Highlights:
Arovella’s CAR-iNKT cells demonstrated potent anti-tumour activity in a model of advanced gastric cancer
Five out of seven (71%) animals treated with the cells survived and showed no sign of tumours after 60-days versus 0% for the control groups.
Cytokine armoured cells in a small sub-group eliminated tumours in all treated animals with 100% animal survival.
Natural anti-tumour activity of iNKT cells was observed, delaying tumour growth even in the absence of a tumour-specific CAR, supporting the natural function of iNKT cells in tumour control.
Data will be presented at the upcoming Consortium for iNKT Research and Therapy (CiRT) meeting at the University of Pennsylvania.
The Board supports advancing the ALA-105 program to GMP manufacturing and requesting formal FDA engagement early in the new year.
Arovella Therapeutics Ltd (ASX: ALA) is pleased to announce positive results from an in vivo study evaluating its Claudin 18.2 (CLDN18.2)-targeted CAR invariant natural killer T (CAR-iNKT) cell therapy, ALA-105, in an animal model of advanced gastric cancer.
ALA-105 demonstrated impressive anti-tumour activity, with CLDN18.2-targeted CAR-iNKT cells leading to complete tumour clearance in five of seven animals (71%). In contrast, all control animals succumbed to tumours within 30-50 days. In a smaller sub-group of mice treated with IL-12-armoured CAR-iNKT cells tumours were eliminated in all treated animals and all animals survived the 60-day study. Animals in each group received a single dose of 4 million CAR-iNKT cells. The study was conducted at the University of North Carolina under Professor Gianpietro Dotti.
Arovella Acting CEO, Dr Nicole van der Weerden, said, "These results provide compelling in vivo validation of our CLDN18.2 CAR-iNKT program. The complete tumour clearance achieved with our IL-12-TM armoured CAR-iNKT cells highlights the potential of combining targeted CAR activity with cytokine armouring to overcome the challenges associated with treating solid tumours. Importantly, these findings are consistent with the strong in vitro efficacy we reported earlier this year and further strengthen our confidence."
Arovella Chairman, Mr David Williams, commented, "These data further demonstrate the versatility and power of our iNKT cell platform. The ability to achieve complete tumour clearance and survival in this challenging gastric cancer model reinforces the significant potential of our technology to address unmet needs in solid tumours. The results are so compelling that we have resolved to speed up a formal approach to the FDA. "
ALA-105 is Arovella’s next-generation, allogeneic CAR-iNKT cell therapy being developed to target Claudin 18.2 (CLDN18.2), a tumour-associated protein expressed in a high proportion of gastric cancers and a subset of pancreatic cancers. By combining a CLDN18.2-directed CAR with the innate tumour-recognition properties of iNKT cells, ALA-105 is designed to selectively recognise and eliminate CLDN18.2-expressing cancer cells and address the substantial unmet need in these difficult-to-treat solid tumours.
Arovella’s armouring technology, licensed from the University of North Carolina at Chapel Hill (UNC), is designed to strengthen the activity and persistence of iNKT cells. The technology produces the cytokine interleukin-12 attached to the membrane, concentrating its immune-stimulatory effects at the engineered cell surface. This enhances local anti-tumour activity while aiming to limit the systemic exposure associated with freely secreted IL-12. To learn more about Arovella’s armouring technology see our whiteboard explainer video here.
The study utilised a NUGC4-CLDN18.2 gastric cancer model in NSG mice, where CLDN18.2-positive tumour cells were introduced into the peritoneal cavity before treatment with iNKT cell therapies four days later. Animals were monitored for tumour burden using IVIS imaging and assessed for overall survival. Four treatment groups were evaluated: untreated control animals that received saline (PBS), iNKT cells expressing a CAR that targeted a protein not present on the tumour cells (control CAR), CLDN18.2-targeted CAR-iNKT cells, and CLDN18.2-targeted CAR-iNKT cells incorporating Arovella's membrane-tethered IL-12 (IL-12-TM) cytokine armouring technology.
In addition to the strong tumour control demonstrated by the CAR-iNKT cells, the study also confirmed that iNKT cells lacking a specific tumour-targeting CAR (iNKT cells with control CAR) possess an inherent ability to recognise and attack tumour cells and were able to delay gastric tumour growth compared with untreated controls. The activity is believed to be driven, at least in part, by natural tumour recognition pathways such as NKG2D-mediated targeting.
The findings build on Arovella's previously reported in vitro data and provide further evidence that CAR-iNKT cells may offer a highly effective approach for treating CLDN18.2-positive solid tumours, including gastric cancer.
With positive proof-of-concept efficacy data in hand, Arovella can now advance ALA-105 toward its next major development milestones, including formal regulatory engagement with the FDA through a pre-IND or INTERACT meeting, commencement of technology transfer for manufacturing under Good Manufacturing Practice (GMP) conditions, and formal IND-enabling studies.