Abscopal responses in patients with metastatic melanoma involving skin and subcutaneous tissues treated with intralesional IL2 plus BCG

Abstract

Cutaneous melanoma is relatively common with increasing incidence and significant mortality. While the mainstay of therapy is surgical, patients with stage III and IV disease fare poorer than those with early-stage disease and often benefit from adjuvant therapies. While systemic immunotherapy has changed the landscape of melanoma treatment, for some patients systemic toxicities related to these treatments prohibit successful administration or completion of therapy. Moreover, it is becoming increasingly evident that nodal, regional, and in-transit disease appears to be resistant to systemic immunotherapy relative to responses observed in distant metastatic disease sites. In this scenario, intralesional immunotherapies may offer benefit. In this case series, we describe the use of intralesional IL-2 and BCG at our institution in ten patients with in-transit plus or minus distant cutaneous metastatic melanoma over the last twelve years. All patients received intralesional IL2 and BCG. Both treatments were very well tolerated with only grade 1/2 adverse events. In our cohort, complete clinical response was 60% (6/10), progressive disease in 20% (2/10), and no response in 20% (2/10) of patients. The overall response rate (ORR) was 70%. The median overall survival was 35.5 months and mean overall survival 43 months in this cohort. Herein we further highlight the clinical, histopathological, and radiological course of two complete responders, showing evidence of an abscopal effect with resolution of distant untreated metastasis. Together, this limited data supports the safe and effective use of intralesional IL2 and BCG for the treatment of metastatic or in-transit melanoma in this challenging patient cohort. To our knowledge, this is the first formal study to report on this combination therapy for the treatment of melanoma.

Keywords: BCG; IL2; in-transit melanoma; interleukin 2; intralesional; intratumoral; melanoma.

Figure 1

Timeline of intralesional IL2 and BCG treatments. Each bar represents a two-week period and are grouped in tens (where applicable) for ease of viewing. iIL2 treatments occur every two weeks (green bars), while BCG was added after partial response to iIL2 every 2-4 weeks for 1-4 treatments. CCR, complete clinical response; PR, partial response; PD, progressive disease; SD, stable disease; NR, no response.

Figure 2

Overall survival of ten patients with metastatic or in-transit melanoma treated with iIL2 and BCG. Survival for each patient is measured as months alive since beginning intralesional therapy, to last follow-up or death. Shaded green is 95% confidence intervals. Mean overall survival was 43 months, and median overall survival in this cohort was 35.5 months.

Figure 3

Representative clinical course of a case of a complete responder, patient #2. (A) Photo of primary lesion on day one of IL-2 treatment. (B) Photo of lesion following IL-2 monotherapy showing progression of lesions. (C) Photo of lesion on the day of BCG initiation, showing stable disease (D) PET-CT early on during IL-2 monotherapy showing extent of disease, with metastatic node highlighted. (E) PET-CT following treatment with IL-2 and one BCG treatment, showing metastasis. (F) Photo of the lesion following two BCG treatments, showing the typical ulceration seen with BCG injection. G. Photo of the treated area following treatment course, showing complete resolution. H. Post-treatment PET CT, showing reactive lymphadenopathy with no further evidence of metastatic disease and radiographic resolution of the cutaneous lesions.

Figure 4

A representative case from a complete responder to intralesional IL-2 and BCG therapy. (A) Representative images of the treated lesion throughout IL-2 monotherapy treatment course. (B) PET-CT scan three years into IL-2 monotherapy showing new uptake among cutaneous lesions, signaling disease progression. (C) Representative image of the treated lesion following IL-2 and BCG treatment. (D) PET-CT scan after three BCG treatments showing regression of main lesions radiographically with new FDG uptake in distal lesions. (E) Representative image of the area after treatment, showing clinical resolution of BCG ulcers and in-transit metastasis. (F) Surveillance PET-CT two years post-treatment, showing no evidence of disease.

Figure 5

Punch biopsy of lesion following intralesional-IL-2 and BCG. (A) No evidence of residual melanoma, central necrosis and surrounding granulomatous reaction (low power) (B) Area of central necrosis (medium power) (C) Granulomatous reaction (medium power) (D) Granulomatous reaction (high power).