NEW YORK – Precision cancer therapeutics company PDS Biotechnology believes it has found a way to target HPV-positive cancers while limiting the adverse side effects of the Merck anti-PD-1 therapy Keytruda (pembrolizumab).
New Jersey-based PDS is using its proprietary Versamune T-cell activating platform to design therapeutic cancer vaccines based on cancer-specific molecular biomarkers, such as HPV16.
Versamune functions in a manner similar to an in vivo CAR T platform, leveraging a patient's own immune system to induce a targeted T-cell response without removing the patient's cells. Versamune lipid nanoparticles are co-delivered with specific peptide antigens to patients via subcutaneous injection. These components are absorbed by dendritic cells, wherein Versamune fuses with and destabilizes cytoplasmic endosomes. This enables the peptide antigens to be processed into smaller chains that can access the MHC class I and MHC class II pathways, which program CD8-positive and CD4-positive T cells, respectively, to target antigen-presenting cells.
All of this occurs inside patient lymph nodes, thereby avoiding systemic exposure to the cytokines in the bloodstream.
The company's lead molecule, PDS0101, is a therapeutic vaccine consisting of recombinant E6 and E7 HPV16 peptides that specifically targets HPV16-positive cancers and is currently going through Phase II clinical testing in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC).
HPV is found in approximately 70 percent of head-and-neck cancers and of those, nearly 90 percent are positive for HPV16.
Company CEO Frank Bedu-Addo says that this incidence is growing due to HPV16's ability to evade immune detection.
PDS Biotech presented interim data on the Versatile-002 trial in a poster presentation at the American Society of Clinical Oncology's annual conference in Chicago earlier this week.
In that presentation, the company showed that 48 patients receiving PDS0101 with Keytruda showed an estimated 12-month overall survival rate of 87.1 percent, compared to previously published results of between 36 and 50 percent, and a median progression-free survival of 10.4 months, compared to two to three months for immune checkpoint inhibitor monotherapy in patients with similar PD-L1 levels.
Bedu-Addo noted that besides these encouraging data, one of the key results to date is that patients receiving PDS0101 experienced fewer adverse side effects than typically seen with Keytruda on its own.
"We appear to be on the right track in terms of the potential to really develop a combination therapy that could enhance patient survival a lot longer, have more patients respond, [and is] also very well tolerated," Bedu-Addo said.
Robert Ferris, chief of head and neck surgery at the University of Pittsburgh Medical Center, attended ASCO and commented that PDS Biotechnology's strategy "seems to be promising."
"Vaccines [for cancer] have not really worked in the past," he said, but the idea "has come back a bit more in the era of PD1 inhibitors that are FDA approved."
It's possible, Ferris explained, that the reason cancer vaccines haven't worked well in the past may have to do with not having been coupled to a PD1 inhibitor such as Keytruda.
While a vaccine may activate immune cells, he said, it could be that the PD1 inhibitors are responsible for maintaining those cells in an active state.
Ferris also said that the Versatile-002 study should generate useful data for better understanding of how PD1 inhibitors like Keytruda work.
"The assumption we've had with pembrolizumab when it works in an HPV-positive cancer patient is that it does so by reactivating some natural, internally developed HPV-specific T cells," he said. "But we don't actually know that."
The drug, he said, might help to develop those HPV-specific T cells, or may stimulate them against some other antigen.
The trial may also help inform the best ways to use PD1 inhibitors in conjunction with HPV-targeted vaccines, Ferris continued.
"There is some data that giving a PD1 inhibitor at the same time as an attempted vaccine may actually be counterproductive," he said, "and that you need to come in with the vaccine first and get a pool of lymphocytes expanded, present, and primed, then come in later with the pembrolizumab. So studies like this will help us perhaps to figure that out in cancer patients."
While PDS0101 is the company's lead candidate therapy and farthest along in testing, PDS Biotechnology is using its Versamune platform to develop other cancer immunotherapies, all working on the same principle as PDS0101.
Another candidate, PDS0103, targets the mucin 1 protein found in a broad range of solid tumors.
"That product is currently in clinical manufacturing and is ready to go into human clinical trials," Bedu-Addo said.
PDS Biotechnology is also testing PDS0101 in other cancer types. The firm is conducting another Phase II study of the compound administered as a vaccine in conjunction with chemoradiation in cervical cancer and is evaluating its potential to treat other HPV-associated cancers in another Phase II study run by the National Cancer Institute.
Other companies are pursuing highly parallel strategies to also target HPV16-positive cancers, as well as HPV-associated cancers more broadly. ISA Pharmaceuticals, for example, recently completed a Phase II trial of ISA101b, a compound also composed of HPV16-derived E6 and E7 peptides, in vulvar intraepithelial neoplasia.
The finalized results of that trial are not yet available, but interim results were published early last year. ISA Pharmaceuticals has since launched a clinical trial of ISA101b in combination with Regeneron's Libtayo (cemiplimab) in oropharyngeal cancers. Recruitment for that study is ongoing.
PDS Biotechnology has completed recruitment in the Versatile-002 trial and expects the final data readout sometime in the second quarter of 2024. The US Food and Drug Administration granted the PDS0101-Keytruda combination fast track designation last year, and Bedu-Addo said that the company has already had discussions with the FDA regarding the steps to take after completion of the Versatile-002 trial. The company plans to file an updated investigational new drug application with the FDA in the third quarter of this year.
PDS Biotechnology currently has approximately 30 employees and has raised approximately $100 million since going public in 2019.
"As of the end of last quarter," Bedu-Addo said, "we announced on our earnings call that we had approximately $62.5 million in cash, which takes us into the third quarter of next year. So we have a pretty decent runway."