Successful treatment with intralesional talimogene laherparepvec in two patients with immune checkpoint inhibitor-refractory, advanced-stage melanoma

Abstract

Monoclonal antibodies that block the programmed death-1 (anti-PD-1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4) immune checkpoint receptors (pembrolizumab, nivolumab, ipilimumab, or the combination of nivolumab with ipilimumab) are approved treatment option for patients with advanced melanoma. Over half of all patients are refractory to these immunotherapies and are in need of alternative or complementary treatment options. Talimogene laherparepvec (T-VEC) is a first-in-class intralesionally delivered oncolytic immunotherapy, which has proven efficacy in the treatment of advanced melanoma. A proportion of patients treated with T-VEC will benefit from an abscopal response of noninjected metastases indicative of a systemic antitumor immune response elicited by the intratumoral injections. At present it remains unknown whether the systemic antitumor responses elicited by T-VEC are nonredundant with immune-checkpoint blockade. Recent data on potential synergy between T-VEC and both PD-1 and CTLA-4 blockade suggest that the mechanism of action may be complementary. We report on the successful treatment with intralesional T-VEC of two female patients with locoregionally advanced BRAF V600 wild-type melanoma who previously progressed on anti-PD-1 and anti-CTLA-4 inhibitors.

Talimogene laherparepvec treatment to overcome loco-regional acquired resistance to immune checkpoint blockade in tumor stage IIIB–IV M1c melanoma patients

“…Two case series highlight the clinical efficacy of T-VEC after progression on multiple previous therapies [26,27]. In accordance with these publications, in our center, four out of eight patients profited from T-VEC after ICB or/and targeted therapy.…”

“…Patients with high tumor burden and a rapid tumor progression did not respond to second-line T-VEC treatment. Even though LDH level is not reported or not correlated to clinical response in other case series with pre-treated melanoma patients who received T-VEC as second-line treatment [12,15,26,27], we suggest that elevated LDH level can serve as a useful indicator. A sensible selection of suitable patients seems to be crucial and high medical need patients seem to require more aggressive therapeutic intervention.…”

PD-1-siRNA delivered by attenuated Salmonella enhances the antimelanoma effect of pimozide

“…Therefore, targeting immune checkpoint molecules is expected to become a very effective antitumor strategy. Currently, targeting PD-1 and its ligand programmed cell death 1-ligand 1 (PD-L1) to block their signaling has achieved great success in the treatment of melanoma 12,30–34 . The PD-1/PD-L1 axis plays a key role in host immune monitoring and tumor microenvironment regulation, and hence inhibiting this pathway may release immune-responsive molecules and generate a long-lasting antitumor response in combination with anticancer drugs 35,36 .…”

Insights into the Molecular Mechanisms Behind Intralesional Immunotherapies for Advanced Melanoma

“…Thus, systemic toxicity is blunted; it seems to be limited to the effects of the cytokine response associated with the anti-tumor immune response, and not to a systemic activation of autoimmune T cells. Importantly, some evidence suggests that intralesional approaches may be able to induce potent systemic anti-tumor immune responses [16,[22][23][24]29,41,48,57,107], likely due to tumor antigen-primed cytotoxic T cells that home towards the chemokine storm induced by the host-tumor immune reaction.…”

“…Furthermore, T-VEC was highly successful in the treatment of melanoma in prior transplant patients with an altered immune landscape [47], further supporting its ability to induce a potent anti-tumor immune response. Indeed, in patients who were treatment refractory to multiple immunotherapies, T-VEC was able to induce CRs and promote systemic immunity [48,107].…”