LTX-315-enabled, radiotherapy-boosted immunotherapeutic control of breast cancer by NK cells

Abstract

LTX-315 is a nonameric oncolytic peptide in early clinical development for the treatment of solid malignancies. Preclinical and clinical evidence indicates that the anticancer properties of LTX-315 originate not only from its ability to selectively kill cancer cells, but also from its capacity to promote tumor-targeting immune responses. Here, we investigated the therapeutic activity and immunological correlates of intratumoral LTX-315 administration in three syngeneic mouse models of breast carcinoma, with a focus on the identification of possible combinatorial partners. We found that breast cancer control by LTX-315 is accompanied by a reconfiguration of the immunological tumor microenvironment that supports the activation of anticancer immunity and can be boosted by radiation therapy. Mechanistically, depletion of natural killer (NK) cells compromised the capacity of LTX-315 to limit local and systemic disease progression in a mouse model of triple-negative breast cancer, and to extend the survival of mice bearing hormone-accelerated, carcinogen-driven endogenous mammary carcinomas. Altogether, our data suggest that LTX-315 controls breast cancer progression by engaging NK cell-dependent immunity.

Development of Anticancer Peptides Using Artificial Intelligence and Combinational Therapy for Cancer Therapeutics

“…However, this method also has some side effects, such as sore skin, tiredness, hair loss, and problems with eating and drinking [ 6 , 7 , 8 ]. It has also been reported that a combination of ACPs and radiotherapy could exert a synergistic effect on killing cancer cells [ 196 ]. The oncolytic peptide LTX-315, a chemically modified 9-mer cationic peptide, is a highly effective ACP that induces immunogenic cell death in cancer cells [ 197 ].…”

“…The oncolytic peptide LTX-315, a chemically modified 9-mer cationic peptide, is a highly effective ACP that induces immunogenic cell death in cancer cells [ 197 ]. In addition, the effect of LTX-315 on breast cancer via activation of anticancer immunity can be boosted by radiation therapy [ 196 ]. This result strongly suggested that combinational therapy with radiotherapy and ACPs might increase the therapeutic efficiency for cancer cells.…”

Oncolytic immunotherapy: multiple mechanisms of oncolytic peptides to confer anticancer immunity

“…The intratumoral injection of LTX-315 in breast tumor models leads to the reconfiguration of the tumor immune microenvironment and the inhibition of tumor growth in an NK-cell-dependent manner. 11 Moreover, in vitro analyses showed that CSP32 regulates the polarization of murine macrophages and induces M1 macrophages with enhanced production of proinflammatory cytokines. 12 Furthermore, the administration of LL37 triggers the activation and maturation of dendritic cells (DCs), by enhancing the transport of self-RNA released by dying cells to the endosomal compartments of DCs.…”

Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis

“…23 This peptide has thereby been investigated in multiple malignancies in preclinical animal models. [24][25][26] Intriguingly, the LTX-315-mediated oncolysis triggers an antitumor immune response through inducing tumor immunogenic cell death, characterized by the exposure or release of diverse danger-associated molecular patterns (DAMPs) including calreticulin, ATP, and high mobility group box 1. 27 28 This process culminates in the recruitment of antigen-presenting cells into the TME, ultimately priming a tumor-targeting cytotoxic T lymphocyte-dependent immune attack.…”

“…22 Moreover, the intratumoral injection of LTX-315 activates natural killer (NK) cell-dependent immunity. 24 25 Recently, Spicer et al reported the first phase I clinical trial on LTX-315 in 27 patients with solid tumors. 29 Consistent with preclinical findings, the intratumoral administration of LTX-315 causes a significant change in the TME, and the security is relatively high.…”