ESTRO 2024 - Abstract Book

S92 ESTRO 2024 A better understanding of individual variation in sensitivity, and its underlying genetic basis, remains a key radiobiological objective. Clinically, we may also need to consider individual variation in fractionation sensitivity (a/b ratio) in our efforts to abolish toxicity. All such efforts need physics and biology working together. Invited Speaker

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Radio-immunotherapy effectiveness and the abscopal effect

Silvia Formenti

Weill Cornell Medicine, Radiation Oncology, New York, USA

Abstract:

Radio-immunotherapy effectiveness and the abscopal effect Silvia C Formenti, Weill Cornell Medicine, New York, NY

Radiation (RT) has revealed to be ideal partner to immunotherapy to enhance cancer immunogenicity. In response to DNA damage, cytosolic DNA released from the nucleus and mitochondria activates sensors like cGAS/STING, leading to release of IFNβ, that recruits and activates BAFT3 + dendritic cells, for cross-presentation and cross-priming of CD8 + T cells ( Deng et al, Immunity 2014; Vanpouille-Box et al, Nature Communications 2017; Yamazaki et al, Nat Immunol. 2020) . As part of DNA damage response to radiation, RT enables for mutated cancer genes to be expressed, availing neoantigens for recognition to the patient’s immune system (Formenti et al, Nature Medicine, 2018; Lhullier et al, JCI 2021). By recruiting both the innate and adaptive immune response RT can convert the irradiated tumor into an in situ vaccine, that both contributes to the response of the irradiated tumor and potentially, unirradiated metastasis, the rare clinical occurrence of the abscopal effect (Mole RH. Br J Radiol. 1953). We originally linked the immunogenicity of RT with the abscopal effect ( Demaria et al IJROBP, 2005) and over the past twenty years investigated how to enhance it. The rarity of abscopal effects when RT is used alone, is easily explained by the multiple immunosuppressive mechanisms that are in place in established human cancers that have evolved to develop specific signatures of immune-evasion (Demaria S and Formenti SC, BJR, 2020) . These individual immunological barriers require correction/abrogation for RT to successfully immunize the patient against her/his cancer. While the concept of an abscopal effect can be modeled in syngeneic murine tumors by injecting two distinct sites and irradiating only one, it only partially mimics the reality of a metastasis outside the radiation field. In the clinical setting of metastatic disease, cancer heterogeneity and heterogeneity of mechanisms of immune evasion across metastasis in different tissues ( De Mattos-Arruda L et al. Cell, 2019 ) warrant the need for radiation to target all detectable metastatic deposits. A multi-institutional Canadian trial on oligometastatic cancer patients (with up to 5 metastases) has demonstrated a promising improvement in time-to-progression and survival after stereotactic body radiotherapy (SBRT) to each metastasis ( Palma DA et al, Lancet, 2019 ), when compared to best supportive care. In addition to targeting heterogeneity, maximal reduction of tumor burden by multi-site SBRT can enable an immunological equilibrium, and potentially prolong survival. Relevant factors to potentiate RT immunogenicity include the selection of treatment fields, the choice of specific radiation dose and fractionation schedules and of sequencing with immunotherapy agents. Preclinical evidence discourages the inclusion of draining nodal stations in the field of radiotherapy, when RT is used in combination with immunotherapy strategies ( Saddawi-Konefka et al, Nature Communications 2022 ). Hypo-fractionated regimens that minimally impact the viability of circulating immune cells sustain the host’s immune fitness (Chen D et al Radiother Oncol. 2020) as does optimal sequencing of administration of radiation and immunotherapy ( Wei et al., Sci. Immunol.