BACKGROUND
The ability of the immune system to recognize, attack, and eliminate tumors is well established. However, several tumor types (such as, but not limited to, melanoma, pancreatic, and breast tumor types) manifest a variety of immunosuppressive mechanisms to evade immune attack. As such, reversing the protective immune suppression mechanisms and stimulating immune cell activation is the fundamental goal of cancer immunotherapy. Local activation of immunogenic cell death (ICD) has been shown to stimulate innate and adaptive immunity in malignant tumors. However, the utilization of ICD to generate dependable antitumor effects remains a challenge.
SUMMARY OF TECHNOLOGY
OSU investigators have designed a gene delivering nanoparticle (NP) for the intratumoral expression of an ICD-stimulating agent, calreticulin (CRT), and synergized it with focused ultrasound (FUS) to prime and activate the antitumor immune effects. In an in-vivo mouse model of melanoma, this new treatment approach (herein referred to as CFUS) augmented CRT expression to modulate innate (CD47) and adaptive checkpoints markers (PD1, and PDL1), and significantly expanded the CD4+ and CD8+ T cells and tumor suppressing M1 phenotype. The resultant activation of the innate and adaptive immune effects suppressed the B16F10 melanoma locally and achieved abscopal effects upon tumor re-challenge. Our data suggests that CFUS primed ICD can be an innovative modality for dependable clearance of malignant melanoma. The CFUS treatment has the potential for use in treatment of various immunosuppressive cancers.
The effect of CRT-NP, FUS and CFUS local treatment in vivo. (a) Experimental design to test the efficacy of CFUS against melanoma tumors. (b) CFUS significantly induced tumor growth delay compared to Control, FUS, and CRT-NPs. (c) Tumor weights at the time of sacrifice showed significant reduction in the overall weight with treatments compared to control. (d) Representative images of the harvested tumor (scare bar: 1 cm).
POTENTIAL AREAS OF APPLICATION
- The CFUS treatment has the potential for use in treatment of various immunosuppressive cancers (e.g. melanoma, pancreatic, breast)
- Possibility to combine CFUS with other immunotherapies for the induction of durable immune-mediated priming and protection against metastatic tumors
MAIN ADVANTAGES
- Treatment’s efficacy and safety demonstrated in an in-vivo mouse model
- Support through the NIH-funded program to evaluate CFUS amplification strategies in murine models and canine melanoma patients
STATE OF DEVELOPMENT
Oklahoma State University has filed a patent application to protect a composition of matter and methods of use for the proposed technology. The current grant from the National Institutes of Health (NIH) allows to optimize activation of CFUS in a genetically-engineered mouse melanoma model, research combinations of CFUS with other immunotherapies and to evaluate feasibility of the proposed treatment in dogs with oral melanoma.