Oncolytic Adenovirus TILT-123 Combined With TIL Therapy Is Safe in Metastatic Melanoma

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Intravenous and intratumoral treatment with TILT-123 was found to be safe and feasible, with no dose-limiting toxicities when given alone or in combination with tumor infiltrating lymphocyte (TIL) therapy in patients with advanced, metastatic melanoma, according to data from a phase 1 trial (NCT04217473) presented at the 2023 ESMO Immuno-Oncology Annual Congress.

Treatment with the oncolytic adenovirus in combination with TIL therapy resulted in 3 grade 3/4 adverse effects (AEs) related to TILT-123 and 5 related to TIL therapy, though no AEs were considered dose-limiting; however, 4 serious AEs were related to TILT-123, including fever (n = 3) and infection in the injected tumor (n = 1).

Notably, the disease control rate was 38% (n = 16). Of the evaluated patients, 62.5% had progressive disease, 25% had stable disease (SD), 6.3% had partial response (PR), and 6.3% had complete response (CR).

“Clinical activity of this combined treatment has been observed, including responses in patients with hard-to-treat melanoma,” said Tine J. Monberg, MD, of the National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital in Herlev, Denmark.

Oncolytic virus therapy is known to kill cancer cells and increase the potential to initiate an immune response against a patient’s tumor, making it an appealing therapeutic approach, Monberg explained in a presentation of the data. TILT-123 is an oncolytic adenovirus that is engineered for intravenous or intratumoral administration and can replicate selectively in cancer cells. In turn, this results in direct lytic tumor killing and exposure of tumor antigens to the immune system. Notably, this therapeutic approach also has a high level of transgene production which leads to the recruitment of T cells.

Based on the promise of utilizing an oncolytic adenovirus in patients, investigators aimed to explore its utility when combined with other types of immune therapy, such as TILs, Monberg said. It was hypothesized that combining TILT-123 with TIL therapy will increase the efficacy of TIL therapy, limit the need for toxic pre- and post-conditioning regimens, and elicit combined anti-tumor benefits of the 2 therapies.

Patients with checkpoint inhibitor refractory or recurrent stage III to IV melanoma aged 18 to 75 years were eligible for enrollment into the phase 1, dose-escalation, multicenter trial. Additional eligibility criteria required a performance status of no more than 1, a resectable tumor greater than 9 mm for TIL production, and at least 1 additional tumor available for injections.

Furthermore, patients had to have evaluable disease burden; adequate organ function; lactate dehydrogenase value of less than 3 x upper limit of normal; and no use of immunosuppressive medications.

Eligible patients were enrolled into cohort 1 (n = 3), cohort 2 (n = 3), cohort 3 (n = 3), cohort 4 (n = 3), and cohort 5 (n = 4). Patients received an intravenous virus dose of 3 x 109 and an intratumoral virus dose of 3 x 109 (cohort 1), 3 x 1010 and 3 x 1010 (cohort 2), 3 x 1011 and 1 x 1011 (cohort 3), 1 x 1012 and 3 x 1011 (cohort 4), and 3 x 1012 and 3 x 1011 (cohort 5).

Tumor resection for TIL therapy was performed at baseline and expansion occurred between weeks 4 and 6.

“A patient received the first dose of TILT-123 as an intravenous treatment, and this was followed by 5 treatments intratumorally over a period of 64 days,” Monberg explained.

Furthermore, TIL therapy was administered as a 1-time or 2-time treatment in between virus injections. Patients were evaluated on day 36 before TIL treatment, and the final evaluation was done on day 78 after all treatment had been completed.

The primary end point of the investigation was to evaluate the safety of TILT-123 therapy. Secondary end points included the safety of TILT-123 in combination with TIL therapy and efficacy evaluated by RECIST v1.1 and PET criteria.

Of the patients enrolled on the study, a majority (56.3%) were female and the median age of those enrolled was 66 years (range, 25-75). Additionally, 75% of patients had a World Health Organization performance status of 0 and 25% had a performance status of 1. Of these enrolled patients, 18.9% of had a BRAF V600 mutation and 81.3% were BRAF wild type.

Moreover, 25% of patients had unresectable stage IIIC disease and 75% had stage IV disease. The median number of prior lines of systemic therapy was 3 (range, 1-7). Histologies of patients enrolled included cutaneous (7), uveal (4), and mucosal (5).

The most common AEs reported in patients related to TILT-123 included fever (63%), pain at the injection site (44%), and fatigue (38%). The most common AEs reported in patients related to TIL therapy were fever (56%), chills (38%), and fatigue (25%).

In the presentation, Monberg stated that 1 patient with mucosal melanoma had a durable CR, 1 patient with cutaneous melanoma had an ongoing PR, and 2 patients (1 with uveal and 1 with cutaneous melanoma) had long-lasting SD of longer than 10 months.

Additional results regarding PET responses on day 78 showed that 50.0%, 21.4%, 7.1%, and 21.4% of patients (n = 14) had progressive metabolic disease (PMD), stable metabolic disease (SMD), minor metabolic response (MMR), and partial metabolic response (PMR), respectively, with the combination approach. Disease control was reported in 7 of 14 patients. Furthermore, 35.7%, 28.6%, 14.3%, and 21.4% of patients had PMD, SMD, MMR, and PMR, respectively, when treated with TILT-123 alone. Disease control was reported in 9 of 14 patients.

Monberg concluded by reviewing the case of the 48-year-old patient with a durable CR who had been diagnosed with resistant, unresectable, mucosal melanoma. She had been previously treated with 7 cycles of ipilimumab (Yervoy) and nivolumab (Opdivo) therapy and on day 78, she had a PR and PMR with study treatment. After day 270, investigators confirmed complete pathological response, and the patient is continuing treatment with TILT-123 in the extension arm of the protocol.

Reference

Monberg, TJ, Pakola S, Dreno B, et al. Safety and efficacy of combined treatment with tumor infiltrating lymphocytes (TILs) and oncolytic adenovirus TILT-123 for patients with metastatic malignant melanoma – results from a phase I trial. Ann Oncol. 2023;20(suppl 1):100520. doi:10.1016/iotech/iotech100520

Disclosures: Dr Monberg disclosed financial interests with Bristol Myers Squibb, invited speaker, personal; and non-financial interests with Lytix Biopharma, co-investigator in clinical trial and TILT Biotherapeutics, co-investigator in clinical trial.