Harnessing COVID-19 Immune Memory, PROTEXI Cancer Vaccine Elicits Antitumor Responses in Mice

The COVID-19 immune memory left by widespread infections and vaccination worldwide may have uses beyond protection against the virus. PROTEXI, developed jointly by Celloram, University Hospitals Cleveland, and Case Western Reserve University, seeks to repurpose the body’s existing antiviral memory as a “helper” for a cancer vaccine, amplifying the immune system’s ability to recognize tumors without directly changing the target of attack.

PROTEXI is a dendritic cell vaccine. Researchers enable dendritic cells to present two types of signals simultaneously: tumor antigens recognized by CD8 cytotoxic T cells, and short peptides derived from the SARS-CoV-2 spike protein that can reactivate existing CD4 helper T-cell memory. The idea is to leverage more mature, faster-responding antiviral memory to help CD8 T cells expand and generate a more durable antitumor response, rather than requiring the immune system to build a new set of helper signals from scratch.

The study, published in *Nature Communications*, first used a surrogate antigen to simulate existing CD4 T-cell memory, then tested the vaccine in mouse models of melanoma and breast cancer. Compared with conventional dendritic cell vaccines presenting only tumor antigens, PROTEXI slowed tumor growth, prolonged survival, and increased the infiltration of CD4 and CD8 T cells and natural killer cells into tumors that previously contained few immune cells. After CD4 T cells were removed, the tumor-suppressing effect disappeared, supporting the conclusion that helper T cells are an essential part of the mechanism.

The study also observed “epitope spreading”: the immune response was no longer limited to the tumor antigen initially provided by the vaccine and could extend to recognize other tumor signals. When some surviving mice were rechallenged with the same type of tumor cells, the tumors remained controlled, suggesting that the vaccine may establish longer-term immune memory. However, this indication of recurrence prevention still comes from animal experiments and cannot be directly extrapolated to patients.

To more closely approximate human immunity, the team also transferred immune cells from COVID-19 vaccine recipients into humanized mice and used compatible spike-protein helper epitopes and melanoma antigens. The results showed that PROTEXI could strengthen tumor antigen-specific CD8 T-cell responses and reduce tumor burden. This more closely reflects the original concept than surrogate-antigen experiments in conventional mice, but it still does not constitute clinical evidence from cancer patients receiving treatment.

In a melanoma model with a poor response to anti-PD-1 therapy, PROTEXI had a stronger effect when combined with an immune checkpoint inhibitor; pairing it with vactosertib, which blocks TGF-β signaling, further reduced tumor progression. These findings suggest that the platform may be better suited for use in combination therapies to disrupt the suppressive environment of immunologically cold tumors, rather than as a standalone replacement for existing treatments.

Celloram and University Hospitals Cleveland said they are advancing a first-in-human study in patients with sarcoma, initially planned to evaluate the safety, feasibility, and immune activity of the personalized dendritic cell vaccine. Clinical trials have not yet demonstrated efficacy, and viral immune memory, HLA types, and tumor antigens vary among patients. Whether PROTEXI can be manufactured consistently, elicit a sufficient response, and translate into actual tumor control remains to be answered by human data.