Histopathological and immunological spectrum in response evaluation of talimogene laherparepvec treatment and correlation with durable response in patients with cutaneous melanoma

Abstract

Talimogene laherparepvec (T-VEC) is an intralesional oncolytic virotherapy for patients with irresectable stage III-IVM1a cutaneous melanoma. Although this treatment is considered to mainly act through T cell-mediated mechanisms, prominent numbers of plasma cells after T-VEC treatment have been described. The aim was to investigate how often these plasma cells were present, whether they were relevant in the response to treatment, and if these or other histopathological features were associated with durable response to treatment. Histopathological (granulomas, perineural inflammation, etc.) and immunological features [e.g. B cells/plasma cells (CD20/CD138) and T cells (CD3,CD4,CD8)] were scored and correlated with durable tumor response [i.e. complete response (CR) persisting beyond 6 months after treatment]. Plasmacellular infiltrate was examined with next-generation sequencing and immunohistochemistry (IgG, IgM, IgA, and IgD). Plasma cells were present in all T-VEC injected biopsies from 25 patients with melanoma taken at 3-5 months after starting treatment. In patients with a durable response ( n = 12), angiocentric features and granulomas were more frequently identified compared with patients without a (durable) response ( n = 13); 75% versus 29% for angiocentric features ( P = 0.015) and 58% versus 15% for granulomas ( P = 0.041). There was a class switch of IgM to IgG with skewing to certain dominant Ig heavy chain clonotypes. An angiocentric granulomatous pattern in T-VEC injected melanoma lesions was associated with a durable CR (>6 months). Plasma cells are probably a relevant feature in the mechanism of response but were not associated with durable response.

Fig. 1

A representative case of successful treatment with T-VEC. This H&E shows a complete response (i.e. no residual melanoma tumor tissue) after 12 months of T-VEC treatment and the presence of (a) diffuse plasma cells [CD138]. Plasma cells can be recognized by their oval shape, round and eccentric nucleus with coarse chromatin, a prominent perinuclear hof, and abundant basophilic cytoplasm. Also, a classical HSV-associated histopathological pattern was seen, including (b) angiocentric and (c) perineural features, and (d) granulomas. H&E, hematoxylin and eosin; T-VEC, talimogene laherparepvec.

Fig. 2

Plasma cell formation after 3 months of T-VEC treatment. H&E shows a subcutaneous in-transit metastasis, identified by (SOX10), with peritumoral plasma cells (CD138). H&E, hematoxylin and eosin; T-VEC, talimogene laherparepvec.

Fig. 3

Immunoglobulin subclasses expressed by plasma cells in T-VEC injected biopsies. H&E showing prominent and diffuse plasma cell formation (CD138), predominantly IgG isotype. Other isotypes (IgM, IgA, and IgD) were barely present. H&E, hematoxylin and eosin; Ig, immunoglobulin; T-VEC, talimogene laherparepvec.