A phase I/II study of the oncolytic peptide LTX-315 combined with checkpoint inhibition generates de novo T-cell responses and clinical benefit in patients with advanced solid tumors.

3094 Background: LTX-315 disintegrates cytoplasmic organelles and induces immunogenic cell death and systemic immune responses preclinically. Systemic efficacy can be enhanced in vivo by combination with immune checkpoint inhibitors (ICI). Clinical safety has been demonstrated as a single agent administered intratumorally in a phase I study Methods: Patients with heavily pretreated advanced solid tumors were treated twice weekly with intratumoral LTX-315 over 3 weeks; as monotherapy, or in combination with ipilimumab or pembrolizumab. Primary endpoint was safety of LTX-315 combined with ICI. Anti-tumor activity was assessed by using immune-related response criteria (irRC). Immunohistochemistry and gene expression analysis were performed on tumor biopsies pre and post treatment. T-cell receptor (TCR) repertoire in peripheral blood and biopsies was assessed by TCRb-gene sequencing. Results: Fifty-nine patients were treated. Eleven experienced LTX-315-related grade 3/4 adverse events, mainly allergic/anaphylaxis, all resolving without sequelae. Out of 36 patients treated with LTX-315 monotherapy, best overall response of SD at 2 months was seen in 28%. Out of 17 TNBC patients treated with LTX-315 plus pembrolizumab, 12 were evaluable, of which 17% had PR, and 25% SD. Six melanoma patients received LTX-315 plus ipilimumab, of those SD was observed in 33%. LTX-315 monotherapy resulted in increased number of CD8+ T-cells in treated lesions in 89% of evaluable biopsied patients. TCR sequencing revealed clonal expansion of T-cells in blood after LTX-315 monotherapy, and 50% of these clones were detected in post-treatment biopsied tumors. Conclusions: Intratumoral LTX-315 is generally safe and tolerable when combined with ICI. The combination has anti-tumor activity. LTX-315 monotherapy enhances TIL population and induces polyclonal T-cell responses, demonstrating the potential of LTX-315 as a T-cell primer combined with other immunotherapies. Clinical trial information: NCT01986426.