On April 19, 2023 Nutcracker Therapeutics, Inc., a biotechnology company dedicated to developing transformative RNA therapies through its proprietary technology platform, reported two posters showcasing the latest preclinical data for the company’s lead oncology mRNA therapeutic, NTX-250, at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Orlando, Fla. (April 14-19) (Press release, Nutcracker Therapeutics, APR 19, 2023, View Source [SID1234630336]).
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The lead indication for NTX-250 is cervical intraepithelial neoplasia (CIN), a precancerous condition caused by human papillomavirus (HPV) infection, which can progress to cervical cancer if left untreated. More than 90 percent of cervical cancer and CIN cases are linked to HPV infection, with HPV16 as the most prevalent high-risk strain.
Nutcracker’s poster presentation #5163 outlined how NTX-250 stimulates an immune response to clear HPV-driven tumors in murine models via the synergistic interactions between its three RNA-encoded protein components — the HPV16 E6 and E7 antigens, and immunomodulators IL-12 and LIGHT — which are delivered locally into the tumor as a single mRNA drug product.
This study confirmed the advantages of intratumoral over intramuscular delivery of NTX-250, finding that intratumoral delivery provided robust tumor infiltration of antigen-specific T cells. This resulted in turning the "cold" tumors "hot," by simultaneously lowering the immunosuppressive effects of the tumor microenvironment and stimulating antigen-specific T cells to clear the tumor. Notable takeaways from the data include:
Complete tumor regression and long-term, recurrence-free survival in all 10 tumor-challenged mice intratumorally administered with NTX-250
No tumor-free mice in the negative control group or in mice treated intramuscularly with NTX-250
Intratumoral injection of NTX-250 resulted in immune cell infiltration and the secretion of proinflammatory Th1/M1 associated cytokines, which aid in turning "cold" tumors "hot"
Further, Nutcracker’s poster presentation #690 described the use of a novel endolysosomal trafficking domain, CD1d, to elicit an improved T cell-mediated adaptive immune response when designing mRNA-based therapies using NTX-250 as an example. Introducing these signaling domains within the drug molecule design can address challenges in antigen presentation and processing by driving specific subcellular localization of antigenic proteins to enhance antigen presentation and the subsequent immune response. Notable takeaways include:
Antigens linked to the CD1d endolysosomal trafficking domain showed sustained intracellular expression that resulted in improved CD4 and CD8 antigen-specific engagement
In vivo, these antigen-CD1d mRNA molecules significantly improved the antigen-specific CD8 T cells responses and enhanced the immunoglobulin response
"The latest data represent an important milestone in the growing body of research supporting the therapeutic potency of NTX-250, while validating the biological versatility and clinical potential of mRNA as a modality on the whole," explained Chief Medical Officer Robert J. Schott, M.D. "We’ll work diligently to build on these promising results in the ongoing fight to improve outcomes for CIN patients by providing a better alternative to the current surgical standard of care."
Additionally at AACR (Free AACR Whitepaper), a late-breaking oral presentation was given, discussing data from a collaborative study between Nutcracker and the research groups of Drs. Lawrence Fong and David Oh at the University of California, San Francisco — which mapped shared tumor antigen reactivity using nanoparticle-encapsulated mRNA in prostate cancer patients.
"As Nutcracker continues to harness the unique characteristics of mRNA to treat a broad range of oncology indications, this recent preclinical achievement further supports our efforts to deliver on the modality’s clinical promise to patients," remarked Chief Executive Officer Igor Khandros, Ph.D. "Beyond our pipeline, Nutcracker’s proprietary RNA design, delivery, and manufacturing platform is also positioned to play a crucial role in streamlining the development of new RNA medicines."
The data presented at the AACR (Free AACR Whitepaper) Annual Meeting build upon previously presented preclinical data on the viability of this mRNA composition as a therapeutic. NTX-250 is expected to enter Phase I clinical trials by early 2024.