Abstract
29 Background: Despite the success of immune-checkpoint blockade (ICB) treatments, a considerable proportion of patients cannot benefit from ICB therapy due to acquired resistance. Recent studies have revealed that successful immunotherapy drives new immune responses arising from peripheral immune system instead of reinvigorating the pre-existing responses in the tumor. Here we designed WTX212, autologous engineered red blood cells (RBCs) conjugated with anti-PD1 antibodies capable of activating the peripheral immune system. We also evaluated its anti-cancer activities in anti-PD1 non-responsive tumor models and a first-in-human (FIH) trial. Methods: The anti-tumor efficacy of WTX212 was evaluated in both PD1 responsive (MC38 colorectal cancer) and non-responsive (KP lung cancer and pB3 breast cancer) mouse tumor models (n=7 / group). Mice were monitored twice a week for clinical signs and tumor sizes. The mechanism of action was investigated in splenectomized mice and by analyzing the biodistribution of WTX212 using a radiolabeling method. The immune landscape was also profiled through cytof mass and scRNA-seq analyses in the spleen, tumor and peripheral blood. The FIH trial (NCT05707325) explores safety, pharmacokinetics and mechanism in cancer patients with acquired resistance to ICB. WTX212 was manufactured by covalently engineering anti-PD1 antibody with RBCs isolated from patients. By 11th April 2023, 3 patients have been enrolled and received at least one dose of WTX212 (20*1010 cells, IV, Q3W). Results: Treatment of WTX212 significantly suppressed tumor growth up to 100% in anti-PD1 responsive and non-responsive tumor models. Unlike antibodies, WTX212 primarily distributed to the spleen and vascular system. The anti-tumor effect of WTX212 was abrogated in corresponding splenectomized mice. Compared to anti-PD1 antibody, single-cell analysis identified the immune landscape remodeling in the spleen from WTX212-treated mice, with down-regulation of PD-L1+ myeloid-derived suppressor cells (MDSCs) and up-regulation of effector CD8+ T cells. In the FIH trial, 3 patients have been administered with total thirteen cycles of WTX212. No treatment-related AEs greater than Grade 2 were observed. WTX212 remained in the peripheral blood day 21 post transfusion. WTX212 rapidly activates peripheral immune systems with decreased MDSCs, Tregs and increased effector T cells in peripheral blood from all patients. The first patient who received six cycles of WTX212 treatment demonstrated stable disease with a 20% reduction at the target lesion. Conclusions: WTX212 demonstrated anti-tumor activities by activating the peripheral immune system to overcome resistance to immunotherapy in both preclinical models and human patients. WTX212 is well-tolerated supporting the future clinical trials. Clinical trial information: NCT05707325 .
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.