Jeffrey Sosman

In-transit metastases of malignant melanoma pose a significant clinical challenge, particularly in patients with contraindications to systemic therapies. While surgical excision and systemic immunotherapies remain standard treatments, localized therapies such as intralesional talimogene laherparepvec (T-VEC) and topical imiquimod, which stimulate tumor-specific T-cell responses, have garnered increasing attention for their potential efficacy and tolerability. Although the individual efficacy of these therapies is well-documented, their combined use and their synergistic effects have not been well-documented. This case series reports on five patients with in-transit melanoma metastases treated with T-VEC and imiquimod at Northwestern Memorial Hospital from November 2018 to May 2023. Patients received a median of 13 (range 8–20) T-VEC injections over a median of 6 months (range 5–9), of which 4 of those months were with concurrent T-VEC and imiquimod cream. Four of the five patients achieved complete response (CR) by the end of the treatment course. One patient developed systemic progression during therapy, leading to early cessation of treatment. All patients with CR elected to continue topical imiquimod applications as maintenance following T-VEC for a median of 6 months (range 2–14 months). Only one of the four patients who achieved CR developed metastatic nodal disease 10 months after the last T-VEC injection. The three other patients are free of cutaneous and systemic disease 2–57 months after their last injection. All patients tolerated treatment well with zero patients discontinuing treatment due to side effects. These findings suggest that the combination of intralesional T-VEC and topical imiquimod can be an effective and safe treatment of in-transit metastases of malignant melanoma.

Antitumor responses of CD8 ⁺ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4–dependent (GPX4-dependent) ferroptosis. Here, we show the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8 ⁺ T cells. Activated CD8 ⁺ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy. Additionally, we identify a particular cluster of intratumoral CD8 ⁺ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH/GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8 ⁺ T cells.

It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies. Since then, the evolution of cancer immunotherapy has led to new and effective treatment approaches for melanoma. However, despite these advances, a sizable portion of patients with advanced melanoma have de novo or acquired resistance to immune checkpoint inhibitors. At the same time, therapies (BRAF plus MEK inhibitors) targeting the BRAF^V600 mutations found in 40–50% of cutaneous melanomas have also been critical for optimizing management and improving patient outcomes. Even though immunotherapy has been established as the initial therapy in most patients with cutaneous melanoma, subsequent effective therapy is limited to BRAF^V600 melanoma. For all other melanoma patients, driver mutations have not been effectively targeted. Numerous efforts are underway to target melanomas with NRAS mutations, NF-1 LOF mutations, and other genetic alterations leading to activation of the MAP kinase pathway. In this era of personalized medicine, we will review the current genetic landscape, molecular classifications, emerging drug targets, and the potential for combination therapies for non-BRAF^V600 melanoma.