OBX-115 With Acetazolamide Induces Safe and Durable Antitumor Responses in Advanced Melanoma

Intravenous infusion with OBX-115, an IL-2–free, regulatable, engineered tumor-infiltrating lymphocyte (TIL) cell therapy was well tolerated and produced durable antitumor responses in patients with immune checkpoint inhibitor (ICI)-resistant advanced melanoma, according to data from a first-in-human, single-center, phase 1 study (NCT05470283) presented at the 2024 AACR Annual Meeting.

The results demonstrated that the investigator-assessed objective response rate (ORR) was 50% among evaluable patients (n = 6), which included 2 complete responses, 1 partial response (PR), and 3 cases of stable disease for a disease control rate of 100%. Additionally, all patients were alive at the January 2, 2024, data cut-off. Notably, despite ongoing tumor growth in most patients prior to OBX-115 infusion, all patients experienced reductions in tumor burden and meaningful disease control for at least 12 weeks following treatment.

Furthermore, durable responses occurred, particularly in cases where OBX-115 was manufactured from core needle biopsy (CNB) tumor tissue. Additionally, the median progression-free survival (PFS) was not reached with a median follow-up of 24.9 weeks (range, 15.7-56.0).

“[OBX-115] demonstrates the successful clinical application of [drug-responsive domain] DRD technology for regulatable transgene expression at the protein product level,” Rodabe N. Amaria, MD, and colleagues wrote in a poster presentation of the data. “[It also] clinically validates membrane-bound human IL-15 [mbIL15] as a cytokine that supports TIL expansion and function.”

Amaria is an assistant professor of medicine in the Department of Melanoma Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

Patients with ICI-resistant advanced melanoma face limited treatment options. Lifileucel (Amtagvi), an FDA-approved non-engineered tumor-derived autologous T-cell immunotherapy, has demonstrated promising activity in PD-1–pretreated advanced melanoma. However, it comes with a treatment-related mortality rate of 7.5%. Additionally, all non-engineered TIL therapies must be administered with high-dose IL-2, which is associated with high-grade toxicity, restricting patient eligibility and often requiring specialized management.

OBX-115 TIL cells are engineered with a transgene to express mbIL15 which encodes a fusion protein coupling mbIL15 with a DRD from the carbonic anhydrase 2 protein. Additionally, upon administration, acetazolamide (Diamox), an FDA-approved small-molecule drug, binds to DRD, stabilizes the fusion protein and facilitates the expression of mbIL15 on OBX-115 cell surfaces.

This combination was investigated in the single-center study. To be eligible for enrollment patients had to have pathologically confirmed, unresectable stage III or IV melanoma that was relapsed or refractory to prior ICI therapy. Additionally, patients had to have at least 1 lesion suitable for OBX-115 manufacturing and another lesion remaining after tumor tissue procurement. ECOG performance status of 0 or 1 was also required.

The dose-escalation phase consisted of two cohorts. In cohort 1 (n = 3), OBX-115 was administered at 30 × 10⁹ cells maximum, though 1 patient received 150 × 10⁹ cells and acetazolamide at 500 mg/day per an earlier version of the protocol. Acetazolamide was also administered at 125 mg/day from day 2 to 9. In cohort 2b (n = 3-6), OBX-115 was administered at 100 × 10⁹ cells maximum alongside acetazolamide at 125 mg/day from day 2 to 9 of the study. Additional escalation/de-escalation cohorts were enrolled as needed.

Regarding administration fresh non-cryopreserved OBX-115 was produced using the patient’s own tumor tissue obtained via excisional or CNB and delivered intravenously after standard- or low-dose lymphodepletion with cyclophosphamide and fludarabine. Acetazolamide was orally administered at cohort-specific doses once daily for up to 7 days, with the option of additional acetazolamide during weeks 6 to 8 if the initial tumor response was less than a PR. Notably, there was no systemic administration of high-dose IL-2.

A total of 12 patients were enrolled but only 6 patients underwent infusion with OBX-115, received at least 1 dose of acetazolamide, and had a follow-up period of at least 12 weeks. All patients had disease that was primary refractory to and had progressed on anti–PD-1 therapy, and all patients had previously undergone and progressed on anti–CTLA-4 therapy. Furthermore, 83.3% of patients had received combination anti–CTLA-4 and anti–PD-1 therapy. Notably, OBX-115 was successfully manufactured for all 6 patients, including from CNB tumor tissue.

The primary end points of the study include assessing safety through the incidence and severity of adverse effects (AEs) and serious AEs (SAEs), evaluating tolerability by monitoring dose interruptions, reductions, and discontinuations, and determining the recommended dose by identifying dose-limiting toxicities (DLTs). Key secondary end points focus on efficacy and include investigator-assessed ORR, duration of response, and PFS per RECIST v1.1 criteria.

The median age of patients evaluated was 47.5 years (range, 28-64). A majority of patients were female (83.3%). Two patients each had BRAF mutations or NRAS mutations. The median target lesion sum of diameters was 39.4 mm (range, 11.7-81.5), 1 patient had brain lesions, and 2 had liver lesions. Furthermore, patients had an ECOG performance status of 0 (66.7%) or 1 (33.3%), and lactate dehydrogenase equal to or below the limits of normal was seen in 66.7% of patients.

Patients had a median of 2.5 prior lines of systemic therapy (range, 1-5) and a median of 2.5 prior lines of ICI therapy (range, 1-3). Types of prior systemic therapies included anti–PD-1 agents (100%), anti–CTLA-4 inhibitors (100%), and a combination of both anti–PD-1 and anti–CTLA-4 inhibitors (83.3%). All patients were anti–PD-1 primary resistant and none underwent systemic bridging therapy.

Regarding treatment characteristics, patients underwent surgical excision (16.7%) and core needle biopsy (83.3%) for tissue procurement, and 83.3% and 16.7% of patients underwent standard-dose and low-dose lymphodepletion, respectively. Regarding OBX-115 infusion the median amount of infused cells x 109 was 54.5 (range, 9.6-150). The median percentages of CD3-positive cells, CD8-positive cells, and IL-15-positive viable cells were 99% (range, 97%-100%), 97.5% (range, 95.9%-99.5%), and 71.5% (range, 48%-78%), respectively. Additionally, the dose of acetazolamide was reduced at week 6 in 80% of patients.

Regarding safety, no DLTs were reported; hematologic AEs were consistent with the known safety profile of lymphodepletion; 3 grade 3 (n = 2) and no grade 4 non-hematologic AEs were reported within 30 days following OBX-115 infusion. Moreover, no confirmed immune effector cell–associated neurotoxicity syndrome (ICANS), capillary leak syndrome, or cytokine release syndrome was reported. Five patients experienced rash and pruritus, 3 patients experienced uveitis (all grade 1 or 2), and no patient died during the study or received care in the intensive care unit. Additional non-hematologic AEs seen included abdominal pain (all grade, 16.7%; grade 3, 16.7%), alanine aminotransferase elevation (50%; 16.7%), and syncope (16.7%; 16.7%).

Further exploration of OBX-115’s efficacy and safety profile in larger cohorts is warranted to validate its therapeutic potential and is currently under study in an ongoing phase 1/2 multicenter study (NCT06060613).

Reference

Amaria RN, McQuade JL, Davies MA, et al. OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy induced deepening and durable responses without interleukin 2 (IL2) in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT176.