Apr 27, 2024

On February 1, 2024, Merck announced its 2023 financial report. Sales of its PD-1 monoclonal antibody, Keytruda (pembrolizumab), surpassed $25 billion, easily clinching the title of 2023's Drug King.

The birth of the new Drug King did not experience many twists and turns. As a PD-1 inhibitor, Keytruda, born with a silver spoon, surged ahead, gaining approval for several significant indications, and then naturally ascending to the throne of Drug King. However, Keytruda's coronation as the Drug King seems to be just a small footnote in the Keytruda myth. Keytruda's combination therapy with other drugs has also yielded numerous successes. Merck's “Keytruda Universe” built around Keytruda is rapidly expanding. People are eager to know, where exactly are the limits of Keytruda?

In August 2023, Geneos Therapeutics announced positive results from its Phase 1b/2a clinical trial combining a personalized cancer vaccine with Keytruda, reporting complete molecular remission in four patients with advanced hepatocellular carcinoma (HCC). The study revealed that this novel tumor vaccine used in combination with Keytruda may open a new avenue for cancers resistant to PD-1 inhibitors. On April 7, 2024, the corresponding research paper was fully published in Nature Medicine under the title “Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial”.

The Beginning of Dreams

In 2017, a research team from the Wistar Institute in the United States, along with Inovio Pharmaceuticals, published a DNA-based vaccine platform in Molecular Therapy. This platform can stimulate T-cell immunity against new antigens to inhibit tumor growth. Although the results were significant in animal models, the efficacy presented in this paper did not show a clear advantage over other oncology-based research. After all, there are ten thousand ways to kill cancer cells in vitro and in animals.

However, the core members of Inovio Pharmaceuticals did not share this view. They firmly believed that the platform they had developed had enormous clinical potential and realized that this technology could produce a strong chemical reaction with the emerging PD-1 therapy. Inovio Pharmaceuticals' COO decisively embarked on a second entrepreneurial venture, founding Geneos Therapeutics, specializing in cancer vaccines, and developed the core product GNOS-PV02, which entered clinical trials in 2020.

After performing a tumor biopsy on patients, Geneos identifies potential new antigens through sequencing and then customizes these new antigens into plasmids. Following GMP plasmid amplification, they obtain the personalized tumor vaccine GNOS-PV02, which is administered to the body using a subcutaneous electroporation device. The first indication selected by Geneos is hepatocellular carcinoma, which has poor efficacy with single immune checkpoint inhibitors and brings a significant medical burden to society.

Cast a Wide Net

Compared to other tumor vaccines, GNOS-PV02's greatest advantage lies in using DNA plasmids as the drug itself, capable of carrying a high number of new antigens. By casting a wide net, GNOS-PV02 can overcome the issue of low anti-tumor immune response encountered by other tumor vaccines. GNOS-PV02 can introduce more than 40 new antigens in a single dose, and as long as some can induce a robust anti-tumor immune response, patients can achieve the anticipated clinical improvement. To ensure the generation of T-cell immunity, the research team also introduced a plasmid encoding interleukin-12. As a vaccine adjuvant, the interleukin-12 plasmid can trigger a local cellular response after intradermal injection, enabling patients to better acquire immunity against tumors.

This article published in Nature Medicine showed that among the 36 patients in the study, the objective response rate of GNOS-PV02 combined with Keytruda reached 30.6%, significantly higher than the 16.9% with Keytruda alone. Among the 11 patients who achieved remission, 3 experienced complete remission.

Further assessment of 22 patients showed that in 19 of the patients, there was a vaccine-specific T-cell immune response. Substantial activation of CD4+ and CD8+ T cells in these patients was observed, showing higher levels of immune response markers and proliferation. Meanwhile, after treatment, there was a significant increase in T-cell clone infiltration in the patients' tumor tissues.

Furthermore, researchers identified three TCR sequences that appeared only after vaccination in tumor-infiltrating T cells, and these TCR clones that appeared after vaccination showed significant specificity to the antigens encoded by GNOS-PV02. All these data demonstrate that the strategy of casting a wide net with GNOS-PV02 is effective.

While demonstrating outstanding therapeutic effects, GNOS-PV02 also showed good safety. The main adverse events were local reactions at the injection site, all of which were grade 1 or grade 2 adverse events. These data suggest that GNOS-PV02 may further expand the application of Keytruda.

Tumor Vaccine and Keytruda

This study isn't the first time Keytruda has collaborated with tumor vaccines. In fact, Moderna, the mRNA vaccine giant that emerged prominently during the COVID-19 pandemic, announced its latest progress in combination with Keytruda at the end of 2023. Their personalized mRNA vaccine, mRNA-4157/V940, combined with Keytruda, showed outstanding efficacy in advanced melanoma, reducing the risk of recurrence or death by 44%. Prior to this, the FDA had granted breakthrough therapy designation to this treatment.

Tumor vaccines work by leveraging the patient's immune system to precisely target cancer cells, achieving individualized customization. Immune checkpoint inhibitors, such as Keytruda, make this attack more persistent and powerful. The complementary nature of these two therapies is highly likely to bring new breakthroughs to the field of cancer treatment.

Reference

[1] Yarchoan, M., Gane, E.J., Marron, T.U. et al. Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial. Nat Med 30, 1044–1053 (2024). https://doi.org/10.1038/s41591-024-02894-y