528 Intratumoural treatment with LTX-, an oncolytic peptide immunotherapy, in patients with advanced metastatic disease induces CD8 effector cells and regression in some injected tumours

Spicer, J.; Awada, Ahmad; Brunsvig, Paal; Saunders, Andrew; Olsen, Wenche Marie; Nicolaisen, Berit; Rekdal, Øystein; Laruelle, M.; Marjuadi, F.; Vakili, Jalal; Aftimos, Philippe; Barthélémy, P.; Deva, Sanjeev; Baurain, J.F.

doi:10.1016/s0959-8049(16)30329-x

Cited by 5 publications

(6 citation statements)

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“…In addition to a modest and predictable safety profile, promising Phase I clinical data has demonstrated to date that LTX-315 induces a partial and complete regression in injected tumors, durable stable disease (global tumor response by CT scan) and significant increases in TILs, indicating a systemic immune response in some patients [41].…”

Section: Discussionmentioning

confidence: 99%

LTX-315: A First-In-Class Oncolytic Peptide that Reprograms the Tumor Microenvironment

et al. 2017

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The oncolytic peptide LTX-315, which has been de novo designed based on structure–activity relationship studies of host defense peptides, has the ability to kill human cancer cells and induce specific anticancer immune response when injected locally into tumors established in immunocompetent mice. The oncolytic effect of LTX-315 involves perturbation of plasma membrane and the mitochondria with subsequent release of danger-associated molecular pattern molecules, which highlights the ability of LTX-315 to induce complete regression and protective immune responses. Treatment with LTX-315 reprograms the tumor microenvironment by decreasing the local abundance of immunosuppressive cells and by increasing the frequency of effector T cells.

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Section: Discussionmentioning

confidence: 99%

LTX-315: A First-In-Class Oncolytic Peptide that Reprograms the Tumor Microenvironment

et al. 2017

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“…Indeed, intratumoral administration of peptide 5 has resulted in complete regression and systemic tumor specific immune responses in several preclinical models. Therefore, peptide 5 is currently being tested in a clinical phase I/IIa study, showing tumor regression and enhanced infiltration of immune cells in injected lesions …”

Section: Discussionmentioning

confidence: 99%

Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide

et al. 2016

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Oncolytic immunotherapies represent a new promising strategy in the treatment of cancer. In our efforts to develop oncolytic peptides, we identified a series of chemically modified 9-mer cationic peptides that were highly effective against both drug-resistant and drug-sensitive cancer cells and with lower toxicity toward normal cells. Among these peptides, LTX-315 displayed superior anticancer activity and was selected as a lead candidate. This peptide showed relative high plasma protein binding abilities and a human plasma half-life of 160 min, resulting in formation of nontoxic metabolites. In addition, the lead candidate demonstrated relatively low ability to inhibit CYP450 enzymes. Collectively these data indicated that this peptide has potential to be developed as a new anticancer agent for intratumoral administration and is currently being evaluated in a phase I/IIa study.

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“…Comparisons of Kaplan-Meier survival curves were performed using the log-rank Mantel-Cox test; NS, not significant LTX-315 overcomes anti-CTLA4 resistance T Yamazaki et al manner by inducing cell death endowed with immunogenic properties. [25][26][27][28][29][30][31][32][33][34][35] In this preclinical study, we found that LTX-315 can be active against sarcomas that poorly respond to CTLA4 blockade, and that the sequential combination of anti-CTLA4 mAb followed by LTX-315 is synergistic, either using systemic or local delivery of anti-CTLA4 mAb, with a mechanism involving CD122 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Disease stabilization was recorded in 75% (6/8) of the patients. 31 We already reported that LTX-315-mediated tumor cell death exhibited immunostimulatory properties in various tumor models. 26,27,29 Here, we show that, in contrast to prototypic cytotoxicants such as anthracyclines, LTX-315-associated cell death does not require type 1 interferon 1α⧸β receptor (IFNAR), Toll-like receptor-3 (TLR3) and TLR4 signaling to mediate its long-term protective antitumor effects.…”

mentioning

confidence: 96%

The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade

et al. 2016

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Intratumoral immunotherapies aim at reducing local immunosuppression, as well as reinstating and enhancing systemic anticancer T-cell functions, without inducing side effects. LTX-315 is a first-in-class oncolytic peptide-based local immunotherapy that meets these criteria by inducing a type of malignant cell death that elicits anticancer immune responses. Here, we show that LTX-315 rapidly reprograms the tumor microenvironment by decreasing the local abundance of immunosuppressive Tregs and myeloid-derived suppressor cells and by increasing the frequency of polyfunctional T helper type 1/type 1 cytotoxic T cells with a concomitant increase in cytotoxic T-lymphocyte antigen-4 (CTLA4) and drop in PD-1 expression levels. Logically, in tumors that were resistant to intratumoral or systemic CTLA4 blockade, subsequent local inoculation of LTX-315 cured the animals or caused tumor regressions with abscopal effects. This synergistic interaction between CTLA4 blockade and LTX-315 was reduced upon blockade of the β-chain of the interleukin-2 receptor (CD122). This preclinical study provides a strong rationale for administering the oncolytic peptide LTX-315 to patients who are receiving treatment with the CTLA4 blocking antibody ipilimumab.

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528 Intratumoural treatment with LTX-, an oncolytic peptide immunotherapy, in patients with advanced metastatic disease induces CD8 effector cells and regression in some injected tumours

Cited by 5 publications

References 0 publications

LTX-315: A First-In-Class Oncolytic Peptide that Reprograms the Tumor Microenvironment

LTX-315: A First-In-Class Oncolytic Peptide that Reprograms the Tumor Microenvironment

Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide

The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade

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