EP-4735010-A1 - DENDRITIC CELLS LOADED WITH LYSATES FROM LATE FERROPTOTIC CELLS TO TREAT CANCER

Abstract

The present invention relates to the field of immunotherapeutical compositions which can be used to treat cancer. More in particular, the present invention discloses dendritic cells loaded with lysates derived from late ferroptotic cancer cells which are useful to treat cancer.

Inventors

• KRYSKO, Dmitri V.
• SAVIUK, Mariia

Assignees

• Universiteit Gent

Dates

Publication Date

20260506

Application Date

20240625

Claims (1)

1. Claims 1. DendriƟc cells loaded with lysates derived from late ferroptoƟc cancer cells for use to prevent or treat cancer. 2. DendriƟc cells for use according to claim 1 wherein said cancer is glioblastoma or 5 melanoma. 3. DendriƟc cells for use according to claims 1-2 wherein said lysate is obtained by freezing and thawing said ferroptoƟc cancer cells. 4. DendriƟc cells for use according to claims 1-3 wherein said late ferroptoƟc cancer cells are obtained by inducing ferroptosis ex vivo via contacƟng said cancer cells with a ferroptosis inducer, wherein said ferroptosis inducer is chosen from the list of: RSL3, sulfasalazine, ML- 162, sorafenib, altretamine, withaferin A, ErasƟn, silica nanoparƟcles, photoacƟvaƟon, or, by using methods aiming to inacƟvate, deplete or affect glutathione peroxidases, squalene synthase, HMG-CoA reductase, ND dehydrogenase, glutathione S-transferase, glutamate- cysteine ligase, acyl-CoA synthetase long-chain family member 4 and lysophosphaƟdylcholine acyltransferase 3, or, by inhibiƟng the import of cysƟne, or, by affecƟng metabolism of polyunsaturated faƩy acids. 5. DendriƟc cells for use according to claims 1-4 wherein said loaded with lysates is obtained by contacƟng said dendriƟc cells with said lysates. 6. A method to treat a cancer paƟent in need thereof comprising: - collecƟng dendriƟc cells, -collecƟng cancer cells, -inducing late ferroptosis of said cancer cells via contacƟng said cancer cell with a ferroptosis inducer, -lysing said late ferroptoƟc cancer cells, -loading said lysates into said dendriƟc cells, and -administering an effecƟve amount of said dendriƟc cells loaded with lysates derived from late ferroptoƟc cancer cells to said paƟent in need thereof, wherein said ferroptosis inducer is chosen from the list of: RSL3, sulfasalazine, ML-162, sorafenib, altretamine, withaferin A, ErasƟn, silica nanoparƟcles, photoacƟvaƟon, or, by using methods aiming to inacƟvate, deplete or affect glutathione peroxidases, squalene synthase, HMG-CoA reductase, ND dehydrogenase, glutathione S-transferase, glutamate-cysteine 5 ligase, acyl-CoA synthetase long-chain family member 4 and lysophosphaƟdylcholine acyltransferase 3, or, by inhibiƟng the import of cysƟne, or, by affecƟng metabolism of polyunsaturated faƩy acids. 7. A method to treat according to claim 6 wherein said dendriƟc cells and/or said cancer cells are collected from said paƟent. 8. A method according to claim 6-7 wherein said cancer is glioblastoma or melanoma. 9. A method according to claims 6-8 wherein said lysate is obtained by freezing and thawing said late ferroptoƟc cancer cells. 10. A method according to claims 6-9 wherein said late ferroptoƟc cancer cells are obtained by inducing ferroptosis ex vivo via contacƟng said cancer cells with a ferroptosis inducer, wherein said ferroptosis inducer is chosen from the list of: RSL3, sulfasalazine, ML-162, sorafenib, altretamine, withaferin A, ErasƟn, silica nanoparƟcles, photoacƟvaƟon, or, by using methods aiming to inacƟvate, deplete or affect glutathione peroxidases, squalene synthase, HMG-CoA reductase, ND dehydrogenase, glutathione S-transferase, glutamate-cysteine ligase, acyl-CoA synthetase long-chain family member 4 and lysophosphaƟdylcholine acyltransferase 3, or, by inhibiƟng the import of cysƟne, or, by affecƟng metabolism of polyunsaturated faƩy acids. 11. A method according to claims 6-10 wherein said loaded with lysates is obtained by contacƟng said dendriƟc cells with said lysates. 12. A pharmaceuƟcal composiƟon comprising dendriƟc cells loaded with lysates derived from late ferroptoƟc cancer cells. 13. A pharmaceuƟcal composiƟon according to claim 12 wherein said cancer cells are glioblastoma or melanoma cells.

Description

DendriƟc cells loaded with lysates from late ferroptoƟc cells to treat cancer Technicalfield of the invenƟon The present invenƟon relates to thefield of immunotherapeuƟcal composiƟons which can be 5 used to treat cancer. More in parƟcular, the present invenƟon discloses dendriƟc cells loaded with lysates derived from late ferroptoƟc cancer cells which are useful to treat cancer. Background art According to World Health Organization (WHO), cancer is the second leading cause of death globally, accounting for an estimated 9.6 million deaths, or one in six deaths, in 2019. 10 Cutaneous melanoma is the neoplasm originated from the melanocytes of the epidermis, and, although it corresponds to only 4% of skin related cancers, it is the causal agent for 80% of deaths from dermatological cancer (Miller et al., 2019). Unlike other tumor types, melanoma incidence and its mortality rate increased each year, an event associated with excesses in sun exposure and the progressive loss of the ozone layer (Chang et al., 2014). There are nearly 15 324.635 new cases of melanoma worldwide and 57.043 deaths (Sung et al., 2021). When surgical excision is performed on tumors with early diagnosis, the average survival rate at 10 years is 80%. However, in the case of metastatic melanoma, survival decreases to <10%. New insights in immuno-oncology and the subsequently developed immunotherapies have caused a major breakthrough in the management of metastatic melanoma in the last decade, 20 creating the hope of curing (metastatic) cancer. Despite encouraging results, the proportion of patients experiencing a long-term/durable response is still limited. Therefore, the major challenge focuses on designing new therapies to treat melanoma in advanced stages with systemic dispersion. To improve response rates multiple combination strategies are currently being explored in clinical trials. However, the number of combinations that has demonstrated 25 clear advantage over monotherapy and has entered clinical practice is scarce. In melanoma the combination of anti-PD1 and anti-CTLA4 immunotherapy is superior to anti-PD1 monotherapy at the cost of considerable toxicity: approximately 60% of the patients experience grade 3 to 4 immune related adverse events (Larkin et al., 2019). These data indicate that there is a need for new immunotherapeutic strategies that could further improve efficacy and toxicity profiles. Gliomas, the most frequent intrinsic type of primary tumors of the central nervous system (CNS) in adults, are associated with significant morbidity and mortality (Miller et al., 2021). 5 According to the newest World Health Organization classification of tumors of the CNS (Torp et al., 2022), gliomas, glioneuronal tumors, and neuronal tumors are divided into six different families. Among these are adult-type diffuse gliomas (i.e., most adult patients with primary brain tumors, e.g., glioblastoma (GBM), IDH- wildtype), pediatric-type diffuse low-grade gliomas (with favorable prognoses), and pediatric-type diffuse high-grade gliomas (with poor 10 prognoses) (Louis et al., 2021). The pediatric and adult types of gliomas are distinctively different biologically and genetically. Of note, pediatric-type diffuse gliomas have been subdivided into low-grade gliomas (LGG) and high-grade gliomas (HGG) (Komori, 2022). GBM is classified as a grade 4 malignancy; it is the most aggressive type of cancer of the central nervous system and has a poorer prognosis (Louis et al., 2021; Tesileanu et al., 2020; Weller 15 et al., 2021). Despite the development of novel, complex, multidisciplinary, targeted therapies, such as focal radiotherapy and adjuvant chemotherapeutics in combination with surgical resection, glioblastoma therapy has not progressed much over the last decades (Lieberman, 2017). The median survival of patients diagnosed with glioblastoma is 12–15 months, with a five-year survival rate of 5% (Ostrom et al., 2015; Stupp et al., 2009). 20 Therefore, there is an urgent need to develop novel patient-adjusted anticancer immunotherapies that actively stimulate antitumor T cells, generate long-term memory, and result in significant clinical benefits. Several recent, novel, therapeutic approaches have emerged that rely on vaccination to activate the patient’s own immune system and to induce a potent and long-lasting immune 25 response against cancer antigens. Dendritic cells are key to initiating and directing immune responses (Harari et al., 2020; O’Keeffe et al., 2015), and one of these approaches involves the use of dendritic cells loaded with antigenic material derived from or based on the autologous tumor. One such approach is based on the identification of neo-antigens, but it has low efficacy due to the high antigenic heterogeneity of glioma (e.g., GBM) (Touat et al., 2020). Moreover, this approach is complex, labor-intensive, and costly. In contrast, the preparation of cancer cell lysate from the glioma tissue of a patient is less comple