQ-001EX and KSQ-004EX, both of which are advancing toward clinical studies for the treatment of solid tumors."

Licensing / partnership • Oncology • Solid Tumor

KSQ-004: Unbiased pair-wise discovery of SOCS1 and Regnase-1 as the top CRISPR/Cas9 dual-edit combination enhancing in vivo TIL potency against solid tumors (SITC 2021) - "Conclusions We used a novel CRISPR^2 screen approach to identify Regnase-1/SOCS1 as the top dual edit combination enhancing T cell function in the tumor microenvironment. We translated these findings to therapeutic use with the discovery of KSQ-004, a dual-edited eTIL therapy engineered that possesses enhanced anti-tumor potency and persistence against solid tumors."

Preclinical • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IFNG • SOCS1