First in human intraarterial delivery of tislelizumab for the treatment of pMMR locally advanced rectal cancer: A single-arm, open label, phase II clinical trial

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• The possibility of immune checkpoint inhibitors combined with neoadjuvant chemoradiotherapy has been explored in multiple phase II clinical trials and reported promising pCR rates. However, severe immune-related toxicities have been a significant concern. Therefore, there is a pressing need for novel strategies to address these toxicities and improve outcomes in locally advanced rectal cancer. • This study introduces a novel regimen: chemo-immuno-embolization with transcatheter rectal arterial intervention plus chemoradiation. This approach demonstrates a favorable pCR rate and excellent tolerance in the treatment of locally advanced rectal cancer, addressing both efficacy and toxicity concerns associated with traditional therapies. • The integration of intraarterial PD-1 antibody delivery with neoadjuvant chemoradiotherapy opens up a promising avenue for the treatment of locally advanced rectal cancer. The encouraging results warrant further investigation in large cohorts, potentially influencing future research directions and clinical practice guidelines regarding the management of this disease. Intravenous immune checkpoint inhibitors (ICIs) have shown efficacy in treating locally advanced rectal cancer (LARC), but concerns about systemic toxicity persist. This study developed a unique approach termed chemo-immuno-embolization with transcatheter rectal arterial intervention (CIETAI), aiming to enhance the anti-tumor response while minimizing systemic toxicity. This is a prospective, single-arm, phase II clinical trial conducted in Daping hospital. Patients with previously untreated stage II/III LARC underwent preoperative CIETAI combined with PD-1 inhibitor tislelizumab plus oxaliplatin, followed by standard concomitant chemoradiotherapy (capecitabine and 50.4 Gy radiation). Intravenous tislelizumab was administered for an additional two cycles. Between January 2023 and December 2023, a total of 38 patients were enrolled. As the primary endpoint, 17 (44.74 %) patients achieved pathological complete response (TRG0), with a major pathologic response (MPR) rate of 65.79 %. The anal preservation rate was 84.21 % (32/38), and importantly, 15 of 21 patients with low rectal cancer achieved organ preservation with functional maintenance. Eight patients experienced grade 3–4 adverse events (AEs). All immune-related AEs were grade 1–2, with the most common being endocrine toxicity (5/6, 83.33 %). No grade 5 AEs occurred. This study provides preliminary evidence supporting the safety and efficacy of intraarterial tislelizumab delivery in the neoadjuvant setting for LARC. These promising results encourage further exploration in larger cohorts to validate the clinical impact of this novel CIETAI strategy. ClinicalTrials.gov Identifier: NCT05957016.

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