134 mNTX-250, a novel multimodal HPV-16 mRNA-based therapeutic, induces potent anti-tumor responses and establishes HPV-16 specific immune memory

Background

Infection with high-risk human papillomavirus (HPV) types is the major etiological cause of cervical cancer and its pre-cancerous lesions, cervical intraepithelial neoplasia (CIN).¹ While prophylactic HPV vaccines are highly effective, there is still a large pool of women at risk for CIN due to accessibility, lack of awareness or personal choice. While loop electrosurgical excision procedure is an effective treatment in many patients with CIN2/3, it does not eradicate the underlying HPV infection and can have significant complications.² Thus, there is an unmet medical need for non-surgical therapeutics for the treatment of high-grade CIN. Nutcracker Therapeutics Inc. has developed mNTX-250, a novel mRNA-based therapeutic vaccine drug candidate, consisting of the human papillomavirus type 16 (HPV-16) E6/E7 oncoproteins in the human cluster of differentiation 1 (hCD1d) scaffold and 2 immunomodulators, human interleukin-12 (hIL-12) and engineered human LIGHT (hLIGHT), encapsulated into LNPs.

Methods

In this study, we studied in vivo efficacy, pharmacodynamics and the establishment of antigen-specific immune memory against HPV-16 antigens of mNTX-250 (a murine surrogate of NTX-250), in comparison with NTX-010 (consisting of noncoding mRNA, murine IL-12 and murine LIGHT) in C3.43 tumors. Tumor-free animals were re-challenged with TC-1 tumors.

Results

Two doses of mNTX-250 treatment resulted in not only eradication of well-established HPV16-transformed B6 C3.43 tumors and overall survival, but also generated significant numbers of HPV16 E7 antigen-specific T cells. The tumor-free animals from both mNTX-250 and NTX-010 treated groups were re-challenged with 10⁵ TC-1 tumor cells (B6 mouse lung epithelial cells transformed by HPV16 E6/E7). All mNTX-250-treated mice that had their C3.43 tumors eradicated showed complete rejection of TC-1 tumors, while 6/11 NTX-010-treated tumors surviving mice showed TC-1 tumor growth. Mice with TC-1 tumor growth also generated fewer HPV16 antigen-specific T cells while treated with NTX-010.

Conclusions

mNTX-250 demonstrated significant antitumor efficacy in the C3.43 tumor model and generated HPV-16 antigen specific immune memory that was sufficient to protect the host from re-challenge with another HPV-16 driven tumor.

References

Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12–19. Young N. The effect of loop electrosurgical excision procedure on the subsequent risk of preterm delivery. [scholarly project]. Toledo, OH: The University of Toledo; 2010.

Ethics Approval

All in vivo studies were in compliance and approved by University of Southern California Institutional Animal Care and Use Committee (USC IACUC).