ESTRO 2020 Abstract book

S40 ESTRO 2020

treatment may hold a promise for patients with highly metastatic tumors. OC-0084 Combining RT with L19-IL2 and aPDL1: from preclinical results towards a phase II trial (ImmunoSABR). R. Lieverse 1 , E. Van Limbergen 2 , V. Olivo Pimentol 1 , C. Oberije 1 , D. Neri 3 , A. Yaromina 1 , L.J. Dubois 1 , P. Lambin 1 1 MUMC/UM, Precision Medicine - The D-lab and The M- lab, Maastricht, The Netherlands ; 2 Maastro-clinic, Radiotherapy, Maastricht, The Netherlands ; 3 Pharmaceutical Sciences, Chemistry and Applied Biosciences, Zurich, Switzerland Purpose or Objective At initial diagnosis 47% of NSCLC patients already have stage IV metastatic disease with limited treatment options and 1-5% 5-year overall survival (OS) rates. Current therapies emphasize the necessity for combinatorial treatment approaches. Interleukin-2 (IL2) plays an essential role in the activation phase of both specific and innate immune responses. To avoid IL2 induced systemic toxicity we have evaluated a more targeted approach using an immunocytokine consisting of the anti-EDB scFv L19 antibody coupled to IL2. Combination with radiotherapy (RT) in tumour models expressing high EDB resulted in long-term primary tumour responses, abscopal effects distant from the irradiated site, and an immunological memory. Aim of the current study was to evaluate preclinically and in a phase 2 clinical trial the combination of precise SABR with the well-tolerated tumour selective immunocytokine L19-IL2 and the immune checkpoint inhibitor (ICI) aPDL1 in an intermediate EDB expressing, immune cold LLC model. Material and Methods Upon an average LLC tumour volume of 200mm 3 , C57BL/6 mice were randomised into following treatment groups: RT (10Gy) + vehicle/L19-IL2 + IgG or RT + vehicle/L19-IL2 + aPDL1/aCTLA4. Vehicle/L19-IL2 (1mg/kg), aCTLA4 (10mg/kg) and IgG (10mg/kg) were given i.v. on day 1, 3 and 5 after RT; aPDL1 (10mg/kg) and IgG were given i.p. 1, 3, 5, 7 and 9 days after RT, Figure 1. Tumour response was quantified as time to reach 4x initial tumour volume (T4xIV). This triple therapy is implemented as 1 st , 2 nd , or 3 rd line in the phase 2 trial, to treat WHO PS 0-1, advanced stage IV NSCLC patients. The main objective is improved PFS at 1.5 years. The secondary objectives will be OS, QoLQ, and abscopal response. The exploratory objectives will be biomarker studies, immune cell subsets, mutational burden, and stool collection will be performed.

OC-0083 Abolition of metastases of mouse triple negative breast cancer by alpha-radiation and immunotherapy V. Domankevich-Bachar 1 , M. Efrati 1 , F. Mansur 2 , M. Schmidt 3 , A. Cohen 2 , E. Glikson 2 , T. Cooks 4 , I. Kelson 3 , Y. Keisari 2 , R. Galalae 5,6 1 Alpha Tau Medical, Basic and Translational Research, Tel Aviv, Israel ; 2 Tel-Aviv University / Faculty of Medicine, Clinical Microbiology and Immunology, Tel- Aviv, Israel ; 3 Tel Aviv Universit, School of Physics and Astronomy, Tel Aviv, Israel ; 4 Ben-Gurion University, Immunology- Microbiology & Genetics, Beer Sheva, Israel ; 5 MedAustron, Wiener Neustadt, Austria ; 6 Medical Faculty, Christian-Albrechts University, Kiel, Germany Purpose or Objective Effective treatment of malignant tumors, requires high levels of local control and eradication of metastases. This may be achieved by in situ obliteration of the primary tumor, and release of tumor antigens that trigger systemic immunity. The anti-tumor immunity can be enforced by immuno-adjuvants and inhibitors of immune suppressor cells. In the present study we examined the feasibility to cure mice bearing highly malignant triple negative breast tumors, using integrated alpha radiation and immunotherapy. Material and Methods Tumor ablation was performed using Diffusion alpha emitters Radiation Therapy (DaRT). DaRT is an innovative alpha radiation-based treatment for solid tumors applied by intratumoral Ra-224 coated metal seeds, which spread alpha emitting short lived atoms. Tumor ablation by DaRT triggers a systemic and specific antitumor immune response. Subcutaneous 4T1 tumors (7 mm in diameter) were treated with DaRT seeds (1/tumor, 70 kBq). Poly I:C PEI (polyinosinic:polycitidylic-polyethylene imine; 20 µg/mouse) injected 72 and 24 hours prior to DaRT was used as immunostimulant. Cyclophosphamide (CP) (100 mg/kg; i.p, 1 day before DaRT) was used to inhibit regulatory T cells. Decitabine (1 mg/kg for 4 days before DaRT) was used to de-condense DNA and increase double strand breaks by alpha particles. Results Three types of experiments were performed: I. The effect of DaRT with polyI:C PEI on the development of the primary tumor and on lung metastases was examined. DaRT-polyIC PEI treatment significantly attenuated tumor growth during 3 weeks follow up (67±34 mm 3 ) compared with DaRT alone (265±128 mm 3 ) [ p (t-test)<0.00005]. Lungs harvested after 4 weeks and imaged for metastases revealed that only 23% in the DaRT+polyIC PEI treated mice carried lung metastases compared with 77% in DaRT or 75% in control groups [ p (χ 2 -test) <0.05]. II. Next was tested the effect of DaRT+polyIC PEI combined with Tregs inhibition by Cyclophosphamide on lung metastases related mortality under neoadjuvant setting. Residual tumors were resected 14 days after treatment and mice were inspected for 142 days. Most of the DaRT+polyIC PEI +CP treated mice (75%) survived, compared with 33% in DaRT, 25% in the Inert (non- radioactive)+polyIC PEI +CP, and 12% in the Inert control groups. III. Finally, DaRT+polyI:C PEI treatment was combined with decitabine. Tumors treated with DaRT+polyI:C PEI +Decitabine, were two-fold smaller compared to the same treatment with non-radioactive seeds (Inert+polyI:C PEI +decitabine), and 4-fold smaller compared to DaRT alone. DaRT+Decitabine retarded tumor development by 64%. Conclusion Tumor ablation by DaRT acts as in situ tumor vaccine and by combining it with immunostimulating, Tregs inhibitors and radiosensitizing agents can achieve a higher tumor control, eliminating distant metastases and curing triple negative breast cancer bearing mice. This combination

Results L19-IL2 and aCTLA4 (p<0.05), but not aPDL1, enhanced the therapeutic effect of RT. Furthermore, RT + L19-IL2 efficacy was better compared to RT + ICIs, especially for RT + aPDL1 (p<0.05). Adding aCTLA4 to RT + L19-IL2 did not improve outcome compared to RT + L19-IL2. However, RT + L19-IL2+aPDL1 enhanced therapeutic efficacy compared to RT + L19-IL2 (p<0.05) and RT + aPDL1