PLATFORM TECHNOLOGY - Versamune®: A New Generation of Cancer Immunotherapies

INTRODUCTION

Despite recent progress in fighting cancer, it remains a leading cause of morbidity and mortality. Cancer immunotherapies have significant potential to treat a broad range of cancers, whether it is via small molecules, antibodies, fusion proteins, autologous, or cell/gene-based therapies. However, significant challenges limiting their clinical effectiveness remain.

Considerable hurdles impeding the ability of immunotherapy to effectively harness the body’s immune system persist. For example, approved checkpoint inhibitors are effective for those patients who respond, but the rates of response reported are in the range of 15%-20%. Immune therapies, including checkpoint inhibitors, CAR-Ts, and live-vector vaccines, are burdened with systemic toxicities limiting their use either in the early-stage cancer setting or in combination with other approved anti-cancer treatments.

The following will discuss Versamune^®, a proprietary T cell-activating platform engineered and developed to overcome some of these challenges to improve the treatment outcomes of patients with cancer.

IMMUNOTHERAPY

Cancer immunotherapy utilizes the power of the body’s own immune system to recognize, attack, and eliminate or regress cancer.

Once the body’s immune system recognizes an organism or cell as foreign or dangerous, it begins a series of complex reactions to identify, target, and eliminate them by mounting an immune response. Cancer immunotherapy takes advantage of the discovery that most cancer cells express unique proteins, called tumor antigens, not normally expressed by healthy cells and thus can be recognized as abnormal and dangerous. As the immune system is precise, it can target these cancer cells exclusively while sparing healthy cells. However, the challenge remains that cancer cells are often not perceived as dangerous or foreign, so the immune system becomes tolerant to them.

An ideal cancer immunotherapy should have the following attributes to maximize the opportunity for clinical e­ffectiveness in patients:

• Generate a humoral (antibody) and cellular (tumor-specific killer and helper T cells) mediated response within the body,
• Activate, arm, and expand large numbers of multi-cytokine-inducing (polyfunctional) T cells that recognize the specific tumor,
• Alter or de-camouflage the tumor microenvironment (TME) to make the cancer cell more visible or susceptible to attack by the immune system,
• Generate immune memory, so that a durable and long-term anti-tumor response may result, and
• Optimize safety and tolerability by limiting systemic inflammation and toxicity.

Versamune^® incorporates each of these attributes, leading to superior anti-tumor responses in pre-clinical (Gandhapudi S, et. al. 2019, J. Immunol.) and clinical studies (ASCO 2022). PDS Biotech’s Versamune^® technology platform is unique in its ability to successfully encompass the mechanistic attributes required to induce a safe and effective anti-cancer immune response.

OVERCOMING THE CHALLENGES OF CANCER IMMUNOTHERAPY – WHAT IS VERSAMUNE^®?

Versamune^® is a proprietary novel T cell-activating platform that effectively stimulates a precise immune system response to a cancer-specific protein. Versamune^® based immunotherapies promote a potent targeted killer (CD8+) T cell attack against cancers expressing the protein by accessing both the MHC class I and II pathways and upregulating Type I Interferon. Targeted immunotherapies built on the Versamune^® platform demonstrate significant disease control with minimal toxicity. The Versamune^® platform is broadly applicable to multiple targets in development.

Versamune^® nanoparticles are based on positively charged (cationic) and immune-activating lipids that form spherical nanoparticles in aqueous media. These lipids include the R-enantiomer of 1,2-dioleoyl-e-trimethyl-ammonium-propane (R-DOTAP). R-DOTAP provides the first demonstration of enantiomeric specificity related to immunological activation. Cationic lipids are positively charged molecules that have a water-soluble portion (head group) attached to a water-insoluble tail. The water-soluble portion of the molecule has a positive charged and the water-insoluble portion is made up of hydrocarbon chains. The nanoparticles, which are coated with a positive charge, are deliberately sized to mimic viruses, facilitating detection by the body’s immune system and uptake by dendritic cells. To treat a specific cancer, the unique or overexpressed antigen found on the surface of the cancer cells is manufactured, then formulated with the Versamune nanoparticles to create a pharmaceutical product for simple subcutaneous injection.

Figure 1

Versamune^® is designed specifically to be taken up by dendritic cells in the skin.  Studies evaluating the uptake of Versamune^® nanoparticles by dendritic cells and epithelial cells, found almost exclusive uptake by the dendritic cells. Four hours following a single subcutaneous injection, ~80% of the dendritic cells in the draining lymph node were found to have taken up the Versamune^® based immunotherapy.

When dendritic cells take up Versamune^® nanoparticles, they become activated, mature, and begin recruiting additional dendritic cells. Once inside the dendritic cell, the tumor-associated antigen is released and processed into the requisite small peptides in the cytoplasm. An important advantage of Versamune^® is its ability to fuse with and destabilize endosomes in the cytoplasm, promoting efficient entry of the antigen into the cell compartment, where processing can take place. Processed antigen is turned into peptides that then utilize both the MHC class I and class II pathways. The MHC class I pathway is critical to programing CD8+ killer T cells and the MHC class II pathway to programming CD4+ helper T cells to recognize tumor antigens. When Versamune^® induced maturation occurs, the dendritic cells express costimulatory molecules on their surface, which facilitate the highly efficient uptake and presentation of antigens to the T cells. This activity overcomes one of the most significant limitations of current immunotherapy development, the efficient priming of critical CD8+ killer T cells against specific tumor antigens. Importantly, Versamune^® has also been shown to promote the induction of antigen-specific CD4+ helper cells. The induction of both CD4+ and CD8+ T cells is important for a robust, durable, and clinically relevant immune response.

Figure 2

Figure 2 shows Versamune^® nanoparticles interacting with antigen agonist peptides. Ultimately, mature dendritic cells migrate into lymph nodes, small glands located throughout the body containing white blood cells including T cells, where much of the key immunological activity pertaining to the priming and expansion of T cells takes place.

In the lymph nodes, the dendritic cells present the tumor antigens to T cells, resulting in activation of the T cells to recognize the particular antigen expressed by the cancer. Importantly, Versamune^® also upregulates type 1 interferon genes (type I IFN), which are responsible for critical immunological processes. This induces an important immunological protein, CD69 that facilitates interactions between the dendritic cell and T cells in the lymph nodes. Upregulation of type I IFN signaling also induces multiple immune messengers, cytokines, and chemokines that further signal T cells to infiltrate into the lymph nodes. Powerful activators of CD8+ killer T cells, such as CCL2 and CXCL10, are documented to be induced by Versamune^®. As the Versamune^® induced production of chemokines appears to be restricted to the lymph nodes, the site of T cell activation, it provides for both superior activation and expansion of CD8+ killer T cells. Localization of these immune messengers within the lymph nodes and their limited presence in the blood circulation enhances the safety of the Versamune^® based immunotherapies. Thus, through the versality of its mechanisms of action, Versamune^® safely promotes the efficient and robust expansion in-vivo of large numbers of highly potent polyfunctional CD8+ killer T cells, both critical factors in developing a successful immunotherapy.

Regulatory T cells (Treg) are a sub-population of white blood cells normally responsible for recognizing normal healthy cells and for preventing autoimmune disease. In cancer, however, they are utilized by the cancer cells to evade immune detection. Versamune^® results in significant alteration of the tumor microenvironment to significantly reduce the Treg to killer CD8+ T cell ratio, making the tumors more susceptible to destruction by killer T cells. Preclinical studies have demonstrated lowering the Treg to CD8+ killer T cell ratio with polyfunctional CD8+ killer and CD4+ helper T cells promotes effective tumor lysis and regression.

Figure 3

Figure 3 shows the significant reduction in tumor size following treatment with PDS0101, compared to R-DOTRAP alone or antigen alone controls.

Overcoming a tumor’s immune tolerance and minimizing its ability to evade detection is a significant goal of a successful cancer immunotherapy that together with potent T cell induction has the potential to translate to enhanced tumor elimination.

Memory T cells allow the body to maintain tumor-recognizing and attacking T cells for an extended period after treatment, with the ideal outcome of long-term clinical benefit. Preliminary studies demonstrated Versamune^® protected mice that had experienced tumor regression against tumor reestablishment even when the mice were reinjected with the tumor cells. This sustained protection was evidence of immune memory: persistence of antigen-specific T cells to recognize tumor proteins associated with a particular cancer, as the animals were not protected against establishment of different tumors. Evidence of the potential for Versamune^® based immunotherapies to induce immune memory has also been demonstrated in a Phase 1 clinical trial in humans.  Enhancing tumor-specific memory responses to monitor for and eradicate cancer cells well following initial treatment provides potential for long-term clinical benefit with the potential to reduce the incidence of tumor recurrence.

Many cancer immunotherapies produce serious systemic autoimmune effects as well as inflammatory toxicities due to the increased off-target T cell activity and spikes of inflammatory cytokines in the blood circulation. The mechanism of action of Versamune^®, as well as its design, both contribute to the localization of cytokines in the lymph nodes and specific targeting of CD8+ killer T cells to antigens in tumor tissue. Therefore, the expectation is that Versamune^® based immunotherapies will exhibit an improved and favorable safety profile compared to currently available treatments.

Versamune^® is injected subcutaneously, and its mechanisms of action are localized primarily in the lymph nodes. Further supporting these observations are data demonstrating that negligible levels of Versamune^® induced cytokines were detected in the blood of mice. Very low quantities of Versamune^® were detected in the blood or in any organ outside of the lymph nodes.

Additionally, Versamune^® is broken down by hydrolysis in the body into fatty acids and excreted, thus mitigating the potential for short- or long-term accumulation of the nanoparticles. These preclinical observations have been confirmed by early clinical data documenting this localized and highly specific cascade of immune activity was associated with an absence of systemic toxicity at all doses tested. In a Phase 1 clinical study designed to evaluate safety, all patients had transient swelling and redness at the injection site due to initiation of the immunological cascade at the injection site, which cleared completely within 3-7 days. No dose-limiting toxicities or long-term safety concerns were observed.

In choosing and designing a Versamune^® based therapy, careful attention is paid to selecting specific, appropriate antigens because, as previously described, Versamune^® induces a strong T cell response to the antigen. All of the antigens currently being evaluated in combination with Versamune^® are present primarily in cancer cells, which should result in tumor-specific T cell attack, minimizing off-target toxicity and minimizing potential for destruction of healthy cells and tissue.

THE NEXT FRONTIERS FOR VERSAMUNE^®

The unique ability of Versamune^® to modulate and enhance numerous critical steps required for an e­ffective clinically relevant immune response and to be combined with targeted antigens found on tumor cells o­ffers several exciting opportunities to treat a variety of cancers. Further, its diverse mechanisms of action together with its favorable safety profile suggest therapeutic promise when used in combination with other treatment modalities or immunotherapies, such as checkpoint inhibitors as well as in the single-agent monotherapy setting.

To date the preclinical data appears to translate well to human clinical results.  Phase 2 safety and efficacy data was presented for PDS Biotech’s lead therapy, PDS0101, for treatment of Human Papillomavirus (HPV)-related cancers at the American Society for Clinical Oncology (ASCO) in 2022 (posters 2518 and 6041) for two ongoing clinical trials. In one trial, PDS0101 is being evaluated in a triple combination and as a dual combination in the second. Both studies showed predominantly low-grade treatment-related adverse events. The dual PDS0101 + checkpoint inhibitor (CPI) combination therapy showed an objective response rate (ORR) in 41% of patients, which compares favorably with a 13%-24% reported in for CPI therapy (ASCO poster 2501). The triple PDS0101 combination therapy showed survival in 17/22 (77%) of CPI refractory patients at 12 months, which compares favorably with the historical survival of a median 3-4 months (Strauss J, et al. 2020 J Immunother Cancer).

In addition to PDS0101, the current PDS Biotech pipeline of Versamune^® based therapies focus on key antigens associated with a broad variety of solid tumors that remain challenging to treat, including T cell receptor gamma Alternate Reading frame Protein (TARP)-Related Cancers (PDS0102), Mucin-1 (MUC1)-Related Cancers (PDS0103), and others in development.

Dr. Joe Dervan joined PDS Biotechnology as VP of R&D in April 2022. He has more than 20 years of biopharmaceutical drug development expertise, from bench to commercialization, including development of a broad range of immuno-oncology therapeutics. He has held varying positions of increased responsibility at Pfizer, F. Hoffmann-La Roche, Protalex, Inc., and GSK. He earned his PhD in Molecular Medicine from Sheffield University Medical School, UK, completed post-doctoral work within the department of Molecular Biophysics & Biochemistry at Yale University, and completed his MBA at Warwick University Business School, UK.