The immunocytokine L19-IL2: An interplay between radiotherapy and long-lasting systemic anti-tumour immune responses

Abstract

Recently, we have shown that the administration of the tumour-targeted antibody-based immunocytokine L19-IL2 after radiotherapy (RT) resulted in synergistic anti-tumour effect. Here we show that RT and L19-IL2 can activate a curative abscopal effect, with a long-lasting immunological memory. Ionizing radiation (single dose of 15Gy, 5 × 2Gy or 5 × 5Gy) was delivered to primary C51 colon tumour-bearing immunocompetent mice in combination with L19-IL2 and response of secondary non-irradiated C51 or CT26 colon tumours was evaluated. 15Gy + L19-IL2 triggered a curative (20%) abscopal effect, which was T cell dependent. Moreover, 10Gy + L19-IL2 treated and cured mice were re-injected after 150 days with C51 tumour cells and tumour uptake was assessed. Age-matched controls (matrigel injected mice treated with 10Gy + L19-IL2, mice cured after treatment with surgery + L19-IL2 and mice cured after high dose RT 40Gy + vehicle) were included. Several immunological parameters in blood, tumours, lymph nodes and spleens were investigated. Treatment with 10Gy + L19-IL2 resulted in long-lasting immunological memory, associated with CD44+CD127+ expression on circulating T cells. This combination treatment can induce long-lasting curative abscopal responses, and therefore it has also great potential for treatment of metastatic disease. Preclinical findings have led to the initiation of a phase I clinical trial (NCT02086721) in our institute investigating stereotactic ablative radiotherapy with L19-IL2 in patients with oligometastatic solid tumours.

Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation

“…39 Rekers et al showed that colon cancer tumors in immunecompetent mice treated with radiation in combination with the L19-IL-2 ICK resulted in long-lasting anti-tumor responses, including an abscopal effect. 40 Also in that study cured mice showed immune memory against tumor rechallenge. However, in our breast cancer model, immune memory responses were observed only in mice treated with fractionated SRT and ICK, suggesting that single high dose SRT has an immunosuppressive effect.…”

Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial

“…As such, this drug has the potential to boost selective anti-tumoural immune responses in patients with NSCLC. We have demonstrated in preclinical studies that L19-IL2, especially in combination with radiotherapy, results in improved disease control in lung and colorectal carcinoma models [21,23]. Therapeutic responses were dependent on the irradiation dose, the target expression levels and are causally related to the presence of CD8 + cytotoxic T cells [21].…”

“…Best responses were found when administrating L19-IL2 after radiotherapy [40,41]. Additionally, we have shown that this combination leads to improved local tumour control as well as tumour regression outside of the radiotherapy field and induces an immune-mediated memory effect preventing tumour-relapse after reinjection of tumour cells [23]. Furthermore, in pre-clinical Lewis Lung Carcinoma (LLC) models, we have observed that the synergy of radiotherapy with L19-IL2 is superior to the combination of radiotherapy with ICI.…”

“…On the other hand, the phase III MYSTIC (NCT02453282) and NEP-TUNE (NCT02542293) trials (both durvalumabtremelimumab) were reported negative for their primary endpoints [19,20]. One option to improve OS is the addition of radiotherapy to ICI, as radiation might act synergistically with ICI on the immune system [21][22][23]. The added value of ICI has already been shown in stage III NSCLC, in which adjuvant durvalumab after concurrent chemoradiotherapy in patients with good PS resulted in an improved median PFS and OS, as well as an improved 3-year survival (66.3% versus 43.5%) [24,25].…”

<p>Research Progress and Existing Problems for Abscopal Effect</p>

“… 30 Administration of the immunocytokine L19-IL2 in combination with radiation therapy (a single dose of 15 Gy) induced the abscopal effect in 20% of the immunocompetent mice with colon tumours. 31 Administration of the granulocyte-macrophage colony-stimulating factor also promoted the occurrence of the abscopal effect in patients with metastatic cancer. 32 The toll-like receptor 7 (TLR7) agonist imiquimod promoted the radiation therapy-elicited in situ vaccination, thereby enhancing the incidence of the abscopal effect.…”