Background Colorectal cancer (CRC) is the second leading cause of cancer-related death in the world and often detected at late stages (38% of metastasis cases at diagnosis). Immunotherapy is showing tremendous progress as treatment option and opening multiple ways to address therapeutic challenges in CRC. Accordingly, we developed a stimulated tumor cells (STC) technology to generate therapeutic vaccines able to educate the immune system to mechanisms of tumor relapse. Vaccine candidate have shown encouraging results in CRC syngeneic models.1 2 We applied this technology to generate the ‘STC-1010’ a human therapeutic vaccine to treat patients with CRC.
Methods STC-1010 is generated using 3 human CRC cell lines (HCT116, HT-29, LoVo) exposed to irradiation, heat-shock, chemotherapy agents and haptenized. Its potential to favor an immune stimulatory response was evaluated using two models. First on ex vivo mixed lymphocyte reaction (MLR) assay using an human monocytes-derived dendritic cells (mDCs) from different donors through the activation of CD8+ T cells and the promotion of apoptosis. Second on human CRC adenocarcinoma from HT-29 cell using chorioallantoic membrane (CAM) assay in immune reactive in ovo model measuring IL-2, IL-12 and interferon gamma (IFNg) secretion, metastatic invasion and tumor infiltration.
Results The ex vivo derived Mixed Lymphocyte Reaction (dMLR) assay showed that STC-1010 induced IL-8 and IL-12 secretion and reduced IL-10 during mDCs maturation. STC-1010 primed mDCs enhanced IFNg production by CD8+ T cells (p=0,06) and amplified their anti-tumor activity, in combination with LPS/IFNg and CD40L. These CD8+ T cells promote apoptosis of HCT116, HT-29, SW620 cells compared to the condition without STC-1010 (p<0,01). In CAM model, STC-1010 vaccine induced: i) IL-12 and IL-2 secretion in peripheric blood during the generation of chicken peripheral blood mononuclear cells batches; ii) IFNg expression in tumor (+130,83%, p=0.0185); iii) cells infiltration CD4+: +79,2%, CD8+: +29,4% , Perforin: +105,5%, TNFα: +78,63%; iv) tumor necrosis (p = 0.0267); and v) metastasis regression (-49%) (no toxicity was registered). On the other hand, proteomic characterization approach showed that around 200 proteins involved in resistances, tumor progression and escape are expressed in the vaccine allowing considerable coverage of patients’ tumor heterogeneity.
Conclusions These studies on ex vivo and in ovo models confirm the efficacy of the STC technology to generate human cancer therapeutic vaccine and give more insight about STC-1010 mechanism of action with the activation and maturation of DCs, induction of CD8+ T cells against tumor cells as the main driver of the response, all without toxicity.
Pinteur B. Therapeutic cancer vaccine based on stress proteins rendered immunogenic (Patent No. WO2015055733)
Gongora C, et al., Antitumor Efficacy of STC an Allogenic Ghost Cell vaccine on Colorectal Cancer, Submission in progress
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