In situ photoimmunotherapy: a tumour-directed treatment for melanoma

Abstract

We report a new immunological treatment for advanced cutaneous melanoma which combines laser stimulation with topical application of a toll-like receptor agonist. This treatment, in situ photoimmunotherapy (ISPI), provides an alternative to traditional therapies for melanoma patients with cutaneous metastases. A 6-week cycle of ISPI is carried out on cutaneous metastases located in a designated 20 x 20 cm treatment area: 2 weeks of pretreatment with twice-daily topical applications of imiquimod (5% cream under plastic occlusion), with a laser treatment session at week 2 and again at week 4. Topical imiquimod is continued for the entire 6-week cycle. Two patients with late-stage melanoma were treated with ISPI. Patient 1 had the primary tumour and local metastases on the left arm, as well as metastatic tumours in the lungs [American Joint Committee on Cancer (AJCC) stage IV]. Patient 2 had a head and neck melanoma with multiple local metastases (AJCC stage IIIC), which had failed repeated attempts at surgical resection and high-dose radiation therapy. Patient 1 is now free of all clinically detectable tumours (including the lung metastases) >20 months after the first treatment cycle. Patient 2 has been free of any clinical evidence of the tumour for over 6 months. These two cases demonstrate that ISPI can clear local tumour and trigger beneficial systemic responses, with a side-effect profile that compares favourably with other treatments for advanced melanoma.

An Exploratory Study of Systemic Administration of the Toll-like Receptor-7 Agonist 852A in Patients with Refractory Metastatic Melanoma

“…CpG, a TLR9 agonist that also induces plasmacytoid dendritic cell IFN-a production, is being investigated in combination with chemotherapy for metastatic melanoma. 9 Combining topical imiquimod with photodynamic therapy induced regression not only of treated cutaneous melanoma metastasis but also of a distant metastasis (43). It can be postulated that the physical destruction of the cells makes more tumor antigens available, allowing imiquimod to more effectively enhance tumor-specific cell-mediated immunity.…”

TLR activation and ionizing radiation induce strong immune responses against multiple tumor entities

“…For example colorectal liver metastases might be injected with the TLR agonists and irradiated even more easily than treating the primary colon cancer with this regimen. Anecdotal reports support this theory, 10 although validation in preclinical models is required prior to the initiation of clinical trials.…”

Clinical effects of in situ photoimmunotherapy on late-stage melanoma patients

“…15 These two patients, one stage IV-M1b and one stage IIIC, had complete responses and are still alive at the time of this writing. In the present study, we report preliminary clinical results for the first series of eleven metastatic melanoma patients, including the original two patients, in terms of safety and efficacy of ISPI.…”

“…These specific cases strongly indicate the feasibility and efficacy of the combination of thermal therapy and immunological stimulation for the treatment of metastatic tumors. 15 …”

“…This includes two patients that were previously reported. 15 Since one patient had his single systemic metastasis treated by cyberknife, the CR was not exclusively due to ISPI, although he has remained tumor free for more than a year at the time of this writing (patient 10, Table 3). CLR was observed in the non-treatment site regional lesions solely as a distant, presumably immunological effect, in 4fourpatients.…”