Dermatologic toxicity from novel therapy using antimicrobial peptide LL‐37 in melanoma: A detailed examination of the clinicopathologic features

Abstract

LL-37 is a naturally occurring 37-amino-acid peptide that is part of the innate immune system in human skin. Preclinical studies have showed that intra-tumoral injections of LL-37 stimulate the innate immune system by activation of plasmacytoid dendritic cells, which mediate tumor destruction. LL-37 intra-tumoral injections have been utilized in a phase 1 clinical trial for melanoma patients with cutaneous metastases. We report dermatologic toxicity in a 63-year-old woman with stage IIIC melanoma of the right calf and inguinal lymph nodes. She was previously treated with nivolumab and combination chemotherapy (cisplatin, vinblastine and dacarbazine) and subsequently treated with LL-37 injections upon progression of both prior regimens. She received a total of 8 weekly LL-37 injections, with interval clinical shrinkage of injected lesions. However, approximately 45 days after initiation of this therapy, she presented with multiple verrucous papules and a vesiculo-bullous lesion on the trunk and extremities. Clinically, most of these lesions were thought to be either squamous cell carcinoma or inflamed seborrheic keratosis. Histologically, 11 of the total 12 skin biopsies showed similar histopathologic features, with a prominent lichenoid inflammatory infiltrate admixed with eosinophils and an overlying atypical squamous epithelial proliferation with verrucous and keratoacanthoma-like features and varying degrees of keratinocytic atypia. Interestingly, a majority of the lesions did not show spongiosis (11/12). All lesions resolved within 2 months of cessation of LL-37 injection therapy. This case highlights adverse dermatological manifestations of LL-37 therapy, similar to the consequences of other novel therapies.

Myeloid cell-derived LL-37 promotes lung cancer growth by activating Wnt/β-catenin signaling

“…Previous studies performed by our research group and other investigators have suggested that the expression of LL-37 is increased in a variety of cancers, including ovarian 18, lung, colon 46, breast 47, and melanoma 48. However, gastric cancers produce lower amounts of LL-37, which inhibit tumor growth in this type of cancer.…”

Significance of LL-37 on Immunomodulation and Disease Outcome

“…Furthermore, LL-37 induced an activation and expansion of OVA-antigenspecific CD8 + T cells in draining lymph nodes and the tumor microenvironment [149]. This process was associated with delay in tumor growth, while preclinical studies have also demonstrated that intratumoral injections of LL-37 stimulate the innate immune system by the activation of pDCs [150]. These cells can induct and maintain antitumor immune responses and mediate tumor destruction [151].…”

Enhanced therapeutic index of an antimicrobial peptide in mice by increasing safety and activity against multidrug-resistant bacteria

“…Antimicrobial peptides (AMPs), which rapidly disrupt bacterial membranes regardless of resistance to traditional antibiotics, constitute a potentially effective therapeutic resource. However, for nearly four decades after their initial discoveries, there are no classical AMPs in clinical use yet, although the recent surge in preclinical and clinical development to overcome the urgent antibiotic resistance problems is a strong indication of the renewed interest in AMP development compared to the previous two decades (4)(5)(6)(7). Notably, LL37 is in clinical trials for leg ulcer and melanoma, D2A21 for burn wound infections, LTX-109 for MRSA skin infections, NP213 for fungal nail infections, and AB103 for soft tissue infections as part of a list of AMPs in clinical development.…”