Among the many types of cancer treatments under preclinical and clinical development, the in situ vaccination technology developed by Lytix stands out as a solution to the major challenge in today’s cancer treatment: the heterogeneity of the cancer cells.
Lytix has successfully generated highly active oncolytic molecules inspired from naturally occurring host defense peptides. When Lytix' improved molecules are injected into solid tumors, they kill cancer cells and activate the patient's own immune system and enable killer T cells to recognize and eliminate cancer cells. As part of this process, in situ vaccination results in an efficient release of a broad range of tumor neoantigens (mutated proteins) and immune activating molecules. This immunogenic cell death results in potent activation of the patient's immune system. The unique oncolytic molecule's mode of action results in significant changes in the tumor microenvironment and infiltration of immune cells into the injected tumor makes cold tumors (no or few T cells) hot (presence of T cells).
Lytix´ oncolytic molecules are therefore ideal in combination with other types of immune therapies where the lack of immune cells in the patients' tumors is one of the major hurdles for successful therapies.
LTX-315, mode of action
The oncolytic effect of LTX-315 involves a unique immunogenic cell death targeting cytoplasmic organelles. This results in the effective release of additional danger signals and a broad repertoire of tumor antigens leading to lysis of plasma membrane (necrosis).
Figure 1: LTX-315 trigger necrotic cell death. U2OS osteosarcoma cells treated with LTX-315 adopted a necrotic morphology with absent plasma membranes and vacuolated cyto-plasms (Forveille et al, Cell Cycle. 2015)
Figure 2: LTX-315 induces immunogenic cell death in cancer cells. When treated with LTX-315, dying cancer cells release damage-associated molecular patterns (DAMP) such as calreticulin, ATP, HMGB1, mitochondria-derived DNA (mtDNA) and formyl peptides (FMIT). DAMPs bind to specific receptors on antigen-presenting cells such as dendritic cells (DC) and promotes their maturation and engulfment of tumor-antigens with subsequent presentation to T cells and execution of effective immune response (Zhou et al, and Eike et al, Oncotarget, 2015, Zhou et al, Cell Death and Disease, 2016, Sveinbjørnsson et al, Future Medicinal Chemistry, 2017)
Figure 3: A proposed mechanism of action for intratumoral treatment with LTX-315
In vivo studies
Preclinical and clinical studies have demonstrated LTX-315`s unique ability to enhance infiltration of T cells by inducing effective release of danger signals and a broad range of tumor antigens. (Figure 4).
Figure 4: LTX-315 induce clonal expansion of T cells in both blood and treated lesion.
Immune-checkpoint inhibitors have shown survival benefit in a small proportion of cancer patients with pre-existing T cells, indicating that combination therapies are needed. Since intratumoral administration of LTX-315 enhances tumor infiltration of T cells, both in number and diversity in cancer patients (personalized in situ vaccination), it is an ideal candidate for combination with other types of immunotherapy and provides the scientific rationale for initiating combination studies with immune checkpoint inhibitors in cancer patients (Figure 5).
Figure 5: LTX-315 works in synergy with immune checkpoint therapy. LTX-315 treatment caused regressions in tumors that were resistant to anti-CTLA4. (Murine MCA205 sarcoma; Yamazaki et al 2016)
LTX-315 is an oncolytic immunotherapy. Time lapse study with confocal microscopy shows that the human melanoma cell (A547) is killed within minutes by LTX-315. (Courtesy of L.M. Eike and B. Sveinbjørnsson, UiT)
Presentation of LTX-315 – the discovery and its mode of action