OBX-115 / Obsidian, UT MD Anderson Cancer Center - LARVOL DELTA

Novel tumor-infiltrating lymphocytes therapy in solid tumors: latest updates from 2025 ASCO annual meeting. (PubMed, Exp Hematol Oncol) - "Notably, innovative TIL-based monotherapies and combination regimens have provided durable clinical responses and survival benefits for patients with various solid tumors. This article summarizes recent advances in TIL therapy for solid tumors presented at the 2025 ASCO Annual Meeting, highlighting monotherapies such as Lifileucel, LM103, OBX-115, GT101, GT300, GT201, and HS-IT101, as well as combination strategies with the oncolytic adenovirus TILT-123 or pembrolizumab."

Journal • Tumor-infiltrating lymphocyte • Melanoma • Oncology • Solid Tumor

Translational data validate OBX-115 mechanism of action: Impact of dosing on clinical outcome in advanced (adv) melanoma (ESMO 2025) - P1/2 | "Background OBX-115 TIL express membrane-bound IL15 (mbIL15) regulated by the FDA-approved small-molecule drug acetazolamide (ACZ), abrogating the need for IL2 and resulting in differentiated safety and promising efficacy (Amaria ASCO 2024, Chesney ASCO 2025). This regimen allows for low-dose LD and no IL2, which may expand pt eligibility. Ph 2 enrollment is ongoing."

Clinical • Clinical data • Metastases • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • IL15 • IL2 • NCAM1

Agni-01: Safety and Efficacy of OBX-115 in Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=52 | Recruiting | Sponsor: Obsidian Therapeutics, Inc. | Trial completion date: Oct 2027 ➔ Jun 2028 | Trial primary completion date: Oct 2025 ➔ Jun 2028

Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Skin Cancer • Solid Tumor • BRAF • PD-1 • PD-L1

OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy with regulatable membrane-bound IL15 (mbIL15) in patients (pts) with immune checkpoint inhibitor (ICI)–resistant advanced melanoma: Phase 1 results of the Agni-01 multicenter study. (ASCO 2025) - P1, P1/2 | "Funded by Obsidian Therapeutics Clinical Trial Registration Number: NCT06060613 Background: OBX-115 TIL are engineered to express mbIL15 regulated by the FDA-approved small-molecule drug acetazolamide (ACZ), abrogating the need for toxic high-dose IL2 after TIL infusion... Early data support clinical benefit (RP2D ORR 67%, DCR 100%) of OBX-115 regulatable engineered TIL cell therapy in the absence of IL2, including with outpatient low-dose LD. The safety profile is highly differentiated, without TRM, ICU transfer, or high-grade CRS. ACZ redosing is well-tolerated and offers an opportunity to deepen responses by inducing re-expression of mbIL15 on engrafted OBX-115 TIL, a unique capability among adoptive cell therapies."

Checkpoint inhibition • Clinical • IO biomarker • Metastases • P1 data • Tumor-infiltrating lymphocyte • Heart Failure • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL15 • IL6

OBX-115 engineered tumor-infiltrating lymphocytes (TIL) with regulatable membrane-bound IL15 (mbIL15): Translational data from a single-center phase 1 trial in patients (pts) with immune checkpoint inhibitor (ICI)–resistant advanced melanoma. (ASCO 2025) - P1, P1/2 | "OBX-115 engineered TIL express mbIL15 under pharmacologic regulation using the FDA-approved small-molecule drug acetazolamide (ACZ), abrogating the need for IL2... These data support the proposed OBX-115 mechanism of action, demonstrating ACZ-driven OBX-115 TIL expansion, engraftment, and persistence; endogenous NK cell expansion, presumably driven by transactivation via mbIL15 on OBX-115, without systemic cytokine elevation; and TCR repertoire remodeling with tumor-derived, antigen-specific T cells. Investigation of OBX-115 TIL cell therapy in pts with advanced solid tumors (NCT06060613) is ongoing. Pre- and post-infusion immune profile.*Pre-lymphodepletion."

Checkpoint inhibition • Clinical • Metastases • P1 data • Tumor-infiltrating lymphocyte • Melanoma • Oncology • Solid Tumor • CD4 • CD8 • IL15 • IL6 • IL7 • NCAM1

Obsidian Therapeutics Announces Positive Clinical Data from OBX-115 in Patients with Advanced Melanoma in Ongoing Multicenter Study at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting (Businesswire) - P1/2 | N=52 | Agni-01 (NCT06060613) | Sponsor: Obsidian Therapeutics, Inc. | "Oral presentation of Phase 1 results from Agni-01 multicenter study of cryopreserved OBX-115, a novel IL2-sparing engineered TIL cell therapy armored with pharmacologically regulatable membrane-bound IL15 (mbIL15), in patients with ICI-resistant advanced melanoma (n=11); OBX-115 ORR was 67% at recommended Phase 2 dose (RP2D) (n=6), including 1 CR; OBX-115 safety profile remains consistent: no DLTs, no treatment-related ICU transfer, no treatment-related mortality....Obsidian is also presenting a poster for abstract 9519 summarizing translational data from the Phase 1 first-in-human single-center study of OBX-115...in ICI-resistant advanced melanoma."

P1 data • Melanoma

Drug-responsive Domains Coupled with Cognate Small-molecule Ligands Drive Synthetic Gene-ON or -OFF Circuits to Regulate Expression of Therapeutic Proteins (ASGCT 2025) - P1 | "Currently, this approach is showing promising activity in a Ph1 clinical trial (NCT05470283) in patients with immune checkpoint inhibitor-resistant melanoma treated with engineered tumor-infiltrating lymphocytes expressing regulatable membrane-bound interleukin 15 (OBX-115; Amaria ASCO 2024)...The gene-ON and gene-OFF circuits have the potential to be important tools for gene and cell therapies where precise and variable control of delivered gene product is needed to manage disease and repeat dosing of biologics or anti-sense oligonucleotides is challenging. Disease Focus of Abstract:Genetic Diseases"

IO biomarker • Genetic Disorders • Melanoma • Oncology • Solid Tumor • APOE • IL12A • IL15 • ZAP70

Obsidian Therapeutics to Present Preclinical Data Supporting Novel Application of cytoDRiVE Platform at the American Society of Gene and Cell Therapy Annual Meeting (Businesswire) - "Obsidian Therapeutics...today announced the publication of an abstract with preclinical data from their cytoDRiVE platform for poster presentation at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting 2025....In OBX-115, Obsidian’s lead clinical TIL program which has demonstrated promising activity in patients with ICI-resistant advanced melanoma, this technology enables regulation of membrane-bound IL15 using the small-molecule drug acetazolamide."

Preclinical • Melanoma

IL2-independent expansion, persistence, and antitumor activity in TIL expressing regulatable membrane-bound IL15. (PubMed, Mol Ther) - "cytoTIL15™ cells express mbIL15 fused to a drug-responsive domain (DRD) that is regulated by the FDA-approved small-molecule drug acetazolamide (ACZ). In patient-derived xenograft (PDX) tumors, spatial profiling revealed infiltrating cytoTIL15 cells to be highly cytotoxic and less exhausted than non-engineered TIL. This novel platform creates a powerful, IL2-free TIL cell therapy with a potentially improved tolerability and safety profile, while allowing individualized pharmacologic regulation of the TIL product."

Journal • Critical care • Melanoma • Oncology • Solid Tumor • CD8 • IL15 • IL2

Trial in progress: Phase 1/2 study of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced solid tumors (AACR 2025) - P1, P1/2 | "OBX-115 TIL are expanded from patient tumor tissue and engineered with a transgene to express membrane-bound human IL15 (mbIL15), regulated by acetazolamide (ACZ), eliminating the need for IL2...Cryopreserved OBX-115 is generated from the patient's own tumor tissue procured by surgical excision or core needle biopsy and is infused after standard- or low-dose lymphodepletion (cyclophosphamide and fludarabine) based on clinical status and prior treatments...ACZ is administered at cohort-defined doses once daily starting day of OBX-115 infusion for ≤14 days (split into two ≤7-day periods within 28 days), with additional ACZ dosing for ≤7 days at weeks 5, 11, 17, and 23, or upon progression when new anticancer therapy is not immediately warranted. Eight sites are open and recruiting, with additional sites being activated."

Clinical • Metastases • P1/2 data • Tumor-infiltrating lymphocyte • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL15

OBX-115 TIL from non-small cell lung cancer (NSCLC) are enriched for putative tumor-reactive, stem-like T cells with enhanced tumor cytotoxicity: Results from multimodal phenotyping analysis (AACR 2025) - P1/2 | "Here, we demonstrate that the OBX-115 manufacturing process from NSCLC tumor tissue, incorporating cell-armored-mbIL15-driven expansion and 4-1BB agonism, generates higher TIL yield and a more stem-like phenotype than conventional non-engineered TIL process. Computational analysis reveals the OBX-115 process enriches for putative tumor-reactive TCR clonotypes, which is further supported by in vitro co-culture assays. Together, these favorable attributes support further investigation of OBX-115 in patients with metastatic NSCLC (NCT06060613)."

IO biomarker • Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD69 • CD8 • ENTPD1 • IFNG • IL15 • IL2 • PD-1

Obsidian Therapeutics Announces Multiple Presentations at the American Association for Cancer Research Annual Meeting (Businesswire) - "The poster for abstract LB025 demonstrates the application of Obsidian’s regulatable cytoDRiVE platform to enhance antigen-responsive ('spatial') promoter-induced activation by adding a critical pharmacologically regulatable ('temporal') signal to exert tight 'spatiotemporal' control over IL12 expression, resulting in a positive impact on safety and tumor control in syngeneic solid tumor models....Obsidian will also present preclinical data from a multimodal phenotyping analysis comparing OBX-115 TIL generated with its proprietary manufacturing process to conventional, non-engineered TIL using NSCLC tumor samples.The poster for abstract LB359 provides evidence that, as observed with melanoma, the OBX-115 process generates a minimally exhausted, CD8+ enriched and memory 'stem-like' T-cell phenotype. Additionally, the tumor reactive gene signature analysis showed that the drug product is enriched for putative tumor-reactive T-cell clonotypes."

Preclinical • Melanoma • Non Small Cell Lung Cancer

Obsidian Therapeutics Announces Multiple Presentations at the American Association for Cancer Research Annual Meeting (Businesswire) - "Obsidian Therapeutics, Inc...announced the publication of...poster presentations at the American Association for Cancer Research (AACR) Annual Meeting 2025. In addition to a trial-in-progress study design update on the ongoing multicenter study Agni-01 (NCT06060613)..."

Trial status • Solid Tumor

Obsidian Therapeutics to Present Clinical Data from OBX-115, its Engineered TIL Cell Therapy, for Patients with Advanced Melanoma in Oral Presentation at the 2025 ASCO Annual Meeting (Businesswire) - "Obsidian Therapeutics...announced two presentations, including an oral presentation on the Phase 1/2 Agni-01 multicenter study of OBX-115...in patients with immune checkpoint inhibitor (ICI)-resistant advanced or metastatic melanoma (NCT06060613), at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting....Oral presentation of Phase 1 results from Agni-01 multicenter study of OBX-115, a novel, IL2-sparing engineered TIL cell therapy armored with pharmacologically regulatable membrane-bound IL15 (mbIL15), in patients with ICI-resistant advanced melanoma. Additional poster presentation summarizing translational data from Phase 1 first-in-human single-center study of OBX-115 (enrollment completed) in ICI-resistant advanced melanoma."

P1 data • Melanoma

Potential feasibility of core needle biopsy tumor tissue procurement method for TIL cell therapy with OBX-115 in non-small cell lung cancer (NSCLC) (SITC 2024) - "(A) Representative images of TIL cytotoxicity against autologous tumor spheroids at 24 hrs (red, tumor spheroids; green, caspase 3/7). (B) Representative quantification of caspase signal inside tumor spheroids over 72 hrs (***p<0.005; one-way ANOVA)"

Biopsy • IO biomarker • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • CD69 • CD8 • ENTPD1 • IL15 • IL2 • PD-1

Potential feasibility of core needle biopsy tumor tissue procurement method for TIL cell therapy with OBX-115 in non-small cell lung cancer (NSCLC) (SITC 2024) - "(A) Representative images of TIL cytotoxicity against autologous tumor spheroids at 24 hrs (red, tumor spheroids; green, caspase 3/7). (B) Representative quantification of caspase signal inside tumor spheroids over 72 hrs (***p<0.005; one-way ANOVA)"

Biopsy • IO biomarker • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • CD69 • CD8 • ENTPD1 • IL15 • IL2 • PD-1

Engineered tumor-infiltrating lymphocytes (TIL) with co-regulated membrane-bound IL15 (mbIL15) and LIGHT (TNFSF14) generate significant antitumor efficacy in fibrotic tumor models (SITC 2024) - P1, P1/2 | "To develop IL2-independent TIL, cytoTIL15TM cells are engineered to express regulatable membrane-bound IL15 (mbIL15) using an FDA-approved small-molecule drug, acetazolamide (ACZ), which binds to the drug-responsive-domain (DRD) carbonic anhydrase 2 (CA2), driving expansion, persistence, and antitumor activity (OBX-115: NCT05470283, NCT06060613). Conclusions These preclinical results show that engineering TIL with regulatable mbIL15 and LIGHT has the potential to enhance their efficacy against challenging-to-treat tumors with a fibrotic and immunologically cold TME, opening the possibility to treat tumors currently unresponsive to non-engineered TIL cell therapy. Ethics Approval Mice were housed at Obsidian Therapeutics in accordance with approved IACUC protocols overseen annually by the Cambridge Commissioner of Laboratory Animals (Cambridge, MA) and an attending board-certified veterinarian."

Preclinical • Tumor-infiltrating lymphocyte • Colorectal Cancer • Melanoma • Oncology • Solid Tumor • CD8 • IL15 • PMEL • TNFA • TNFSF14

Session II: Next Generation TIL - OBX-115: An engineered, pharmacologically regulatable membrane-bound IL15 TIL cell therapy for advanced solid tumors (SITC 2024) - "(Luncheon), and KSQ Therapeutics, Inc. (Luncheon)."

Metastases • Oncology • Solid Tumor • IL15

Obsidian Therapeutics to Present Preclinical Data Supporting OBX-115 and cytoDRiVE Platform at the Society for Immunotherapy of Cancer (SITC) Annual Meeting 2024 (Businesswire) - "Preclinical data confirm the successful generation of OBX-115 using core needle biopsy tumor tissue procurement in NSCLC. Additional posters showcase the ability of cytoDRiVE regulation technology to potentially unlock the therapeutic window of potent cytokines and broaden the reach of armored cell therapies. mbIL12 poster (abstract 463) selected by SITC Communications Committee to be presented at the SITC 2024 Annual Meeting Press Conference, scheduled for Wednesday Nov. 6, 2024, from 12:00-1:30pm CT."

Preclinical • Non Small Cell Lung Cancer

Trial in Progress: Phase 1/2 Study of OBX-115 Engineered Tumor-Infiltrating Lymphocyte (TIL) Cell Therapy in Patients with Advanced Solid Tumors (IASLC-WCLC 2024) - P1, P1/2 | "OBX-115 is a tumor-derived autologous T-cell immunotherapy (TIL cell therapy) expanded from patient tumor tissue and engineered with a transgene to express membrane-bound human IL15 (mbIL15), regulated by acetazolamide (ACZ), eliminating the need for high-dose IL2 ( Figure 1 )...Cryopreserved OBX-115 is generated from the patient’s own tumor tissue procured by surgical excision or core needle biopsy and is infused after standard- or low-dose lymphodepletion (cyclophosphamide and fludarabine), based on clinical status and prior treatments ( Figure 2 )...ACZ may be redosed (melanoma or NSCLC) upon progression when new anticancer therapy is not immediately warranted. Four sites are open and recruiting, with additional sites being activated."

Clinical • IO biomarker • Metastases • P1/2 data • Tumor-infiltrating lymphocyte • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL15

Trial in Progress: Phase 1/2 Study of OBX-115 Engineered Tumor-Infiltrating Lymphocyte (TIL) Cell Therapy in Patients with Advanced Solid Tumors (IASLC-WCLC 2024) - P1, P1/2 | "OBX-115 is a tumor-derived autologous T-cell immunotherapy (TIL cell therapy) expanded from patient tumor tissue and engineered with a transgene to express membrane-bound human IL15 (mbIL15), regulated by acetazolamide (ACZ), eliminating the need for high-dose IL2 ( Figure 1 )...Cryopreserved OBX-115 is generated from the patient’s own tumor tissue procured by surgical excision or core needle biopsy and is infused after standard- or low-dose lymphodepletion (cyclophosphamide and fludarabine), based on clinical status and prior treatments ( Figure 2 )...ACZ may be redosed (melanoma or NSCLC) upon progression when new anticancer therapy is not immediately warranted. Four sites are open and recruiting, with additional sites being activated."

Clinical • IO biomarker • Metastases • P1/2 data • Tumor-infiltrating lymphocyte • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL15

Obsidian Therapeutics Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for OBX-115 for the Treatment of Advanced Melanoma (Businesswire) - "Obsidian Therapeutics, Inc...announced that the U.S. Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to OBX-115 for the treatment of patients with unresectable or metastatic melanoma that is resistant to immune checkpoint inhibitor (ICI) therapy."

FDA event • Melanoma • Oncology • Skin Cancer • Solid Tumor

Obsidian Therapeutics Announces FDA Fast Track Designation for OBX-115 for the Treatment of Advanced Melanoma (Businesswire) - "Obsidian Therapeutics, Inc...announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation to OBX-115, a novel engineered tumor-derived autologous T cell immunotherapy (tumor-infiltrating lymphocyte [TIL] cell therapy) armored with pharmacologically regulatable membrane-bound IL15 (mbIL15), for the treatment of patients with metastatic or locally advanced melanoma that is refractory to or has relapsed after PD-1/PD-L1–based immune checkpoint inhibitors (ICI)....'We are highly encouraged by the most recent safety and efficacy data presented at the 2024 American Society of Clinical Oncology Meeting. With this designation, we look forward to continued collaborative interaction with the FDA as we advance OBX-115 clinical development in the broad post-ICI setting'."

Fast track • Melanoma • Oncology • Skin Cancer • Solid Tumor

OBX-115, an interleukin 2 (IL2)-sparing engineered tumor-infiltrating lymphocyte (TIL) cell therapy, in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma. (ASCO 2024) - P1, P1/2 | "OBX-115 autologous engineered TIL cell therapy does not require co-administration of IL2 due to its regulatable expression of membrane-bound IL15 (mbIL15) using the FDA-approved small-molecule drug acetazolamide (ACZ) to provide cytokine support for TIL expansion and persistence...After lymphodepletion (cyclophosphamide, fludarabine), pts receive OBX-115 followed by ACZ once daily for up to 7 days; ACZ redosing (up to 7 days) is permitted at Wk 6 for non-responders... OBX-115regulatableengineeredTIL cell therapy was well-tolerated and produced consistently deepening and durable responses, indicating that OBX-115 may mediate CRs and durable clinical benefit in ICI-resistant metastatic melanoma without high-dose IL2. OBX-115 investigation continues in this and an ongoing Phase 1/2 multicenter study (NCT06060613)."

Checkpoint inhibition • Clinical • IO biomarker • Metastases • Tumor-infiltrating lymphocyte • Hepatology • Melanoma • Oncology • Pain • Solid Tumor • CD69 • CD8 • ENTPD1 • IL15 • IL2 • PD-1

A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with advanced solid tumors. (ASCO 2024) - P1, P1/2 | "OBX-115 TIL are engineered to express membrane-bound IL15 (mbIL15) under dose-dependent regulation using acetazolamide (ACZ), an FDA-approved small-molecule diuretic, avoiding the need for high-dose IL2...Cryopreserved OBX-115 is generated from the pt's own tumor tissue procured by surgical excision or core needle biopsy, and is infused after standard- (5 days) or low-dose (4 days) lymphodepletion (cyclophosphamide and fludarabine), based on clinical status...3. Creelan Nat Med 2021; Schoenfeld SITC 2021."

Clinical • IO biomarker • Metastases • P1/2 data • Tumor-infiltrating lymphocyte • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL15