Cancer Vaccine Design Gets Personal

The landscape of cancer immunotherapies is evolving rapidly. Although peptides or mRNA vaccines encapsulated in lipid nanoparticles are the most popular platform for personalized cancer vaccines (PVCs), drugmakers are exploring other technologies in the hope of boosting response, improving safety, or streamlining the manufacturing process. Many of these new platforms are at or near the clinical stage and showing great promise. Design concepts include viral, bacterial, and synthetic vectors as well as the direct use of tumor cells to sensitize the immune system. Each system comes with its own set of trade-offs in terms of manufacturing process, safety, and ease of use for patients.

Targeting the gut

In December, NEC Bio presented results from a Phase I trial of a bacteria-based, oral vaccine, NECVAX-NEO1, in combination with a checkpoint inhibitor, showing that among six patients with melanoma, renal cell cancer, or head and neck cancer, 83% had stable disease after 24 weeks of treatment.

According to NEC Bio CEO Heinz Lubenau, PhD, the convenience, ease, and safety of the firm’s bacterial vector approach set it apart from competitors. The treatment process begins with DNA and RNA sequencing of tumor and blood samples. The company uses its artificial intelligence-driven NEC Immune Profiler platform to select and rank the top 15 neoantigens present in the tumor, and these are incorporated into a DNA plasmid, which is then used to transform the Salmonella enterica Typhi strain Ty21a bacteria. This species has been used for decades in a live, oral typhoid vaccine and is known to be highly effective in delivering its payload to the small intestine.

“We use the most immunocompetent organ of the human body, the [gastrointestinal] tract, which fights billions of bacteria every day,” Lubenau said, noting that the product is easy to administer, well-tolerated, and can be propagated by a simple fermentation process. Although NEC Bio has not shared publicly what the total turnaround time is for the therapy from biopsy to treatment, Lubenau said that the fermentation itself requires just one liter of culture and takes only 15 hours.

Viral delivery

Transgene uses NEC Bio’s AI-driven neoantigen prediction platform to create individualized vaccines targeting up to 30 neoantigens based on a Modified Vaccinia Ankara (MVA) vector for a Phase I trial of its lead product, TG4050, for head and neck cancers. Trial results published on medRxiv ahead of peer review showed a 100% disease-free survival after a median follow-up of 30 months in all treated patients with newly diagnosed, locally advanced, HPV-negative, resectable head and neck squamous cell carcinoma when given TG4050 as a monotherapy immediately following standard adjuvant therapy. Transgene scientists also saw neoantigen-specific cytotoxic T cell responses in 11 of the 15 TG4050-treated patients.

Transgene CTO Simone Steiner, PhD, said the vaccinia virus offers some advantages over protein or mRNA vaccines, including a capacity for a large number of genetic neoantigens and the ability to generate strong and durable immune responses. Transgene uses a miniaturized manufacturing process that generates about two liters per batch of viral culture, or about 100 vials of purified vaccine per patient.

“We are currently aiming for a 90-day [turnaround],” Steiner said. “We would like to shorten this time even more, but at the small volumes with the Phase I and Phase II trials, it is challenging to get very short turnaround times.”

A red flag

TATUM bioscience CEO Jean-François Millau, PhD, said that as far as he knows, TATUM is the only company developing an immunotherapy based on multi-specific nanofilaments. Unlike PCVs, nanofilament immunotherapy stimulates robust antitumor immune responses without the need to know the tumor neoantigens.

Inspired by the success of checkpoint inhibitors, which activate immune cells to hunt down cancer, Millau said the team at TATUM designed the nanofilament to “act like a giant red flag on the surface of cancer cells to attract and activate the immune system.” The nanofilament is derived from a bioengineered bacteriophage in a process similar to the Nobel prize-winning phage display method for studying protein interactions.

Instead of programming the immunotherapy with neoantigens, as is the case with most other PCV, TATUM’s lead off-the-shelf immunotherapy TAT003 binds to PD-L1 and displays a TLR9 agonist and interleukin-2 to orchestrate the immune attack on cancer cells. In mice, TATUM has seen 100% complete responses and complete tumor clearance in certain cancer models.

“We kept the mice for six months after they had been cured, and when we re-injected the cancer cells in those mice, the tumors started to grow, but then were eliminated,” Millau said. “That means our treatment taught the immune system to recognize those cancer cells, and now the mice are fully protected against this cancer.”

Because the manufacturing process for TAT003 is a simple bacterial fermentation, Millau said it can easily be scaled up by increasing the size of fermenters. Once Series A funding is secured, the company plans to begin clinical trials of TAT003 in Q1 of 2028.

A totally personal vaccine

AIVITA Biomedical is also leveraging the patient’s own tumor to prime its dendritic cell-based vaccine. The process starts when doctors collect two sets of samples from the patient. The first is a tumor sample, which is grown into a cell line in the laboratory. Separately, the company collects immune cells from the patient’s blood, isolates the monocytes, and derives dendritic cells. AIVITA irradiates the cultured tumor cells to make them incapable of replication and uses them to prime the dendritic cells with the antigenic signature of the tumor. The dendritic cells are then returned to the patient.

“A lot of companies are analyzing the whole genome of the patient for all of the non-synonymous mutations and using computer algorithms to pick the ones they think would most likely induce an immune response,” said Robert Dillman, MD, AIVITA CMO. “We’re letting the body do that itself.”

According to Dillman, AIVITA’s approach should work in the same contexts in which immunotherapy works. “It’s also a bit more complete than other personalized approaches, in that it would also pick up any germline and oncofetal antigens the patient has,” Dillman said. “It’s not a personalized vaccine; it’s a totally personal vaccine.”

AIVITA completed a Phase II trial of its lead immunotherapy product, AV-GBM-1, in 57 patients with glioblastoma, with results showing a median progression-free survival of 10.7 months, and is planning a follow-up Phase III trial. It is also conducting a Phase IB in metastatic melanoma and is planning a Phase II-III trial in the same indication.

Deactivated tumor cells

In the 1990s, researchers hypothesized that a PCV could be created by deactivating the patient’s tumor cells with radiation and then using the tumor to prime the immune system against the cancer. However, that method not only rendered the tumor cell incapable of replication but also damaged the cell metabolically and altered its antigenic profile. That strategy was largely abandoned until Ray Goodrich, PhD, founded PhotonPharma with Amanda Guth, DVM, PhD, in 2018 to develop a tumor-based PCV, Innocell, using Mirasol Pathogen Reduction Technology, which Goodrich invented to disinfect donated blood products. Mirasol PRT relies on ultraviolet light and riboflavin to disrupt nucleic acids in pathogens, but Goodrich realized the same principle would apply to tumor cells.

The treated tumor cells are unable to replicate, but they still maintain metabolism. “They still have the natural membrane and all of the neoantigens associated with the patient’s tumor,” Goodrich said.

PhotonPharma has seen reduced tumor growth and metastatic disease in mice and spontaneous cancer resolution in dogs. One canine subject, an 11-year-old Labradoodle with hepatocellular carcinoma, received two doses of Innocell a week apart and went on to survive more than 20 months without disease recurrence.

In 2024, the FDA cleared PhotonPharma’s investigational new drug application for Innocell. The company began enrolling patients in a Phase I clinical study in February. The company also hopes to evaluate Innocell in combination with other treatments like checkpoint inhibitors and anti-VEGF antibodies. “Those combination approaches will be ways that we enhance and hopefully extend the lifespan, reduce disease recurrence, and add to the armament that physicians have to deliver a more lasting remission,” Goodrich said.

The post Cancer Vaccine Design Gets Personal appeared first on GEN – Genetic Engineering and Biotechnology News.

Source