Abstract 738P
Background
Despite major improvements in immunotherapy, some 80% of patients with solid tumors face resistance to available treatments. Overcoming T-cell exhaustion is crucial in combating immune resistance. Our group has developed signal peptide domains (SPDs) as antigen-specific multi-epitope vaccine candidates. Our work in animals and cancer patients showed that SPDs derived from human and bacterial antigens can trigger robust CD8+ T-cell responses across MHC barriers via multiple MHC-I binding. SPs also have unique TAP-independent ER-localization properties which is critical to fight MHC-I downregulation in tumors with TAP deficiency. Recently, we explored the use of SPDs as novel decoys for effective anti-tumor therapy.
Methods
The Orion immune engager is a 33 kDa R-protein comprising the Herceptin (Her2) ScFv connected via a furin linker to the 24-mer SPD from BCG lipoprotein LpqH and a known 9-mer CMV epitope.
Results
We utilized Orion to label and eradicate tumor cells by redirecting non-exhausted BCG-induced CD4/CD8+ T-cell immunity. Orion demonstrated specific Her2-binding and internalization kinetics (up to 72 hours) in A431 and BT-474 Her2-positive tumors. Orion mediated 60%-specific killing of Her2+/HLA-A2.1+ OvCar3 cells using T-cells primed against BCG or CMV. Splenocytes from BCG-vaccinated BALB/c mice showed some 50%-specific killing of Orion-treated CT-26Her2 cells. Finally, Orion intratumoral therapy of CT-26Her2-inoculated & BCG-vaccinated mice exhibited statistically significant anti-tumor activity, which was associated with an eightfold increase of non-exhausted T-cells in the tumor microenvironment (TME).
Conclusions
Our results suggest a straightforward strategy to combat immune resistance in the TME by directing pre-existing polyclonal functional T-cell immunity against pathogens, such as BCG & CMV. Our initial proof of concept with Orion has proven that using SPDs as a Trojan horse can overcome T-cell exhaustion and elicit potent anti-tumor responses. These findings have implications for developing effective therapies to combat immune resistance in solid tumors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The author.
Funding
BioPharma IM.
Disclosure
The author has declared no conflicts of interest.