(596e) Enhancing Prostate Cancer Immunity through the Rational Design of Vaccine Structure

Immunotherapies, such as “cancer vaccines,” potently activate the immune system against disease, stimulating targeted responses. Using both an adjuvant (immune system activator) and an antigen (immune system target), these vaccines can drive the immune system to seek out and kill tumor cells. In prostate cancer (PCa), currently approved and clinically-used immunotherapeutics,¹ while tremendous proof-of-concept achievements to treat metastatic castration-resistant prostate cancer (mCRPC), are limited in scope and efficacy. They either do not significantly delay disease progression or only induce complete remission in a fraction of patients, likely due to immunologically cold PCa tumor microenvironments.^2–4 Immunotherapy vaccines that “turn tumors hot” are thus attractive for PCa because there are multiple well-established proteins upregulated on cancerous tissue compared to normal tissue. Indeed, numerous clinical trials have identified one particular protein, prostate-specific membrane antigen (PSMA), and attempted to pulse dendritic cells (DCs) with PSMA peptides to reinfuse into patients as a way of specifically-activating the immune system.^5,6 However, this approach is logistically difficult, labor-intensive, and expensive to produce at scale, as it requires the handling of human cells. Thus, the development of effective, easy to use, and relatively inexpensive immunotherapeutics to activate the immune system against specific PCa targets is needed. However, therapeutic design remains a major challenge in the field. The design is exceptionally important as it was previously thought that solely the composition of the vaccine influenced the downstream response. However, recent work has demonstrated that the presentation of the relevant components plays a key role.⁷

In this work, we have explored the effect of vaccine structure on function in PCa using the spherical nucleic acid (SNA) architecture, an emergent therapeutic which consists of a dense shell of oligonucleotides radially conjugated to a nanoparticle core. This arrangement imparts these structures with enhanced properties, including increased cellular uptake and higher resistance to nuclease degradation compared to linear counterparts, and gives them the potential to induce immune activation through toll-like receptors (TLRs).⁸ Their modularity has allowed us to uncover key structure-activity relationships and design highly potent immunostimulatory SNA constructs. We have successfully developed an SNA vaccine against PCa incorporating PSMA peptides considering the importance of architecture and its effect on the kinetic relationships between antigen and adjuvant co-delivery. In a direct comparison of the SNA against the clinical formulation of PSMA peptides using humanized mice, we observe a significant increase in pro-inflammatory cytokine secretion and T cell effector memory for the SNA architecture, overall correlating to an improved ability of T cells raised from mice immunized with the SNA vaccine to kill pulsed target cells ex vivo. Importantly, these vaccines are capable of raising responses in human peripheral blood mononuclear cells (PBMCs), more potently generating T cells that induce human prostate cell apoptosis.

Through this work, we have enhanced the potency of previously discovered PCa-specific tumor-associated antigens, and demonstrated the power of leveraging vaccine architecture in improving an immune response. These results show that by not considering structure in previous vaccine formulations, the field has likely missed previously correctly identified targets, writing them off due to the use of incorrect structures. With these findings, we have the opportunity to repurpose clinically-unsuccessful antigens by incorporating them into a potent vaccine architecture to enhance PCa therapy, thereby improving clinical outcomes through rational design at the nanoscale.

References:

(1) Bilusic, M.; Heery, C.; Madan, R. A. Immunotherapy in Prostate Cancer: Emerging Strategies against a Formidable Foe. Vaccine. NIH Public Access September 2, 2011, pp 6485–6497.

(2) Maeng, H. M.; Berzofsky, J. A. Strategies for Developing and Optimizing Cancer Vaccines. F1000Research 2019, 8, 1–14.

(3) Madan, R. A.; Gulley, J. L. Optimizing Immunotherapy in the Cold Prostate Cancer Microenvironment. In ASCO-SITC Clinical Immuno-Oncology Symposium; 2018.

(4) Bonaventura, P.; Shekarian, T.; Alcazer, V.; Valladeau-Guilemond, J.; Valsesia-Wittmann, S.; Amigorena, S.; Caux, C.; Depil, S. Cold Tumors: A Therapeutic Challenge for Immunotherapy. Front. Immunol. 2019, 10 (168), 1–10.

(5) Murphy, G.; Tjoa, B.; Ragde, H.; Kenny, G.; Boynton, A. Phase I Clinical Trial: T-Cell Therapy for Prostate Cancer Using Autologous Dendritic Cells Pulsed with HLA-A0201-Specific Peptides from Prostate-Specific Membrane Antigen. Prostate 1996, 29 (6), 371–380.

(6) Murphy, G. P.; Tjoa, B. A.; Simmons, S. J.; Rogers, M. K.; Kenny, G. M.; Jarisch, J. Higher-Dose and Less Frequent Dendritic Cell Infusions with PSMA Peptides in Hormone-Refractory Metastatic Prostate Cancer Patients. Prostate 2000, 43 (1), 59–62.

(7) Wang, S.; Qin, L.; Yamankurt, G.; Skakuj, K.; Huang, Z.; Chen, P.-C.; Dominguez, D.; Lee, A.; Zhang, B.; Mirkin, C. A. Rational Vaccinology with Spherical Nucleic Acids. Proc. Natl. Acad. Sci. 2019, 116 (21), 10473–10481.

(8) Radovic-Moreno, A. F.; Chernyak, N.; Mader, C. C.; Nallagatla, S.; Kang, R. S.; Hao, L.; Walker, D. A.; Halo, T. L.; Merkel, T. J.; Rische, C. H.; Anantatmula, S.; Burkhart, M.; Mirkin, C. A.; Gryaznov, S. M. Immunomodulatory Spherical Nucleic Acids. Proc. Natl. Acad. Sci. 2015, 112 (13), 3892–3897.