Recent breakthroughs in discovering innovative immune signaling pathways and immunomodulators have created new opportunities to harness the power of the immune system for the treatment of different diseases, but the instability of therapeutic molecules and the presence of biological barriers at the tissue, cellular, and subcellular level can prevent them from accessing the therapeutic targets and therefore compromise the therapeutic efficacy. Furthermore, the off-target effect can also cause severe side effects. My lab is interested in working at the interface of pharmaceutical sciences and immunotherapy and developing innovative formulations to overcome the above challenges and fully unleash the power of immunotherapy. The major research areas include: (1) Develop innovative formulations that can overcome the drug instability and biological barriers; (2) Tune the spatiotemporal distribution of drug molecules at different levels (e.g., tissue, cellular, and subcellular level) and investigate its relationship with the host immunity; (3) Explore the use of formulations for the treatment of different diseases (e.g., cancer, infectious diseases, and autoimmune diseases) and elucidate the mechanism of action.

Increasing evidence has shown that the levels of antitumor T cells are positively correlated with the prognosis of cancer patients, so improving the antitumor T cell responses is a major goal in cancer immunotherapy. However, a highly safe and effective strategy that can induce strong T cell responses remains lacking. We addressed the unmet need by overcoming the key barriers that limit T cell responses in the context of peptide vaccines and chemotherapy. In particular, we developed high-density-lipoprotein mimetic nanodiscs based personalized cancer vaccines and chemotherapeutic formulations that were significantly more efficient than existing formulations to deliver T cell-activating signals to the targets, thus “educating” the immune system to induce potent T cell responses. We also developed a dual adjuvant system that can significantly improve the immune responses against subunit antigens. Our studies provide simple solutions to enhancing the immune responses, validate critical steps that profoundly impact immune responses, and identify a set of design criteria that can aid in the design of next-generation formulations for immunotherapy. These results have formed the foundation for a startup company “EVOQ Therapeutics”.

1. Development of vaccine nanodiscs for personalized cancer immunotherapy Recent breakthroughs in the identification of neoantigens have signaled the new era of personalized cancer immunotherapy, but how to safely and efficiently “educate” the immune system for T cell activation remains challenging. We coupled adjuvants and mutated tumor antigens (neoantigens) to synthetic high-density-lipoprotein mimetic nanodiscs and obtained personalized vaccines. After subcutaneous injection, nanodiscs dramatically enhanced the lymph nodes draining of antigens and adjuvants, promoted the uptake by dendritic cells, and increased/prolonged antigen presentation on the surface of dendritic cells. Consequently, vaccine nanodiscs induced potent tumor antigen-specific T cell responses that can be used to treat different tumors.

Figure 1. Personalized vaccine for precise cancer immunotherapy

2. Development of a chemotherapeutic drug-based formulation for cancer chemoimmunotherapy Recent studies have shown that chemotherapeutic drugs can not only directly kill tumor cells, but also induce “immunogenic cell death” of tumor cells to activate the antitumor T cell immunity. However, the short half-life and insufficient tumor accumulation of chemotherapeutic drugs can limit their therapeutic potential. We used a lipid tail to anchor the chemotherapeutic drug to high-density-lipoprotein mimetic nanodiscs and obtained the nanodisc-based chemotherapeutic drug formulation. After intravenous injection, nanodiscs significantly improved the pharmacokinetics and drug accumulation in the tumor, thus increasing the chance for the chemotherapeutic drug to kill tumor cells. Dying tumor cells provided tumor antigens and released “danger signals” to activate the host immune system and elicit antitumor T cell responses that further contribute to the killing of remaining tumor cells

Figure 2. Chemotherapeutic drug-based formulations for cancer chemoimmunotherapy

3. Development of a dual adjuvant formulation to improve the immunogenicity of subunit antigens Subunit antigens such as peptides and recombinant proteins are attractive due to their simplicity for manufacturing/quality control and good safety, but the weak immunogenicity can limit their wide use. Combining different immunostimulatory agents for synergistic signaling is a promising approach to improve the immunogenicity of subunit antigens, but how to deliver different immunostimulatory agents to their targets remains a big challenge. We loaded two different TLR agonists (TLR4 agonist and TLR9 agonist) to the lipid bilayer of nanodiscs through hydrophobic interactions and obtained the dual adjuvant formulation that can efficiently reach their targets. After simple mixing with different subunit antigens, the dual adjuvant formulation induced potent immune responses against subunit antigens.

Figure 3. A dual adjuvant formulation to improve the immunogenicity of subunit antigens.

2018              Chinese Government Award for Outstanding Students Abroad
2017              Norman Weiner Graduate Fellowship
2017              Gordon Research Conference Excellent Poster Award
2017              American Association of Pharmaceutical Scientists Innovation in Biotechnology Award
2016              PSTP Annual Symposium Poster Award
2015-2017     American Heart Association Predoctoral Fellowship
2013              Broomfield International Student Fellowship
2013              Outstanding Master’s Thesis Award, Sichuan Province
2011             “China Shiyao Pharmaceutical Group Co., Ltd” Outstanding Student Award

1. Levy O#, Kuai R#, Siren EM#, Bhere D, Milton Y, Nissar N, Biasia MD, Heinelt M, Reeve B, Abdi R, Alturki M, Fallatah M, Almalik A, Alhansan AH, Shah K, Karp JM. Shattering barriers towards clinically meaningful mesenchymal stromal cell (MSC) therapies.   Science Advances, 2020; 6: eaba6884
2. Kuai R#, Singh PB#, Sun X#, Xu C, Najafabadi AH, Scheetz L, Yuan W, Xu Y, Hong H, Keskin DB, Wu CJ, Jain R, Schwendeman A, Moon JJ. Robust anti-tumor T cell response with efficient intratumoral infiltration by nanodisc cancer immunotherapy. Advanced Therapeutics, 2020, (In press)
3. Kadiyala P, Li D, Nunez F, Altshuler D, Doherty R, Kuai R, Yu M, Kamran N, Edwards M, Moon JJ, Lowenstein P, Castro M, Schwendeman A. High density lipoprotein-mimicking nanodiscs for chemo-immunotherapy against glioblastoma multiforme. ACS Nano, 2019, 13, 2, 1365-1384.

4. Kuai R#, Yuan W#, Son S, Nam J, Xu Y, Fan Y, Schwendeman A, Moon JJ. Elimination of established tumors with nanodisc-based combination chemoimmunotherapy. Science Advances, 2018; 4: eaao1736. Featured by ecancer, News Medical, ScienceNewsline, Newswise, Medical Press, EurekAlert.

5. Kuai R#, Sun X#, Yuan W, Xu Y, Schwendeman A, Moon JJ. Subcutaneous nanodisc vaccination with neo-antigens for combination cancer immunotherapy. Bioconjugate Chemistry, 2018, 29 (3), 771-775.

6. Nam J, Son S, Ochyl LJ, Kuai R, Schwendeman A and Moon JJ. Combination chemo-photothermal therapy elicits potent anti-tumor immunity and eliminates distal tumors. Nature Communications, 9, 1074 (2018).

7. Ochyl LJ, Bazzill JD, Park C, Xu Y, Kuai R, Moon JJ. PEGylated tumor cell membrane vesicles as a new vaccine platform for cancer immunotherapy. Biomaterials, 2018, 182, 157-166.

8. Park H#,  Kuai R# , Jeon JE, Seo Y, Jung Y, Moon JJ, Schwendeman A, Cho S. Dual effective high-density lipoprotein-mimicking substance P nanodiscs for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia. Biomaterials, 2018, 161, 69-80.

9. Kuai R, Sun X, Yuan W, Ochyl LJ, Xu Y, Najafabadi AH, Scheetz L, Yu M, Balwani I, Schwendeman A, Moon JJ. Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy.   Journal of Controlled Release, 2018, 282, 131-139.

10. Kuai R#, Subramanian C#, White P#, Timmermann BN, Moon JJ, Cohen MS, Schwendeman A. Synthetic high density lipoprotein nanodiscs for targeted delivery to adrenocortical carcinoma. International Journal of Nanomedicine. 2017, 12, 6581-7594.

11. Kuai R, Ochyl LJ, Bahjat KS, Schwendeman A, Moon JJ. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nature Materials, 2017, 16 (4), 489-496. Featured by Nature World News, Science Daily, Fierce Biotech, Yahoo! News, R&D, eCancer, Medical Physics Web, Nanotechweb, Technology Networks, Technology.org, C2W.nl, La Stampa, Scientias, Controlled Environments, Tech Times, STRF.ru, Business Standard, CanIndia, La Razon, Health Canal, E! Informador, My Science, Azonano, Nanowerk, Health Medicine, The Medical News, Health Medicinet.

12. Fan Y, Kuai R, Xu Y, Ochyl LJ, Irvine DJ, Moon JJ. Immunogenic cell death amplified by co-localized adjuvant delivery for cancer immunotherapy. Nano Letters, 2017, 17, 7387-7393.

13. Kuai R, Li D, Chen YE, Moon JJ, Schwendeman A. High-density lipoproteins: nature’s multifunctional nanoparticles. ACS Nano, 2016, 10 (3), 3015–3041.

14. Kuai R#, Yuan W#, Li W, Qin Y, Tang J, Yuan M, Fu L, Ran R, Zhang Z, He Q. Targeted delivery of cargoes into a murine solid tumor by a cell-penetrating peptide and cleavable poly(ethylene glycol) comodified liposomal delivery system via systemic administration. Molecular Pharmaceutics, 2011, 8 (6), 2151-2161.

15. Kuai R#, Yuan W#, Qin Y, Chen H, Tang J, Yuan M, Zhang Z, He Q. Efficient delivery of payload into tumor cells in a controlled manner by TAT and thiolytic cleavable PEG co-modified liposomes. Molecular Pharmaceutics, 2010, 7(5), 1816-1826.

1. Kuai R#, Ochyl LJ#, Schwendeman A, Moon JJ. (2016) Lipid-Based Nanoparticles for Vaccine Applications. In: Jo H., Jun HW., Shin J., Lee S. (eds) Biomedical Engineering: Frontier Research and Converging Technologies. Biosystems & Biorobotics, vol 9. Springer, Cham. https://doi.org/10.1007/978-3-319-21813-7_8