A phase I study of the oncolytic peptide LTX-315 generatesde novoT-cell responses and clinical benefit in patients with advanced sarcoma

Background: LTX-315 is a first-in class oncolytic peptide that has the ability to kill cancer cells and induce specific anticancer immune response when injected locally into experimental tumors in mice. The underlying mechanism of action includes induction of immunogenic cell death with subsequent infiltration of T cells into the tumor. A multicenter Phase I study was conducted to evaluate the safety and tolerability of LTX-315 in patients with solid tumors who had no treatment options available. Methods: Patients with unresectable metastatic cancer were recruited to the study.The primary objective was to assess the safety and tolerability of multiple, intratumoral doses of LTX-315 as a monotherapy. The secondary objective was to evaluate clinical efficacy (assessed by irRC) and the ability of LTX-315 to evoke local and systemic immune responses. Paired pre and post treatment tumor samples were collected throughout the study. Immunohistochemistry and gene expression analysis were performed on the paired tumor biopsies. T-cell receptor (TCR) repertoire in peripheral blood and biopsies was assessed by TCRβ-gene sequencing. Results: Twenty-seven patients were treated with LTX-315 monotherapy and had at least one post baseline efficacy assessment, of which 8 patients had melanoma. Best overall response seen in the melanoma patients was SD which was evident in 5 out of these 8 patients (62.5%). Five patients had a marked tumor regression (25-82% reduction) in distant non-injected lesions post treatment. Treatment emergent adverse events occurred in all 8 patients, but no patients experienced a serious adverse event. Six patients experienced LTX-315-related adverse events, the commonest being tingling post injection, others included rash, fatigue, diarrhea, hypo- and hypertension and weakness. Ninety percentage of LTX- 315 related events were grade 1, and one patient experienced a grade 3 event of hypertension. All toxicities resolved without sequale except weakness which was ongoing at time of study completion. Increased number of CD8+ T cells was observed in all treated lesions with evaluable biopsies. Gene expression profiling by Immunosign® 21 was assessed in injected lesions from 2 patients. A “cold to hot’’ signature change was found in one patient whereas “warm to hot” signature was seen in the other patient. Sequencing of T cell receptor from peripheral blood samples from pre- and post LTX-315 treatment revealed significant clonal expansion of T cells after treatment in the patient with “cold to hot” signature, and 24% of these clones were also detected in the post-treatment biopsy tumor sample. Conclusions: Intratumoral LTX-315 is safe and well tolerated. LTX-315 monotherapy enhances TIL population and induces polyclonal T-cell responses. Based on the data from the Phase I study, further development of LTX-315 will focus on therapeutic combination with other targeted immune therapies such as checkpoint inhibitors to address unmet need in a selected indications. Registration Number: NCT01986426 Citation Format: Aurelien Marabelle, Jean-Francois Baurain, Ahmad Awada, Rebbecca S. Kristeleit, Delphine Loirat, Dag E. Jossang, Nina L. Jebsen, Baldur Sveinbjornsson, Oystein Rekdal, Vibeke S. Gjerstad, Paal Brunsvig, Jerome Galon, Fabienne Hermitte, Hamina Patel, James Spicer. A Phase I study of the oncolytic peptide LTX-315 generates de novo T-cell responses and clinical benefit in patients with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT069.