Collinson, Fiona

773 Background: BCG-unresponsive High-risk non-muscle invasive bladder cancer (HRNMIBC) tumours have an ominous prognosis and require effective, tolerable treatments. Uptake remains low for FDA approved agents (including systemic pembrolizumab, nogapendekin alfa inbakicept-pmln or N-803) due to toxicity concerns. We hypothesize direct intravesical administration of a PDL1 inhibitor could be effective with less systemic toxicity. However, it is unknown whether antibodies delivered via this route can reach tumor vasculature. INVEST is a phase Ib window of opportunity study investigating the safety and preliminary activity of passive instillation and direct injection of intravesical atezolizumab into the tumour/bladder wall. Methods: Eligible participants (ECOG performance status 0-2) are awaiting radical cystectomy (RC) for any stage urothelial cell carcinoma. Participants with muscle invasive bladder cancer, must be ineligible for/ refuse cisplatin based neo-adjuvant chemotherapy. Atezolizumab (600mg or 1200mg) is administered via direct injection into the tumour/bladder or by instillation into the bladder. The 3+3 design is utilised in the dose confirmation stages where participants receive either Single or Multiple (between 3 and 6) dose(s) of treatment before RC. Efficacy signals are derived from pathological complete response at RC and progression-free survival at 2 years. Primary endpoint, Dose confirmation stage: The number of dose-limiting toxicities (DLTs) observed from first dose of trial treatment to RC. Results: Enrolment began in May 2023. 13 participants were recruited to the single dose cohorts: 11 male, and 2 female. Age (Range; 43-86); median 70y, 9 NMIBC, 4 MIBC. 7 for direct injection (4 at 600mg and 3 at 1200mg dose) and 6 for passive instillation (3 at 600mg and 3 at 1200mg). Due to technical issues (syringe size) the first direct injection participant did not receive the full 600mg and were replaced. 12 participants received trial treatment as planned. There were no DLTs; 5 participants experienced non-trial treatment related SAEs (4 infections, 2 ileus, 2 renal impairment; 7/8 events occurred post-RC and all SAEs resolved). All participants underwent planned RC within the protocol stipulated timeline. Median time from last treatment to RC was18 days. 5 of 13 participants had downstaging of tumour in cystectomy specimen. Following independent Safety Review Committee review, recruitment is now open for the dose confirmation phase (Multiple 1200mg dose) in both treatment routes. Conclusions: Single dose atezolizumab treatment at a dose of 600mg and 1200mg in passive instillation and direct injection cohorts was well tolerated. Early efficacy data is encouraging. Multiple weekly doses of 1200mg in each treatment route are now being investigated within the INVEST trial. Clinical trial information: ISRCTN15842444 .

Abstract Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec–associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.

Intravenous infusion of oncolytic reovirus in patients leads to infection of brain tumors, infiltration by cytotoxic T cells, and up-regulation of PD-L1.