Pipeline

Our lead candidate THE001 (DPPG2-TSL-DOX) is a thermosensitive liposomal formulation of doxorubicin (DOX). We are building a pipeline around THE001 for the treatment of DOX-sensitive tumors with locally advanced soft tissue sarcoma (LA-STS) as the lead indication. An open label, Phase I dose escalation study of THE001 in STS in combination with regional hyperthermia was initiated in April 2023.

Advantages

We aim to replace the established gold standard for the treatment of LA-STS (conventional DOX) with THE001, which has several advantages:

  • Significantly improved tumor treatment efficacy
  • Enabling life-saving surgery for previously unresectable tumors
  • Additive immune induction through regional hyperthermia and doxorubicin-induced immunogenic cell death with the goal of preventing tumor recurrence – an added benefit in case of locally advanced solid tumors

Our vision is to offer a curative treatment option to patients with a very high unmet medical need.

Rationale

THE001 was compared to DOX in a Phase 1-equivalent animal study in cats with histologically confirmed, locally advanced feline fibrosarcomas. These naturally occurring tumors grow invasively and share clinical and biological similarities with human sarcomas. Cats treated with THE001 showed a durable anti-tumor response while animals treated with DOX showed early tumor progression (read publication).

THE001 has also been successfully tested in other settings, including bladder cancer.

Background

Soft tissue sarcomas (STS) are a heterogeneous group of tumors with more than 50 histologic subtypes that can develop at almost any anatomic site. Locally advanced STS (LA-STS) are large invasive tumors that are difficult or impossible to resect. Neoadjuvant therapy is used to shrink the tumor preoperatively and allow tumor surgery with curative intent. The current standard of care for all chemosensitive LA-STS is DOX in combination with ifosfamide or dacarbazine.

Guidelines also recommend combining DOX-based therapy with regional hyperthermia. Nevertheless, there is a very high unmet medical need in patients: response rate <30%, often unresectable tumors or extensive/function-restricting surgery, high recurrence rate, and high risk of distant metastases.

Relevant Publications

Issels RD, Noessner E, Lindner LH, Schmidt M, Albertsmeier M, Blay JY, Stutz E, Xu Y, Buecklein V, Altendorf-Hofmann A, Abdel-Rahman S, Mansmann U, von Bergwelt-Baildon M, Knoesel T.Immune infiltrates in patients with localised high-risk soft tissue sarcoma treated with neoadjuvant chemotherapy without or with regional hyperthermia: A translational research program of the EORTC 62961-ESHO 95 randomised clinical trial.Eur J Cancer. 2021; 158:123-132read publication
Lindner LH, Blay J, Eggermont AMM, Issels RDPerioperative chemotherapy and regional hyperthermia for high-risk adult-type soft tissue sarcomas.Eur J Cancer. 2021:147:164e169read publication
Issels RD, Lindner LH, Verweij J, Wessalowski R, Reichardt P, Wust P, Ghadjar P, Hohenberger P, Angele M, Salat C, Vujaskovic Z, Daugaard S, Mella O, Mansmann U, Duerr HR, Knoesel T, Abdel-Rahman S, Schmidt M, Hiddemann W, Jauch KW, Belka C, Gronchi A.Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial.JAMA Oncol. 2018 Feb 15.read publication
Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, Basso U, Blay JY, Tendero O, Beveridge RD, Ferraresi V, Lugowska I, Merlo DF, Fontana V, Marchesi E, Donati DM, Palassini E, Palmerini E, De Sanctis R, Morosi C, Stacchiotti S, Bagué S, Coindre JM, Dei Tos AP, Picci P, Bruzzi P, Casali PG.Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial.Lancet Oncol. 2017 Jun;18(6):812-822.read publication
Fendler WP, Chalkidis RP, Ilhan H, Knoesel T, Herrmann K, Issels RD, Bartenstein P, Cyran CC, Lindner LH, Hacker M.Evaluation of several FDG PET parameters for prediction of soft tissue tumour grade at primary diagnosis and recurrence.Eur Radiol. 2015 Aug;25(8):2214-21.read publication
Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem BC, Abdel-Rahman S, Daugaard S, Salat C, Wendtner CM, Vujaskovic Z, Wessalowski R, Jauch KW, Dürr HR, Ploner F, Baur-Melnyk A, Mansmann U, Hiddemann W, Blay JY, Hohenberger P; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG); European Society for Hyperthermic Oncology (ESHO).Neo-adjuvant chemotherapy alone or with regional hyperthermia for localized high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study.Lancet Oncol. 2010 Jun;11(6):561-70.read publication